The potential for mitochondrial therapeutics in the treatment of primary open-angle glaucoma: a review

Abstract

Glaucoma, an age-related neurodegenerative disease, is characterized by the death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields. This disease is the leading cause of irreversible blindness worldwide, making early diagnosis and effective treatment paramount. The pathophysiology of primary open-angle glaucoma (POAG), the most common form of the disease, remains poorly understood. Current available treatments, which target elevated intraocular pressure (IOP), are not effective at slowing disease progression in approximately 30% of patients. There is a great need to identify and study treatment options that target other disease mechanisms and aid in neuroprotection for POAG. Increasingly, the role of mitochondrial injury in the development of POAG has become an emphasized area of research interest. Disruption in the function of mitochondria has been linked to problems with neurodevelopment and systemic diseases. Recent studies have shown an association between RGC death and damage to the cells’ mitochondria. In particular, oxidative stress and disrupted oxidative phosphorylation dynamics have been linked to increased susceptibility of RGC mitochondria to secondary mechanical injury. Several mitochondria-targeted treatments for POAG have been suggested, including physical exercise, diet and nutrition, antioxidant supplementation, stem cell therapy, hypoxia exposure, gene therapy, mitochondrial transplantation, and light therapy. Studies have shown that mitochondrial therapeutics may have the potential to slow the progression of POAG by protecting against mitochondrial decline associated with age, genetic susceptibility, and other pathology. Further, these therapeutics may potentially target already present neuronal damage and symptom manifestations. In this review, the authors outline potential mitochondria-targeted treatment strategies and discuss their utility for use in POAG.

Full text

The potential for mitochondrial
therapeutics in the treatment of
primary open-angle glaucoma: a
review
Grace Kuang
1
,
2
, Mina Halimitabrizi
1
,
2
, Amy-Ann Edziah
1
,
2
,
Rebecca Salowe
1
,
2
and Joan M. O’Brien
1
,
2
*
1
Perelman School of Medicine, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA,
United States,
2
Penn Medicine Center for Genetics in Complex Diseases, University of Pennsylvania,
Philadelphia, PA, United States
Glaucoma, an age-related neurodegenerative disease, is characterized by the
death of retinal ganglion cells (RGCs) and the corresponding loss of visual fields.
This disease is the leading cause of irreversible blindness worldwide, making early
diagnosis and effective treatment paramount. The pathophysiology of primary
open-angle glaucoma (POAG), the most common form of the disease, remains
poorly understood. Current available treatments, which target elevated intraocular
pressure (IOP), are not effective at slowing disease progression in approximately
30% of patients. There is a great need to identify and study treatment options that
target other disease mechanisms and aid in neuroprotection for POAG.
Increasingly, the role of mitochondrial injury in the development of POAG has
become an emphasized area of research interest. Disruption in the function of
mitochondria has been linked to problems with neurodevelopment and systemic
diseases. Recent studies have shown an association between RGC death and
damage to the cells’mitochondria. In particular, oxidative stress and disrupted
oxidative phosphorylation dynamics have been linked to increased susceptibility
of RGC mitochondria to secondary mechanical injury. Several mitochondria-
targeted treatments for POAG have been suggested, including physical
exercise, diet and nutrition, antioxidant supplementation, stem cell therapy,
hypoxia exposure, gene therapy, mitochondrial transplantation, and light
therapy. Studies have shown that mitochondrial therapeutics may have the
potential to slow the progression of POAG by protecting against mitochondrial
decline associated with age, genetic susceptibility, and other pathology. Further,
these therapeutics may potentially target already present neuronal damage and
symptom manifestations. In this review, the authors outline potential
mitochondria-targeted treatment strategies and discuss their utility for use
in POAG.
KEYWORDS
glaucoma, mitochondrial dysfunction, mitochondrial therapeutics, neurodegeneration,
oxidative Stress
OPEN ACCESS
EDITED BY
Umberto Lucia,
Polytechnic University of Turin, Italy
REVIEWED BY
Yutao Liu,
Augusta University, United States
Jiaxing Wang,
Emory University, United States
Najam Sharif,
Santen Inc., United States
*CORRESPONDENCE
Joan M. O’Brien,
joan.o'brien@pennmedicine.upenn.edu
RECEIVED 10 March 2023
ACCEPTED 21 July 2023
PUBLISHED 02 August 2023
CITATION
Kuang G, Halimitabrizi M, Edziah A-A,
Salowe R and O’Brien JM (2023), The
potential for mitochondrial therapeutics
in the treatment of primary open-angle
glaucoma: a review .
Front. Physiol. 14:1184060.
doi: 10.3389/fphys.2023.1184060
COPYRIGHT
© 2023 Kuang, Halimitabrizi, Edziah,
Salowe and O’Brien. This is an open-
access article distributed under the terms
of the Creative Commons Attribution
License (CC BY). The use, distribution or
reproduction in other forums is
permitted, provided the original author(s)
and the copyright owner(s) are credited
and that the original publication in this
journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.
Frontiers in Physiology frontiersin.org01
TYPE Review
PUBLISHED 02 August 2023
DOI 10.3389/fphys.2023.1184060

1 Introduction
Primary open-angle glaucoma (POAG) is a chronic
ophthalmic disease characterized by progressive retinal ganglion
cell (RGC) damage with gradual loss of peripheral-to-central
vision. Classically, the etiology of POAG has been primarily
attributed to elevated intraocular pressure (IOP) within the
anterior chamber of the globe, exerting deleterious mechanical
pressure on the optic nerve and surrounding structures. Thus,
IOP-lowering therapies, including topical drops, laser, and
surgery, are currently the primary treatments for POAG. While
they cannot restore vision loss, IOP-lowering therapies can help to
slow disease progression and prevent further damage. However,
only 30% of patients on IOP-lowering medications experience a
decrease in IOP lasting a year (Jampel, 2014). Furthermore, IOP-
lowering therapies are ineffective in approximately 30% of patients
with POAG, pointing to the influence of other etiologies in disease
manifestation (Doucette, 2015). Multiple supplementary
mechanisms for glaucomatous optic nerve head (ONH) insult
have been suggested: neurotoxin build-up, vascular
dysregulation, abnormal glial response, axonal transport
disruption, genetic vulnerability, cerebrospinal fluid circulatory
failure, mitochondrial dysfunction, and others (Mancino, 2018).
New research focus surrounding the vascular theory of glaucoma
has investigated the ischemic and reperfusion dysfunction relating
to glaucomatous optic neuropathy. Mitochondrial dysfunction has
been implicated in vascular endothelial damage, and ischemic
injury in turn can produce mitochondrial dysfunction (Qu,
2022). Although the underlying etiology of POAG is still
undefined, research evidence proves a multifactorial etiology to
the pathology of glaucomatous optic neuropathy. Current
therapeutics are often limited and ineffective to target this
unclear multifactorial etiology. Thus, there is a great need to
identify and study alternative pathogenic mechanisms and
treatment options that carry neuroprotective properties. In
particular, mitochondrial therapeutics represent a promising
area to provide more accessible and effective treatments for
POAG (Jampel, 2014;Gorman, 2016;Osborne, 2016).
Mitochondria are integral organelles that affect many cellular
functions and are crucial to cell survival. Disruption in
mitochondrial function and structure has been linked to an array
of diseases, which are generally classified as primary mitochondrial
diseases (caused by mitochondrial dysfunction directly) or
secondary mitochondrial diseases (caused indirectly) (Murphy
and Hartley, 2018). Both primary and secondary mitochondrial
diseases include ophthalmic pathologies. A high concentration of
mitochondria is present in the eyes, which is a possible explanation
for why they are highly affected by and more sensitive to
dysregulation in mitochondrial function (Schrier and Falk, 2011;
Osborne et al., 2016). In particular, the retina is the most
metabolically active tissue in the human body, and RGCs have
long axons that contain a high density of mitochondria to generate
energy for distal transport (Barron, 2004). Consistent with the
observation that mitochondrial diseases preferentially affect
tissues with greater energy demands, disruptions in
mitochondrial function have been suggested to have a role in the
development of POAG (Beidoe and Mousa, 2012;Yang, 2013;
Zinovkin and Zamyatnin, 2019).
Evidence suggests that mitochondrial alterations in RGCs are
among the first changes to occur in glaucoma, inducing early
neuronal alterations that precede neurodegeneration (Williams
et al., 2017). Various mechanisms of mitochondrial injury have
been proposed, including pathway dysfunction, signaling
dysregulation, genetic variations, and the build-up of reactive
oxygen species (ROS) caused by hindered or inefficient oxidative
phosphorylation (OXPHOS) (Chrysostomou et al., 2013;Williams
et al., 2017). Genetic connections between mitochondrial function
and POAG have also been discovered in both mitochondrial and
nuclear DNA. For example, the expression of OPA1, a gene
expressed in RGC soma and axons and associated with
spontaneous and inherited mitochondrial optic neuropathies, is
significantly downregulated in POAG (Yang, 2013). Published
findings point to mitochondrial alterations as part of the disease’s
etiology and a consequence of cellular degeneration, linking
glaucoma to possible primary and secondary mitochondrial
diseases (Lee, 2011).
Current mitochondrial therapies under consideration for POAG
span a wide degree of interventions, from lifestyle changes to
biologic alterations. Despite this variety, these therapeutic options
have all demonstrated some biologic benefit applicable to POAG
pathophysiology. Main intervention aims include decreasing optic
nerve degeneration, cellular oxidative stress, and age-related
vulnerability, as well as increasing mitochondrial biogenesis and
functioning capacity. Overall goals for mitochondrial therapy
research and application include preventing POAG, slowing
progression, and reversing disease pathology.
Although researchers are still in the process of understanding
mitochondrial pathophysiology, different approaches to
mitochondrial treatment have been suggested as treatments for
various diseases, including POAG. This paper aims to bring
attention to therapies that target mitochondrial dysfunction in
POAG, including physical exercise, diet and nutrition,
antioxidant supplementation, stem cell therapy, hypoxia
exposure, gene therapy, mitochondrial transplantation, and light
therapy. Rather than providing an all-encompassing review of the
published literature, the authors seek to offer an informative
background and overview of the present options and future
possibilities of mitochondrial therapeutics in POAG.Review
2 Therapeutic approaches
Below, we provide an overview of mitochondrial therapeutics for
POAG, including key points in each strategy’s mechanism of action,
strengths, and limitations. This information is also summarized in
Table 1.Figure 1 depicts the basic concept of the vicious cycle of
mitochondrial dysfunction and disease (Woods, 2014;Johnson,
2017).
2.1 Exercise
Current treatments for mitochondrial diseases focus on
reducing ROS production, promoting normal mitochondrial
DNA (mtDNA), and increasing the proportion of healthy
mitochondria, thereby preventing further damage during periods
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TABLE 1 Summary of mitochondria-targeted therapeutic strategies for primary open-angle glaucoma.
Therapeutic
strategy
Mechanism of action Strengths Limitations
Exercise - Increased physical activity reduces reactive oxygen
species (ROS), promotes enzymatic activity for
cellular respiration, increases mitochondrial
biogenesis and mitophagy, and enhances
neurotrophic factors and cerebral pathways
- Low cost - Greater efficacy studies needed to confirm
neuroprotection in glaucoma-
- Accessible Lack of clinical trials
- Non-invasive - Unclear standardization of recommendations
and consistent delivery of treatment
- Protective against other risk factors such as
diabetes
Diet and nutrition - Altering diet and food intake (ketone-based diet,
low-fat diet, Mediterranean diet, vitamin
supplementation) or adjusting quantity of caloric
intake
- Low cost - Greater efficacy studies needed to confirm
neuroprotection in glaucoma
- Accessible - Lack of clinical trials
- Improves abnormal protein accumulation,
neurotoxicity, energy utilization, inflammation,
ROS production, and overall mitochondrial
dysfunction
- Non-invasive - Difficult to adhere to in real-world scenarios
- Protective against other risk factors such as
diabetes
- Strict diets can cause inadequate nutrition
balances
Antioxidant
supplementation
- Enzymatic or non-enzymatic antioxidants to
counter oxidative stress
- Low cost - Difficult to achieve specific and concentrated
subcellular delivery into mitochondrial
organelle
- Decreased proinflammatory cytokines in the retina
and optic nerve
- Accessible - Improved standardized methods of effective
antioxidant supplementation and
augmentation strategies needed
- Increased retinal ganglion cell (RGC) survival and
axonal transport
- Non-invasive - Larger sample clinical trials necessary to
confirm efficacy in humans
- May work synergistically with trophic factors to
rescue RGCs
- Positive results in animal and human small
sample trials
Stem cell
transplantation
- Direct stem cell replacement of diseased RGCs - Neuroprotective potential for surviving
RGCs
- Expensive
- Mesenchymal stem cell transplantation promotes
survival of RGCs through neurotrophic factors,
growth factors, and other neuroprotective cytokines
- Neuroregenerative potential for
degenerated RGCs
- Invasive
- Stem cell replacement of trabecular meshwork cells
improves aqueous humor outflow and RGC
neuroprotection
- Demonstrated potential for integration
with preserved functionality
- Sparse human clinical trials in glaucoma that
show equivocal results
- Challenges in cell purification and protocol
- Unclear risks and benefits regarding the origin
of different stem cell transplant sources
Exposure to hypoxia - Low-dose intermittent hypoxia exposure
preconditions neuroprotective cellular responses,
increases antioxidant production, promotes
hypoxia-inducible factors expression, and protects
RGCs against future hypoxic stress
- Strengthens adaptive neuroprotection
response that sustains past initial treatment
exposure
- Lack of clinical trials in glaucoma
- Potential for post-injury treatment
exposure to have positive effects via adaptive
cellular plasticity
- Unclear standardization of recommendations
and treatment protocol
Gene therapy - Targeted alteration of a multitude of genes can act
by upregulating expression of healthy DNA,
proteins, and mitochondria or by downregulating
pathogenic mutant forms
- Several genetic associations with POAG
have been identified
- Expensive
- Potential for high-risk loci alteration prior
to disease onset or progression
- Highly individualized care - Invasive
- Genes associated with glaucoma pathogenesis and
progression have been identified at various steps
throughout the pathway of disease
- Clinical utilization of genetic screening in
families
- Early stages of human studies in glaucoma
- Distinct anatomy of the ocular system
conducive to gene therapy
- Improved DNA vector design for effective
delivery of genetic material needed
(Continued on following page)
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of physiological stress and pathologic conditions (Parikh et al., 2009;
Bhatti et al., 2017). Many previous studies in experimental and
clinical settings have demonstrated decreases in mitochondrial
mass, alterations in mitochondrial morphology, reductions in
oxidative capacity, and decreases in mitophagy (i.e., the ability to
remove dysfunctional mitochondria) associated with aging and
diseases, including glaucoma (Chistiakov, 2014;Coughlin, 2015).
Physical exercise has been shown to promote mitochondrial
biogenesis pathways and cellular respiration capacity, increasing
healthy mitochondrial mass, structure, and function (Rey, 2022).
Exercise has also displayed beneficial effects on mtDNA and its
expression (Theilen, 2017). Downregulation of mitochondrial
complex I, the first enzymatic protein complex in the
mitochondrial OXPHOS pathway, has been suggested to
contribute to mitochondrial dysfunction and neurologic diseases
(Norat, 2020). Previous experimental studies in mice have shown
that exercise addresses this deficiency by promoting mitochondrial
complex I activity in the brain through both increased mRNA
TABLE 1 (Continued) Summary of mitochondria-targeted therapeutic strategies for primary open-angle glaucoma.
Therapeutic
strategy
Mechanism of action Strengths Limitations
Mitochondrial
transplantation
- Restores mitochondrial function and cell structure - Multiple routes of administration possible
to achieve desired results
- Expensive
- Invasive
- Increases the proportion of healthy mitochondria
within a heteroplasmic state
- Successful uptake in human induced
pluripotent stem cell-derived RGCs
- Persistent challenges in functional integration
and incorporation of mitochondrial material
- Ability to produce neuroprotective and
altering results in brain neural tissue
- Need for more glaucoma-specific studies
Light therapy - Enhances mitochondrial energy production,
enzymatic activity, cell signaling, neurobiogenesis,
and neuronal growth
- Low cost - May not be suitable for patients with
photosensitivity
- Accessible
- Preventsdendritic pruning and RGC degeneration - Non-invasive - Unclear treatment protocol standardization
- Innate characteristics of ocular and
mitochondrial systems conducive to light
therapy
- Demonstrated results in various ocular
pathologies
- Lack of clinical trials
FIGURE 1
Basic diagram of the relationship between mitochondrial dysfunction, disease, and therapeutics.
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expression and inhibitor resistance (Aguiar, 2014;Gudson et al.,
2017). Published studies involving humans have centered around
the effects of exercise on mitochondrial health in skeletal muscle. In
concordance with experimental studies in the animal brains, these
studies in human skeletal muscle demonstrate advantageous
outcomes of exercise through similar mechanisms of improved
biogenesis and mitophagy (de Oliveira et al., 2021).
Physical exercise has demonstrated benefit in addressing the
pathogenesis and symptoms of a wide variety of diseases, with
recommendations for exercise as treatment in at least 26 chronic
diseases (Pedersen and Saltin, 2015). These include psychiatric,
metabolic, cardiovascular, pulmonary, musculoskeletal, cancer,
and other systemic disorders (Pedersen and Saltin, 2015).
Exercise has been found to act on multiple pathways to produce
beneficial results in these varied diseases. In metabolic disorders
(e.g., diabetes mellitus) linked to oxidative stress resulting from
chronic hyperglycemia, exercise has been found to decrease disease
risk by alleviating ROS overproduction (Oguntibeju, 2019). Exercise
has also been shown to be particularly beneficial in
neurodegenerative diseases through the promotion of neural
mitochondrial activity (Wang and Zheng, 2019). In both rodent
models and human trials, physical exercise has been shown to
increase neurotrophic factors (e.g., brain-derived neurotrophic
factor), which in turn activate cascade pathways that eventually
reduce mitochondrial dysfunction and neural excitotoxicity (Gold
et al., 2003;Rojas Vega et al., 2006;Lau et al., 2015;Vecchio et al.,
2018). These findings have been cited to occur following a range of
physical activity, from acute anaerobic to regular aerobic exercise,
though meta-analyses suggest that regular aerobic exercise may be
more effective in increasing peripheral neurotrophic factor levels,
synaptic plasticity, and neurogenesis (Ferris et al., 2007;Rothman
et al., 2012;Dinoff et al., 2016). Other beneficial effects believed to be
exerted on the brain by exercise include support of surrounding glial
cells and maintenance of cerebrovasculature (Vecchio et al., 2018).
Consistent with findings in studies of other neurodegenerative
diseases, investigations regarding exercise in glaucoma specifically
have also identified favorable outcomes. In experimental mouse
models with induced IOP elevation, exercised aged mice had similar
retinal and optic nerve function compared to non-exercised young
mice, as well as improved inflammatory stress response
(Chrysostomou et al., 2014). Aerobic exercise has also proved to
be effective in reducing IOP, though the exact mechanism has not
yet been determined and requires further study (Yuan et al., 2021).
Evidence does show that the IOP-lowering effects of exercise are
longer-lasting in people who consistently engage in high intensity
activity (Qureshi et al., 1996). In a study comparing ocular
parameters before and after aerobic exercise in POAG patients
and control participants, researchers noted a decrease in IOP and
increase in Schlemm’s Canal (i.e., a structure involved in aqueous
humor drainage and IOP reduction) dimensions in both cohorts
(Yuan et al., 2021). These findings suggest that physical activity may
be useful in preventing age-induced RGC vulnerability and in
treating various contributors to POAG pathology.
Although studies linking the effects of exercise to mitochondrial
function in glaucoma models are limited, published findings suggest
that exercise may potentially address glaucoma pathology through
mitochondrial pathways. Decreases in nicotinamide adenine
dinucleotide (NAD+), a protective metabolite and important
molecule in energy production, occur with age in the
mitochondria of both normal and glaucomatous RGCs, with
negative impacts on mitochondrial ability to manage oxidative
stress and resist damage from high IOP (Williams et al., 2017).
Gene therapy and NAD+ precursor (B3) supplementation
treatments aimed at inducing NAD+ production have been
successful at preventing further RGC and visual function loss,
which suggest that NAD+ generation may be a key target for
mitochondrial homeostasis and neuroprotection in RGCs
(Cimaglia et al., 2020). Exercise may act as a neuroprotective
mitochondrial treatment approach for POAG through this
pathway, as research has shown that aerobic and resistance
exercise training increases the levels of NAD+ in human tissues
(Bhatti et al., 2016;de Guia et al., 2019). More research on the
effectiveness of exercise in improving mitochondrial output and
function in glaucomatous eyes is warranted.
2.2 Diet and nutrition
Dietary management of chronic conditions presents an
attractive opportunity for more low-cost, accessible treatments as
compared to conventional pharmacologic options. Some diets have
more conspicuous connections with specific diseases (e.g., low-
glycemic diet for type 2 diabetes mellitus, low-sodium diet for
chronic kidney disease), while other diets have been suggested to
generate an overall health benefit (e.g., Mediterranean diet
associated with increased longevity) (Trichopoulou and
Vasilopoulou, 2000). The beneficial and deleterious effects of
different types of diets in mitochondrial diseases and POAG have
been the subject of investigation, with researchers in search of the so-
called “mitochondria nutrients”that sustain mitochondrial function
(Khalil et al., 2022).
Change in patient diet to treat mitochondrial disease is highly
dependent on the targeted disease and the individual patient’s
metabolism (Parikh et al., 2009). Ketone-based treatments
(ketogenic dietary supplements and ketogenic diet) are a group
of diet-based treatments shown to have the potential to improve
cognitive function, as demonstrated in studies conducted on
neurodegenerative diseases such as mild cognitive impairment
(MCI) and Alzheimer’s disease (AD). Ketone-based treatments
are thought to improve cognitive health in these diseases through
a variety of mechanisms, including attenuation of the abnormal
protein accumulation process, reduction of neurotoxicity, improved
neurovascular function, and energy rescue in the setting of impaired
neuronal glucose utilization (Kashiwaya et al., 2013;Zilberter et al.,
2013;Cunnane et al., 2020;Neth et al., 2020). One study found that a
ketogenic diet increased optic nerve mitochondrial biogenesis and
axonal survival in murine models of glaucoma through the proposed
mechanism of increased monocarboxylate transporters that
improve substrate availability (Harun-Or-Rashid et al., 2018).
Another study in murine models noted a dose-dependent
neuroprotective effect of ketone bodies on RGC survival against
neurotoxic conditions, suggesting a mechanism of action against
neurotoxic metabolites and their downstream effects (Thaler et al.,
2010).
Increased fatty acid exposure commonly seen in modern-day
dietary habits has also been associated with mitochondrial
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dysfunction and induction of pro-inflammatory adipocytokines
(Khalil et al., 2022). Adoption of a low-fat diet can address a
significant source of fatty acid exposure that predisposes to
mitochondrial dysfunction and metabolic diseases (Civitarese
et al., 2007). Additionally, the Mediterranean diet is another
dietary regimen that has been found to increase fatty acid
oxidation, mitochondrial biogenesis, and antioxidant capacity
through its antioxidant polyphenol-rich foods (e.g., grapes, wine,
nuts, legumes, olive oil) (Khalil et al., 2022). Adequate levels of many
other micronutrients, vitamins, and minerals (e.g., vitamins B, C, E,
selenium, coenzyme Q10, caffeine, carnitine, lipoic acid, etc.) are
also suggested to contribute to mitochondrial energy metabolism,
ATP-production, biogenesis, and molecular metabolism (Wesselink
et al., 2019;Fila et al., 2021).
Another approach in dietary treatment of mitochondrial
diseases is caloric restriction. Caloric restriction has been
demonstrated to reduce ROS production, attenuate age-related
oxidative damage, and increase ROS scavenging (Civitarese et al.,
2007). Previous studies also demonstrate that caloric restriction
increases mitochondrial density, with some proposing increased
transcription-induced mitochondrial biogenesis, while others
suggest prevention of age-related existing mitochondrial
deterioration (Civitarese, 2007;Lanza et al., 2012). Caloric
restriction in the form of fasting has been studied in
glaucomatous mice models, finding that this method effectively
decreases RGC death and has an overall neuroprotective effect
(Guo et al., 2016). However, it is essential to note that IOP was
not changed in this study, so the neuroprotective effect in this case
was unrelated to IOP (Guo et al., 2016). Dietary modifications, such
as changes in meal frequency or fasting, require further exploration
in patient populations (Parikh et al., 2009).
Iron and zinc are both ion cofactors utilized throughout the
nervous system for neurotransmitter biosynthesis, cellular signaling,
synaptic modulation, as well as mitochondrial structures and
functions (Tang et al., 2021). Dysregulation and typically
excessive accumulation of mitochondrial iron and zinc ions (e.g.,
disruptions in transport, expression, chelation, accumulation, etc.)
have led to glaucomatous injury to RGCs via mitochondrial
structural damage, membrane potential alteration, transportation
modification, and other pathways (Tang et al., 2021). Although still
early in understanding, dietary modification of iron and zinc ion
levels reaching the mitochondria can be considered as a future
direction of exploration. Nicotinamide adenine dinucleotide
(NAD+) is an integral part of cell respiration, and a decrease in
NAD+ content is seen in the aging process linked to the progression
of glaucoma (Williams et al., 2017). Nicotinamide (vitamin B3) is an
NAD+’s precursor, and previous studies have focused on the effects
of vitamin B3 on glaucoma development in mice. Vitamin B3 oral
supplements were given to mice before and after IOP elevation, and
results displayed reductions in optic nerve degeneration in both
groups (Williams et al., 2017). These findings suggest that Vitamin
B3 oral supplementation is a possible prophylactic and therapeutic
option for glaucoma. Like vitamin B3, other molecules with
antioxidant properties are a promising focus of nutrition studies.
Oxidative stress in glaucoma patients becomes present as the disease
progresses, increasing the importance of antioxidants. Resveratrol,
coenzyme Q10, vitamin E, alpha-lipoic acid, omega-3 fatty acids,
and hesperidin are suggested antioxidants that could be introduced
into the patient’s diet (Dziedziak et al., 2021). Since antioxidant
supplementation is a non-invasive and possibly an easily accessible
treatment, further study of this subject through clinical trials would
be valuable. This topic of antioxidant therapy is further discussed in
this paper.
Improvement in the quality and quantity of calorie intake has
been suggested to produce multiple benefits in mitochondrial
function. A variety of dietary alterations that involve decreasing,
increasing, or substituting certain nutrients have been demonstrated
to mitigate mitochondrial dysfunction and POAG. Increased studies
in patient populations would be necessary to assess efficacy in
human populations and real-world conditions, which could
demonstrate poorer adherence to strict dietary restrictions and
raise concerns for inadequate nutrition balance in vulnerable
populations (Włodarek, 2019).
2.3 Antioxidant supplementation
The mitochondria constitute a major energy source for cellular
functions via the mitochondrial oxidative phosphorylation system.
A deleterious byproduct of mitochondrial cellular respiration is the
release of ROS, which are a class of free radicals and oxidants. While
ROS and other pro-oxidants are necessary for cellular signaling and
defense, overaccumulation leads to oxidative stress and damage to
both the organelle and the cell (Silwal et al., 2020). Disruptive
consequences of excessive oxidative stress include increased
membrane permeability, altered calcium regulation, induced
mtDNA and nDNA mutations, and resultant cell death (Guo
et al., 2013). Of note, the mitochondrial genome primarily
encodes for protein products necessary for the mitochondrial
cellular respiration system, which assumes approximately 85% of
a cell’s oxygen usage (Tezel, 2006). As a result of their close
connection in the location, production, and utilization of
oxidant-producing mechanisms, mitochondria are particularly
vulnerable to the effects of ROS-induced oxidative stress. In the
eye, ocular tissues are consistently exposed to natural and artificial
lights, which are prominent sources of oxidative damage (Maiuolo
et al., 2022). In order to counter the adverse effects of pro-oxidant
species, innate antioxidant pathways exist to preserve mitochondrial
and cellular conditions. A variety of enzymatic (e.g., superoxide
dismutase, catalase, glutathione peroxidase) and nonenzymatic (e.g.,
glutathione, vitamin C, vitamin E) antioxidants derived from both
endogenous and exogenous (e.g., diet) sources work synergistically
to maintain oxidative balance (Oyewole and Birch-Machin, 2015;
Caceres-Velez et al., 2022). This favorable antioxidant effect is
achieved through a variety of described methods, including
blocking the formation of free radicals, interrupting key steps in
the oxidation chain, scavenging free radicals, reducing reactive pro-
oxidants, chelating metal pro-oxidants, and donating electrons to
stabilize free radicals (Tan et al., 2018;Ali et al., 2020).
Mitochondrial oxidative stress is found to be contributory to
diseases of aging and chronicity, such as diabetes mellitus,
cardiovascular disease, chronic kidney disease, osteoporosis and
cancer (Leyane et al., 2022). This connection is also particularly
noted in neurodegenerative diseases, including Alzheimer’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis, and POAG
(Chrysostomou et al., 2013;Guo, 2013). Studies have
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demonstrated significantly lower plasma antioxidant
concentrations, higher oxidative stress biomarkers, and more
mitochondrial morphologic abnormalities in tissue biopsies of
patients with neurodegenerative diseases (Bourdel-Marchasson
et al., 2001;Sasaki et al., 2007;Guo et al., 2013;Baierle et al.,
2015). ROS-induced oxidative stress leads to neuron damage
through glutamate neurotoxicity, which has also been found to
apply to RGC’s(Ko et al., 2000;Atlante et al., 2001;Nucci et al.,
2005). In RGCs, oxidative stress has direct cytotoxic effects, indirect
effects via downstream second messenger signaling and
modification, and alteration of surrounding glial cell activity
(Tezel, 2006). Studies have noted increased antioxidant enzyme
activity throughout the retina in patients with POAG, suggesting a
compensation mechanism to higher oxidative stress (Yang et al.,
2001;Ferreira et al., 2004). In several experimental models, IOP
elevation induced ROS generation and antioxidant depletion in the
retina of rodents (Moreno et al., 2004;Ko et al., 2005;Tezel, 2006).
In addition to neuronal RGCs, previous studies also demonstrate
the impact of oxidative stress on other cells involved in the disease
etiology of POAG. Trabecular meshwork cells facilitate aqueous
humor outflow from the anterior chamber, which is necessary to
maintain physiologic IOP homeostasis. Dysfunction in these cells
leads to increased aqueous humor outflow resistance and elevated
IOP, so they are often a target in surgical treatment. Trabecular
meshwork cells are more sensitive to oxidative damage (as measured
by a biomarker for ROS-induced DNA damage) than other ocular
tissues (e.g., cornea, iris), and patients with POAG have higher levels
of this biomarker in their trabecular meshwork cells (Izzotti et al.,
2003;Izzotti et al., 2009;Wang et al., 2019). Some studies have
shown that patients with POAG have decreased antioxidant levels
and increased oxidative biomarkers in aqueous humor and blood
samples (Ferreira et al., 2004;Sorkhabi et al., 2011;Nucci et al., 2013;
Li et al., 2020;Caceres-Velez et al., 2022). Overall antioxidant
potential has also been shown to be significantly decreased (64%)
in patients with POAG and inversely correlated with IOP levels
(Ferreira et al., 2004;Tanito et al., 2015). Evidence of ROS-induced
damage is evident at multiple steps throughout the
neurodegenerative process of POAG.
Consistent with these findings, antioxidant augmentation has
demonstrated potential in the therapeutic management of POAG.
Previous studies have proved the ability of antioxidants to attenuate
glaucomatous neurodegeneration in several experimental animal
studies and clinical human trials. Experimental animal glaucoma
models with enhanced antioxidant transcription exhibited decreased
proinflammatory cytokines in the retina and optic nerve (Yang et al.,
2016). Conversely, mice with genetically altered dysfunctional
antioxidant responses displayed decreased RGC survival despite
similar IOP elevations as controls (Inman et al., 2013). Bovine
trabecular meshwork cells genetically programmed to lack the
antioxidant glutathione and subsequently exposed to H
2
O
2
demonstrated outflow resistance, whereas H
2
O
2
exposure had no
effect in control eyes (Kahn et al., 1983). Antioxidants are also
suggested to work synergistically with trophic factors to rescue
RGCs more effectively than trophic factors alone (90% vs. 81%)
(Ko et al., 2000). Coenzyme Q10 (CoQ10) is an antioxidant cofactor
of mitochondrial enzymes that is integrally involved with
mitochondrial ROS balance and membrane integrity.
CoQ10 administration in rat models with high IOP-induced
transient retinal ischemia, reduced glutamate excitotoxicity, and
RGC apoptotic death (Nucci et al., 2007;Maiuolo et al., 2022). The
potential for antioxidant supplementation to be used as not only
prevention but also intervention in POAG neurodegeneration
pathology was emphasized in a recent study. In this study, two
groups of glaucoma mice models were either raised on an
antioxidant-supplemented diet or were later added to the same
antioxidant-supplemented diet. Both cohorts demonstrated
improved oxidative balance, RGC survival, and axonal transport
compared to controls (Inman et al., 2013). This would be a
significant direction for research as a possible therapy to reverse
neurodegeneration.
Exogenous dietary sources of antioxidant supplementation have
also exhibited beneficial effects in RGC and mitochondrial
functional and structural retainment (Garcia-Medina et al., 2020).
Vitamin B3 supplementation in the diet of glaucoma-induced mice
led to increased RGC density and soma size as well as higher
mitochondrial density within RGCs (Chou et al., 2020).
Resveratrol supplementation in the diet of glaucoma-induced rats
and administration in human RGC cultures mitigated RGC
apoptotic death, RGC morphologic abnormalities, mitochondrial
dysfunction, and ROS generation (Zhang et al., 2018). In a small
human clinical trial, Ginkgo biloba extract supplementation in the
diet of patients with normal tension glaucoma (NTG), a subtype of
POAG, resulted in an improvement in visual fields (Cybulska-
Heinrich et al., 2012). In another study in patients with
glaucoma, oral antioxidant supplementation showed an increase
in antioxidant potential and decrease in oxidative DNA damage in
patients with high oxidative stress level (Himori et al., 2021).
Much of what is currently known about antioxidant efficacy in
disease treatment has been derived from animal studies. Results of
human clinical trials are limited due to the challenge of delivering
and concentrating agents into the targeted subcellular mitochondria
with specificity (Tan et al., 2018;Zinovkin and Zamyatnin, 2019).
There are currently no available antioxidant treatments for
application to neurodegenerative diseases and no ongoing human
clinical trials in POAG specifically. However, several mitochondria-
targeted antioxidants (e.g., MitoQ, SkQ1, SS-31, other quinones)
have demonstrated promising results in neurodegenerative disease
models and human clinical trials in other ocular diseases (e.g., Leber
hereditary optic neuropathy, dry eye syndrome, diabetic macular
edema, age-related macular degeneration, Fuchs’dystrophy)
(Zinovkin and Zamyatnin, 2019;Jiang, 2020;Ji and Yeo, 2021).
Although researchers are currently in the process of developing
effective antioxidant supplementation and augmentation strategies
for better evaluation of trial efficacy, early studies in animal models
and humans have demonstrated the potential for antioxidant
therapies in the prevention and treatment of neurodegenerative
diseases such as POAG.
2.4 Stem cell transplantation
RGCs, like other neurons, are postmitotic cells that do not
undergo further differentiation or division. Due to this, RGCs are
unable to regenerate following loss in degenerative diseases such as
POAG, and this is one of the major challenges to the development of
POAG therapeutics. On the other hand, stem cells are
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undifferentiated cells capable of regeneration, division, and further
differentiation into specific cell types. The advances in stem cell
culture, reprogramming, and transplantation techniques presents a
novel opportunity for RGC replacement therapy. RGC stem cell
transplantation therapy research utilizes retinal progenitor cells,
embryonic stem cells, induced pluripotent stem cells, and other
source cells to develop RGCs (Zhang et al., 2021). It is possible for
stem cells to be first transplanted into a model prior to
differentiation into targeted RGCs, however, more commonly,
stem cell sources are induced into RGCs in vitro prior to
transplantation into the subretinal space or the vitreous cavity
(Zhang et al., 2021).
Stem cell transplantation therapy that aims for direct
replacement of dysfunctional or degenerated cells has been
explored in both the treatment of mitochondrial diseases and
POAG. Clinical trials are in progress to test the safety of stem
cell transplantation in mitochondrial neurogastrointestinal
encephalopathy (MNGIE), a disorder causing muscular
degeneration in the gastrointestinal tract, malabsorption, and
weakness in the eyes and other parts of the body (Russell et al.,
2020). Studies conducted thus far in a small number of patients have
shown that stem cell transplantation, which replaces deficient
thymidine phosphorylase and thus prevents mtDNA damage by
excess deoxynucleotides, is a successful method for improving
symptoms and survival (Parikh et al., 2009;Bax et al., 2019).
Likewise, the potential of stem cell replacement of RGCs presents
an avenue for further study. Researchers have successfully
differentiated human induced pluripotent stem cells into pure
populations of mature RGCs and integrated them into murine
retina with preserved functionality (Chavali et al., 2022). Other
investigators have utilized human adult periodontal ligament stem
cells to develop retinal progenitor and retinal ganglion-like cells that
also demonstrate maintained functional status as well as capacity for
further differentiation (Huang et al., 2013;Ng et al., 2015).
The effects of transplanting stem cells that are not intended to
differentiate into RGCs have also been studied in glaucoma
pathology. Intravitreal transplantation of mesenchymal stem cell
into the eyes of glaucoma-induced rats resulted in increased survival
of RGCs, likely due to stem cell secretion of neurotrophic factors,
growth factors, and other neuroprotective cytokines (Yu et al., 2006;
Zhang et al., 2021). Mesenchymal stem cells are also capable of
transferring healthy mitochondria and cell materials to damaged
cells, leading to improved overall mitochondrial function and
reduced apoptosis (Zhang et al., 2021). This transfer has been
successfully demonstrated in corneal endothelium, retinal
pigmented epithelium, and photoreceptors cells, but researchers
have noted sparser transfer to cells located in the inner retina such as
RGCs (Zou et al., 2019;Jiang D. et al., 2020). Stem cell replenishment
of the trabecular meshwork system in experimental glaucoma
models has also been shown to act on underlying disease
pathologies, with studies demonstrating improvements in IOP
levels, aqueous humor outflow, trabecular meshwork cellularity,
and RGC neuroprotection (Zhu et al., 2016;Zhu et al., 2017).
Human clinical trials on stem cell treatment of glaucoma are
largely absent. One trial involving mesenchymal stem cell
transplantation in two eyes with advanced glaucoma showed no
changes in visual function or electroretinographic response (Vilela
et al., 2021). Although limited in sample size, this study is the only
completed human clinical trial of stem cell therapy in glaucoma
reported at this time. Only a few other clinical trials with small study
sample sizes are published on optic neuropathies in general, which
have reported positive results. In a case report of mesenchymal stem
cell transplantation into both eyes of a patient with autoimmune
optic neuropathy, researchers observed marked improvements in
visual function, macular thickness, fast retinal nerve fiber layer
thickness, and medication requirements (Weiss et al., 2015). In a
study of patients with toxic optic neuropathy, a combined
application of mesenchymal stem cell and electromagnetic
stimulation resulted in significant improvements in visual acuity
and mean fundus perimetry deviation index (Ozmert and Arslan,
2021). In patients with neuromyelitis optica spectrum disorder, stem
cell transplantation was associated with improved self-rated
disability, neurologic, and health scores. Impactful molecular
changes were also reported, including seroconversion and
complement system mitigation (Burt et al., 2019).
There are currently many barriers to human transplantation,
such as the cell purification process and determination of the best
developmental stage for cells to maximize therapeutic outcomes
(Zhang et al., 2021). Additionally, the question of whether to use
allogeneic donor cells or autologous induced pluripotent stem cells
(iPSC) from the patient’s own body remains (Zhang et al., 2021).
While autologous cells are less likely to form tumors and are easier to
source, cells derived from a glaucoma patient may still be vulnerable
to glaucomatous damage due to genetic risk factors that are still
present. This issue suggests that using gene editing techniques to
first correct mutations that increase RGC susceptibility to damage,
such as the aforementioned changes that occur in mitochondria and
affect factors such as NAD+ production and membrane structure,
could improve the efficacy of RGC transplantation.
While further exploration is needed in this area, these study
findings show a possibility for different stem cell transplantations to
both replace already degenerated cells and promote neuroprotection
of proximal surviving RGCs (Zhang et al., 2021). Such future clinical
application of stem cell therapy would be transformative to
glaucoma management, particularly in patients with advanced
optic nerve degeneration.
2.5 Exposure to hypoxia
Hypoxia, the state of low oxygen concentration in cells, can be
caused by factors such as low partial pressure of oxygen in the
environment and states of vascular ischemia (MacIntyre, 2014). The
body is capable of compensating for hypoxic atmospheric
conditions, such as those found at high altitude and large depths,
through homeostatic adaptations like pulmonary vasoconstriction,
hyperventilation, and increased production of 2,3-
diphosphoglycerate (MacIntyre, 2014). All of these adjustments
provide increased oxygen delivery to at-risk tissues. Given
oxygen’s importance in ATP production and therefore cellular
function, acute and prolonged hypoxia can be deadly. Studies in
RGCs, specifically, have shown that exposure to extended periods of
hypoxia (achieved through vascular hypoperfusion, evoked hypoxic
states, or hypoxia-mimetic agents) induced ROS and oxidative stress
elevation, upregulating pathways to RGC apoptosis (Tezel, 2006;
Tulsawani et al., 2010).
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However, several published studies in the current literature
delineate that low-dose intermittent exposure to hypoxia can be a
beneficial therapeutic in the treatment of various conditions
(Navarrete-Opazo and Mitchell, 2014). Intermittent hypoxia (IH)
refers to protocols with modest (9%–16%) inspired oxygen levels
and short, infrequent daily cycles of normoxia and hypoxia
(Navarrete-Opazo and Mitchell, 2014). Studies showed that IH
built tolerance for and was protection against stressors such as
myocardial infarction through multiple mechanisms, including
increased antioxidant enzyme expression and the opening of
ATP-sensitive K+ channels in the inner mitochondrial membrane
of cardiac mitochondria (Kolár et al., 2005;Navarrete-Opazo and
Mitchell, 2014).
IH in the treatment of mitochondrial disease is an emerging field
of exploration. A recent study in a Ndufs4 knockdown mouse model
of Leigh syndrome revealed that IH led to improvement in brain
lesions, neurological behavior, and survival compared to normoxic
controls (Parikh et al., 2009;Jain et al., 2016). In contrast, mild
hyperoxic conditions were found to decrease survival in these mice
(Parikh et al., 2009;Jain et al., 2016). Additionally, this study
illustrated that important elements of the hypoxic response
pathway such as hypoxia-inducible factors are preserved in
diseased cells even in normoxic conditions (Parikh et al., 2009;
Jain et al., 2016). Hypoxia-inducible factors (HIF) are transcription
factors that regulate cellular response to environmental oxygen
levels and these are involved in the induction of non-oxidative,
alternative energy-generating processes (Tezel and Wax, 2004).
Together, these findings depict a state of oxygen hypersensitivity
in mitochondrial dysfunction, suggesting that oxygen metabolism is
an important determinant of prognosis in mitochondrial disease and
may play a role in its pathogenesis (Jain et al., 2016). This study also
found that hypoxia-inducible factor 1-alpha (HIF-1α) levels were
not uniform throughout the retinal layers and controlled hypoxia of
the entire circulatory system may result in more uniform levels and
possibly positive effects on disease progression, as seen in Leigh
Syndrome (Jain et al., 2016). The study findings illustrate that
reducing oxygen consumption and therefore the demand for
OXPHOS may decrease the abundance of ROS and slow disease
progression in Leigh syndrome and other mitochondrial diseases.
This hypersensitivity to oxygen levels and metabolism along
with its contributory role to disease pathogenesis has also been
observed in POAG. Mechanisms for mitochondrial injury related to
oxygen consumption, such as deficient complex-I driven cellular
respiration seen in POAG lymphoblasts, point toward the potential
of POAG treatments targeting respiration and therefore
mitochondria (Lee et al., 2012). It has also been shown that in
the glaucomatous ONH, HIF-1αis significantly more highly
expressed in cases than in controls (Tezel and Wax, 2004). In
addition, evidence suggests that alongside decreases in important
metabolites protective against oxidative stress like NAD, HIF-1αis
induced early in disease development (Williams et al., 2017). This
result suggests that ischemia in the glaucomatous ONH and hypoxic
stress may be involved in the underlying disease mechanism (Tezel
and Wax, 2004).
Despite HIF being an indicator of hypoxic conditions, it is
important not to directly associate these cellular responses with
pathology. Rather, studies have shown that retinal exposure to
multiple brief hypoxic stimuli and corresponding increases in
cellular response molecules promotes sustained retinal hypoxia
tolerance in a process called “preconditioning”(Tezel, 2006;Zhu
et al., 2007;Tulsawani et al., 2010;Gidday et al., 2015). In
experimental models of mice preconditioned with hypoxia, levels
of HIF-1αwere elevated for 1 week and its gene target heme
oxygenase-1 was elevated for more than 4 weeks following
exposure (Zhu et al., 2007). Studies in RGCs have also
demonstrated increased antioxidant peroxiredoxin 6 levels within
24 h of exposure, followed by decline and activation of apoptotic
pathways after 48 h of exposure (Tulsawani et al., 2010). This finding
of adaptive cellular plasticity has also been investigated following
glaucoma onset in a “postconditioning”setting (Gidday et al., 2015).
In mice with induced ocular hypertension, repetitive hypoxia
exposure was associated with improvements in visual evoked
potential testing, visual acuity, RGC survival, and optic nerve
axon integrity (Gidday et al., 2015).
Although the time periods tested are not consistent across study
types and methodologies, the literature concurs that brief, limited
hypoxia exposure may lead to an advantageous adaptive
neuroprotection response, whereas prolonged hypoxia instigates
cell death. The IH approach to treating Leigh syndrome,
glaucoma, and other mitochondrial diseases has not yet been
applied to humans, but a few clinical trials to test IH in cardiac
and neurological diseases are currently ongoing. The potential for
therapeutic benefit of controlled hypoxia to protect mitochondria in
glaucomatous eyes is worthy of further study.
2.6 Gene therapy
Gene therapy is the targeted alteration of a patient’s genetic
material that is aimed towards achieving the desired results in
disease management. This process can involve a variety of
alterations, including insertion, removal, replacement, repair, and
regulation of genetic material (Wirth et al., 2013). Vectors
introduced to enact genetic change include viruses, nucleic acids,
chemical particles, and other microorganisms (Wirth et al., 2013;
Panikker et al., 2022). Viral vectors are more commonly employed
than non-viral vectors in trials and applications to introduce
exogenous genetic information into target cells (Razi Soofiyani
et al., 2013). Commonly employed viruses include lentivirus,
adenovirus, and adeno-associated virus (AAV) (Razi Soofiyani
et al., 2013). Target cells can be germline or somatic in nature,
but current clinical application is centered around somatic cell DNA
editing to prevent unknown effects on future progeny (Wirth et al.,
2013).
Gene therapy was first approved for a human trial in the
United States in 1990 to target genetic defects in adenosine
deaminase severe combined immunodeficiency (ADA-SCID)
(Wirth et al., 2013). Since then, as advancements in gene
understanding and targeting continue; exploration into the utility
of gene therapy has become an increasingly emphasized field of
research. Researchers have noted the value of gene-based therapies
in a variety of genetic diseases, due their advantages of providing
precise, direct, and effective approaches. Individualization of
healthcare is increasingly emphasized, and gene therapy
personalized to each patient’s genome and targeted risk loci is a
leader of progress in the era of precision medicine. Currently, gene
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therapy trials and approved clinical applications are focused around
cancer and single-gene defect, monogenic diseases (e.g., acute
lymphoblastic leukemia, cerebral adrenoleukodystrophy, aromatic
L-amino acid decarboxylase deficiency, hemophilia, spinal muscular
atrophy, beta-thalassemia) (Wirth et al., 2013;Shahryari et al.,
2019). Yet even in multifactorial diseases, targeting of specific
contributory genes has been shown to provide benefit(Hou and
Kiss, 2019). Clinical trials involving gene therapy in polygenic
diseases with multifactorial etiologies are currently ongoing.
Gene therapy has notable ties with the field of ophthalmology
due to several features distinctive to the ocular system.
Administration of genetic material can occur either in vivo,in
which new genetic material is introduced directly to the
anatomy, or ex vivo, in which cells outside of the body are
modified before introduction back to the patient (Wirth et al.,
2013). While many internal organs are reached using in vivo
methods, the eyes provide opportunity for both options due to
external accessibility and established intravitreal and subretinal
delivery methods (Razi Soofiyani et al., 2013). The ocular system
is also one of the rare immune-privileged sites of the body, where
damaging inflammatory immune responses are limited in area and
severity. This improved immune response in eyes is important to
note, as concern for the immunogenicity of foreign vectors has been
highlighted by the death of a gene therapy clinical trial patient in
1999 due to a massive immune response following high-dose
adenovirus vector administration (Stolberg, 1999;Wirth et al.,
2013). Additionally, this same physiologic response restriction of
the ocular system concentrates vectors to work in the desired area,
leading to a lower required dose of vector needed to produce the
desired results (Razi Soofiyani et al., 2013;Panikker et al., 2022).
Furthermore, neuronal cells of the eyes, which are the pathologic
cells and targets of most gene therapies, are differentiated
postmitotic cells that allow for even better retention of vectors
(Panikker et al., 2022).
Much progress is already underway in the application of gene
therapy to eye diseases, especially in the field of retinal diseases
(Gregory-Evans et al., 2012). Multiple gene therapy clinical trials are
currently ongoing in ocular dystrophies, including Leber congenital
amaurosis (LCA), retinitis pigmentosa (RP), choroideremia,
Stargardt disease, retinoschisis, achromatopsia, and age-related
macular degeneration (Panikker et al., 2022). The U.S. Food and
Drug Administration (FDA) approved a gene therapy product in
2017 that uses an AAV2 vector to target the RPE65 gene in patients
with LCA2 and RP (Panikker et al., 2022).
Gene therapy targeting mitochondrial diseases has additional
considerations due to the nature of mitochondrial physiology.
Originally extracellular bacteria, mitochondria have a separate
double-stranded circular DNA (mtDNA) separate from nuclear
DNA (nDNA). Additional differences in mtDNA include
separate repair mechanisms, ability to replicate independently
from nDNA, and heteroplastic capability (Rong et al., 2021).
Both mtDNA and nDNA have been found to contribute to
mitochondrial diseases and have been the targets of gene-based
therapies. Currently, the only ongoing gene therapy clinical trials in
a primary mitochondrial disease is in an ocular disease: Leber’s
hereditary optic neuropathy (LHON), which is caused by the
mitochondrially-encoded MT-ND4 gene (Slone and Huang, 2020).
In human genome data, researchers found that single nucleotide
polymorphisms (SNPs) in the mitochondrially-encoded genes MT-
ND4 and MT-CYB, as well as the mitochondrial genome haplogroup
K, were associated with POAG (Lo Faro et al., 2021). In a previous
study investigating nuclear-encoded mitochondrial gene-sets and
POAG, the authors found that multiple lipid metabolism and
carbohydrate metabolism pathway gene-sets were significantly
associated with POAG and the NTG subgroup specifically
(Khawaja et al., 2016). The published literature describes multiple
genetic factors that influence mitochondrial pathways contributory
to POAG. Nicotinamide adenine dinucleotide (NAD+), a molecule
important to protecting cells from oxidative stress and
mitochondrial dysfunction, has been shown to decrease in aging
RGCs (Williams et al., 2017). In experimental mouse models of
glaucoma, gene editing that increased retinal Nmnat1 expression,
which encodes for a NAD+-producing enzyme, was found to be
effective in both prevention and treatment of POAG through
protecting RGCs from IOP-induced cellular stress (Williams
et al., 2017).
Investigators have also noted correlations between
glaucomatous mitochondrial dysfunction and endoplasmic
reticulum (ER) stress conditions in which unfolded or misfolded
proteins accumulate within the ER and lead to a cascade of unfolded
protein response (UPR) (McLaughlin et al., 2022). This stress
response leads to increased oxidative stress, mitochondrial stress,
and cellular vulnerability (McLaughlin et al., 2022). Researchers
found that genetic alterations of ER stress related-chaperones, such
as DNAJ proteins, were found to alleviate the ER stress response and
enhanced cell survival (McLaughlin et al., 2022). MYOC gene
produces a trabecular meshwork protein called myocilin, and
mutations have been consistently associated with raised IOP and
inherited POAG (Sharma and Grover, 2021). Researchers have
explored various methods to stabilize the mutant form of the
protein, decrease pathologic accumulation within trabecular
meshwork cells, alleviate the aggregated protein UPR stress
response, and prevent subsequent IOP elevation (Burns et al.,
2010;Jain et al., 2017;Sharma and Grover, 2021). These include
utilizing select chemical chaperone proteins, clustered regularly
interspaced short palindromic repeats (CRISPR)-mediated gene
editing, and methods to promote myocilin clearance (Burns
et al., 2010;Jain et al., 2017;Sharma and Grover, 2021).
In addition to genetic alteration, epigenetic modification has also
been explored in the setting of glaucomatous optic atrophy models.
Studies of short-term delta-opioid receptor agonist treatment in
animal glaucoma models produced long-term RGC neuroprotective
effects, preserving RGC functional integrity and cell count (Husain,
2018). One of the proposed mechanisms for the beneficial effects of
delta-opioid agonism is epigenetic modification. Histone deacetylase
activity has been positively correlated with glaucoma progression,
and delta-opioid agonism was demonstrated to suppress this activity
in ocular hypertensive animal models (Zaidi et al., 2020).
Modification of the epigenetic pathway has also been researched
in non-retinal cells, including restoration of cells comprising the
trabecular meshwork and Schlemm’s canal system (Sharif, 2021).
The inevitable presence of epigenetic variation inherent to humans,
which can influence symptom presentation, disease onset, response
to therapy, and other aspects of pathophysiology, is another
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challenging consideration in human disease research and
management (Levin et al., 2022).
Application of gene and epigenetic therapy to glaucoma is still in
its early stages of development as researchers continue to uncover
the underlying relationships between mitochondrial genetics and
POAG. Nevertheless, the suitability of the ocular system to gene
therapy, mitochondrial gene therapy trials in the ocular disease
LHON, and expansion of gene therapy to target multifactorial
diseases are promising signs towards future application of gene
therapy to POAG.
2.7 Mitochondrial transplantation
Mitochondria are primarily inherited maternally by daughter
cells in a vertical fashion; however, the exchange of mitochondria
has also been noted to occur across cells and tissues within an
individual organism (Gäbelein et al., 2021). Mitochondrial
transplantation, also called mitotherapy, refers to transplanting
active and functional organelles to targeted cells with
mitochondrial dysfunction. Since healthy and active
mitochondria are essential for cell survival and regulation, the act
of replacing dysfunctional mitochondria with normally functioning
counterparts offers a direct approach to eliminating the underlying
problem and treating the resulting disease (Nascimento-dos-Santos
et al., 2021).
Mitochondrial dysfunction has been linked to many diseases,
especially cardiac, neurodegenerative, and other chronic systemic
diseases (Roushandeh et al., 2019). This mitochondrial connection
to a wide variety of diseases positions mitotherapy to be a currently
relevant topic with potentially revolutionary effects in treating these
diseases of high prevalence (Roushandeh et al., 2019). Mitotherapy
has been studied in relation to multiple systemic diseases, including
cardiac, respiratory, hepatic, and neurological disorders
(Nascimento-dos-Santos et al., 2021). Studies of the effects of
mitochondrial transplantation on neurodegenerative diseases have
demonstrated promising results, such as the regrowth of neurites
and restoration of membrane potentials in neurons (Chang et al.,
2019). Other beneficial outcomes include balanced
neuroinflammatory response and improved cerebrovasculature
supply (Zhang et al., 2019).
The feasibility and impacts of mitochondrial transplantation
have also been investigated in neurodegenerative ocular diseases
involving RGCs. In an in vivo murine study assessing the effects of
mitotherapy in rat retina, healthy mitochondria derived from the
liver were intravitreally injected into the optic nerve following nerve
crush injury (Nascimento-dos-Santos et al., 2020). The results of
mitotherapy showed enhanced oxidative metabolism and
electrophysiological response, short-term neuroprotection, and
increased axon extension beyond the lesion site (Nascimento-
dos-Santos et al., 2020). Another study of mitotherapy in in vivo
mice retina also demonstrated functional uptake of intravitreally
injected isolated mitochondria by RGCs (Rotfogel, 2020). These
studies suggest the possibility for injected isolated exogenous
mitochondria to maintain normal structure and function in in
vivo RGCs. Additionally, the potential of mitotherapy has also
been demonstrated in human in vitro studies. A study evaluating
iPSC-derived RGCs generated from human Leber hereditary optic
neuropathy (LHON) fibroblasts with experimentally corrected
mtDNA exhibited restoration of a regular rate of apoptosis and
lower levels of mitochondrial oxidative stress (Wong et al., 2017).
Another study evaluating the outcomes of mitochondrial
transplantation to human skeletal muscle cell-generated iPSC-
derived RGCs following induced oxidative damage demonstrated
recovery of ATP production and oxygen utilization (Vrathasha et al.,
2022). Results of these studies show the ability for mitochondrial
alteration to reverse key aspects of disease in human cell-generated
iPSC-derived RGC models.
Different logistical parameters, such as the origin of the
transplanted mitochondria and its delivery route, affect the
ultimate transplantation results (Chang et al., 2019). Currently,
two regularly utilized routes of administration for mitochondrial
transplantation exist: direct (or proximal) and systemic
(Nascimento-dos-Santos et al., 2021). In the systemic route,
administration of mitochondria through intravascular injection
allows more area to be covered and mitochondria to be
distributed more evenly (Nascimento-dos-Santos et al., 2021).
However, if a more concentrated delivery of mitochondria is the
goal, direct injection to the target site is a more efficient method
(Norat et al., 2020). Of note, both direct and systemic routes of
administration have produced desired results in murine brains,
exhibiting the capability of mitotherapy to overcome the
common challenge of crossing the highly selective blood-brain
barrier to produce results in brain neural tissue (Shi et al., 2017).
Development of novel mechanisms of cell-to-cell transplantation of
mitochondria (and other macromolecules and organelles) are
currently ongoing (e.g., FluidFM-based, cybrid technique) (Wong
et al., 2017;Gäbelein et al., 2021).
Published studies support the potential for mitochondrial
transplantation to be an effective method of reversing debilitating
glaucomatous damage caused by mitochondrial pathologies. The
current literature contains studies and evidence pointing to the
effectiveness of mitochondria transplantation in different animal
and cell models across neurodegenerative and ocular diseases.
However, a need for more literature investigating mitochondrial
transplantation in studies pertinent to POAG is evident.
2.8 Light therapy
Light therapy, also called phototherapy, refers to the specific
exposure of tissue to artificially generated light energy in the
treatment of various conditions. Perhaps the most widely known
medical application today is in the field of psychiatric disorders as an
intuitive counter to seasonal affective depression (Rosenthal et al.,
1984). The impact of light therapy on the human condition has been
demonstrated throughout studies in different scientificfields. Meta-
analyses of randomized control trials have revealed significantly
decreased depression symptoms and significantly increased efficacy
of light therapy compared to placebo in seasonal affective disorder
and nonseasonal depression (Golden et al., 2005;Pjrek et al., 2019).
Other common utilizations of light therapy that are well-known to
both the scientific and general communities today include its
dermatologic applications. Phototherapy has established uses in
diseases with dermatologic involvement (e.g., neonatal jaundice,
psoriasis, vitiligo, eczema), as well as dermatologic features of
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cosmetic concern (e.g., wrinkles, texture, pigmentation) (Ablon,
2018;Rathod et al., 2022).
Researchers have noted that different light exposures (e.g., time
of day, length of exposure, wavelength of light, amplitude of light,
duration of use) can be designed to address different types of disease
(Rathod et al., 2022). For example, bright white phototherapy is
heavily utilized in mood disorders in contrast to light emitting diode
(LED) phototherapy that is utilized in dermatologic diseases
(Golden et al., 2005;Ablon, 2018). One subset of light therapy
includes low-level laser therapy (LLLT), also called
photobiomodulation therapy (PBMT). LLLT is so-named as it
applies red to near-infrared (NIR) light energy at lower densities
to tissues (Chung et al., 2012;Hamblin, 2018). Following the
invention of the first lasers circa 1960, LLLT quickly emerged as
a possible therapeutic modality and research subject of interest when
a ruby laser was demonstrated to promote wound healing and hair
growth in mice (Chung et al., 2012). Due to its lower energy
densities, LLLT also has noted benefit in preventing unwanted
increases in the temperature of recipient tissues (Chung et al.,
2012;Hamblin, 2018). No significant side effects have been
reported with LLLT in the studied literature, making it a non-
invasive and non-toxic procedure suitable for further studies
(Osborne et al., 2016).
LLLT is particularly applicable to mitochondria and eyes due to
several features distinct to these systems. Mitochondria are the
primary locations for light absorption throughout human tissues
due to many mitochondrial proteins containing compounds (e.g.,
chromophores, porphyrin, flavins) programmed for light absorption
(Osborne et al., 2017;Hamblin, 2018). Additionally, the
mitochondrial electron transport chain has been found to be
particularly photosensitive to LLLT due to its terminal enzyme
cytochrome C oxidase (Tafur and Mills, 2008). Cytochrome C
oxidase has been identified as the primary photoreceptor of
LLLT, and it is particularly important for oxidative metabolism
in the eyes and neurons (Tafur and Mills, 2008;Zhu et al., 2021).
Studies have shown that NIR light delivery significantly increases
cytochrome c oxidase production, activity, and reduction in neurons
(Eells et al., 2004;Zhu et al., 2021). In addition to increasing electron
transport chain enzymatic activity, LLLT has also been associated
with increased production of ATP in mitochondria (Karu et al.,
1995). Studies that demonstrated LLLT-induced increases in ROS to
levels conducive to enhanced cell signaling observed promotion of
several transcription factors and genes involved in cellular
biogenesis, growth, and signaling (Chung et al., 2012). In regard
to the ocular system’s relation with light, retinal tissue is known to be
the only tissue in the central nervous tissue that receives light
exposure (Osborne et al., 2017). The retina absorbs light in the
wavelength range of 390–1,000 nm, which encompasses red to
infrared light (630–1,000 nm) in the visible light spectrum
(Osborne et al., 2017). In consideration of what is presently
known regarding the impacts of light therapy on the innate
biology, it is vital to study the effects of LLLT on mitochondrial
and ocular diseases (Hamblin, 2018).
LLLT has been explored in the treatment of a variety of conditions,
such as inflammation reduction, wound and skin ulcer healing, spinal
cord injury axonal regrowth, and nerve repair (Zhu et al., 2021). A study
of mice hippocampus using 660 nm light showed an increase of brain-
derived neurotrophic factor (BDNF) and inhibition of cell death due to
a decrease in oxidative stress (Heo et al., 2019). Further studies showed
NIR light therapy to benefit retinal pathologies, including prevention of
RGC degeneration by correcting mitochondrial dysfunction (Zhu et al.,
2021). In addition, 670 nm light has displayed neuroprotective effects
against toxins such as cyanide and excessive light-induced damage
(Albarracin et al., 2011;Zhu et al., 2021). Dendritic pruning has been
linked to glaucoma, and it has been suggested that damage to dendritic
cells occurs prior to RGC death in experimental cases (Beirne et al.,
2015). Evidence shows that if the retina is treated early after optic nerve
axotomy with 670 nm light, dendritic pruning could be prevented in the
following hours (Beirne et al., 2016). Other benefits of LLLT include the
mitigation of oxygen-induced degeneration, amelioration of lesions in
diabetic retinopathy, and attenuation of histopathological changes in
animal retinas in situ (Osborne et al., 2017). In studies of patients with
retinal diseases, LLLT was associated with improved drusen volume and
visual function in patients with dry age-related macular degeneration, as
well as improvements in retinal thickening and visual acuity in patients
with diabetic macular edema (Tang et al., 2014;Eells et al., 2017;Merry
et al., 2017). A human clinical trial comparing LLLT to routine IOP-
lowering pharmacology in patients with glaucoma is currently listed
with no participants recruited to date (He, 2022).
Research regarding LLLT in POAG is limited, but currently light
therapy appears to be a promising option as a non-invasive
treatment approach with particular impacts on the structures of
interest. Further research on LLLT in POAG is recommended to
clarify underlying mechanisms and potential impact.
3 Discussion
Mitochondrial involvement in disease has become a topic of
heightened scientific interest in recent years. Studies reporting the
profound impact of the mitochondria on cellular processes have
fueled growing research inquiries, which now cover a wide range of
diseases and mechanisms, including glaucoma (Murphy and Hartley.
2018). The role of mitochondria in glaucoma pathogenesis has been
explored in a variety of animal and human studies, revealing both
pathology inducing and ameliorating outcomes that coincide with
different mitochondrial alterations (Williams et al., 2017). Although
many steps still need to be taken prior to clinical application in patients,
published studies in the current literature suggest the possibility of
future utilization of mitochondrial therapeutics as treatment modalities
in glaucoma. In the present review, we discussed the key mitochondrial
therapies with proposed relevance to POAG, highlighting the
background, published studies, and limitations or future directions
of each approach.
The published literature has identified mitochondrial
dysfunction as a contributory factor involved in the pathogenesis
of glaucoma (Murphy and Hartley, 2018). Proposed mechanisms
demonstrated in previous studies include increased oxidative stress,
mtDNA and nDNA genetic mutations, age-related vulnerability,
pathway dysfunction, and signaling dysregulation (Chrysostomou
et al., 2013;Williams et al., 2017;Mancino et al., 2018).
Mitochondrial therapeutics have been found to address key steps
in each of these underlying pathologies, and many therapies overlap
in areas of influence and action. One of the most common
therapeutic targets reported in the described therapies is
mitigation of ROS overaccumulation and oxidative stress through
Frontiers in Physiology frontiersin.org12
Kuang et al. 10.3389/fphys.2023.1184060

various mechanisms of reducing ROS production, promoting
antioxidant capacity, and increasing ROS scavenging (Civitarese
et al., 2007;Tulsawani et al., 2010;Williams et al., 2017;Heo et al.,
2019;Oguntibeju, 2019;Nascimento-dos-Santos et al., 2020;Himori
et al., 2021). As retinal tissues are particularly vulnerable to oxidative
stress due to high concentrations of mitochondria and high
bioenergetic requirements present physiologically, treatment
options targeted towards this etiology are especially relevant and
beneficial to POAG (Barron et al., 2004). Another common target of
therapy includes increasing cellular and mitochondrial biogenesis or
supply of healthy mitochondria, which can improve normal
heteroplasmic proportions by increasing transcriptional
expression, growth factors, or direct transfer (Chung et al., 2012;
Harun-Or-Rashid et al., 2018;Rotfogel, 2020;Zhang et al., 2021;Rey
et al., 2022). Several mitochondria targeted therapeutics have also
demonstrated advantageous effects on IOP, which is POAG’s
primary modifiable risk factor. Exercise, antioxidant
supplementation, and stem cell transplantation have resulted in
reductions in IOP through structural impacts on the trabecular
meshwork system that led to increased aqueous humor outflow (Zhu
et al., 2017;Wang et al., 2019;Yuan et al., 2021). Additionally,
several treatment options were shown to improve mtDNA
expression through promotion of mRNA transcription factors
and DNA signaling molecules (Gudson et al., 2017;Williams
et al., 2017;de Guia et al., 2019). RGC regeneration is the most
sought-after outcome in POAG therapy. Studies in stem cell therapy,
mitotherapy, and antioxidant therapy have demonstrated the
potential for cellular regeneration or reversal of apoptotic
pathways (Inman et al., 2013;Wong et al., 2017;Zhang et al.,
2021). Ultimately, all described mitochondrial therapeutics
demonstrated some degree of benefit in RGC neuroprotection
and survival (Thaler et al., 2010;Tulsawani et al., 2010;Inman
et al., 2013;Williams et al., 2017;Cimaglia et al., 2020;Nascimento-
dos-Santos et al., 2020;Zhang et al., 2021;Zhu et al., 2021).
Mitochondrial studies focused on POAG are still fairly limited
across all study types (e.g., basic science research, experimental animal
models, human clinical trials). Much of the published research on
mitochondrial therapeutics was conducted in diseases with more
established mitochondrial connections (e.g., cardiac, musculoskeletal,
and neurologic disorders) or cells with more accessible tissues (e.g.,
human skeletal muscle cells). Although application of mitochondrial
therapies in disease have demonstrated promising results in
experimental animal models, human trials are particularly lacking.
Many barriers exist in human trials, including treatment
administration, accurate data collection, and cross-study comparison.
As many of these mitochondria-targeted treatment modalities are in the
early stages of understanding and development, administration
techniques and protocols are not yet standardized to allow for
consistent, effective, and specific delivery of treatment. For example,
gene therapy is challenged with DNA vector design, mitotherapy is
challenged with functional incorporation into target cells, stem cell
therapy is challenged with induced differentiation into a specific cell
line, and antioxidant therapy is challenged with subcellular delivery into
mitochondria (Tan et al., 2018;Zinovkin and Zamyatnin, 2019;Zhang
et al., 2021;Di Donfrancesco et al., 2022). Therapies with more
straightforward delivery methods also have concerns surrounding
study design and treatment administration. For example, diet and
nutrition restrictions are difficult to assure and assess in human
studies, and light therapy lacks standardized treatment protocols
(Włodarek, 2019;Zhu et al., 2021).
4 Conclusion
Currently available therapeutics for the treatment of POAG are
both limited and ineffective, rendering certain populations (e.g.,
non-responders to IOP-lowering treatments and those with
advanced neurodegeneration) defenseless amidst a significant gap
in care (Doucette et al., 2015). This lack of effective treatment
highlights the value of and need for better understanding of
POAG and its underlying pathophysiology.
As the present literature continues to draw increasing attention
to the mitochondrial contribution in POAG, it is time to also
consider the possible future therapeutic applications of this
knowledge to affected individuals. Future applications of
increased mitochondria-targeted knowledge and therapies include
preventative neuroprotection, post-degenerative neuron
replacement or regeneration, genetic testing, and family screening.
Although not completely comprehensive of all studied
mitochondrial therapies (e.g., another suggested mitochondrial
therapeutic not mentioned in this review includes pharmacologic
drugs), the present review provides an overview to the current state
of understanding, research, and application of several key
mitochondrial therapies in POAG. Further experiments, studies,
and reviews of all categories are recommended to advance the fields
of mitochondrial study and POAG therapeutics.
Author contributions
GK led manuscript preparation and provided substantial
revision. MH and A-AE conceived the title and wrote critical
components of the paper. RS provided valuable feedback in the
editing and literature search process. JO’B is the corresponding
author who designed and conceptualized the topic of this review as
well as supervised its completion. All authors contributed to the
article and approved the submitted version.
Funding
This study was supported by the National Eye Institute,
Bethesda, Maryland (grant #1R01EY023557-01) and Vision
Research Core Grant (P30 EY001583). Funds also come from the
F.M. Kirby Foundation, Research to Prevent Blindness, The UPenn
Hospital Board of Women Visitors, and The Paul and Evanina Bell
Mackall Foundation Trust. Support also came from Regeneron
Genetics Center, the Ophthalmology Department at the Perelman
School of Medicine, and the VA Hospital in Philadelphia, PA.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Frontiers in Physiology frontiersin.org13
Kuang et al. 10.3389/fphys.2023.1184060

Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
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