Still finding ways to augment the existing management of acute and chronic kidney diseases with targeted gene and cell therapies: Opportunities and hurdles

Abstract

The rising global incidence of acute and chronic kidney diseases has increased the demand for renal replacement therapy. This issue, compounded with the limited availability of viable kidneys for transplantation, has propelled the search for alternative strategies to address the growing health and economic burdens associated with these conditions. In the search for such alternatives, significant efforts have been devised to augment the current and primarily supportive management of renal injury with novel regenerative strategies. For example, gene- and cell-based approaches that utilize recombinant peptides/proteins, gene, cell, organoid, and RNAi technologies have shown promising outcomes primarily in experimental models. Supporting research has also been conducted to improve our understanding of the critical aspects that facilitate the development of efficient gene- and cell-based techniques that the complex structure of the kidney has traditionally limited. This manuscript is intended to communicate efforts that have driven the development of such therapies by identifying the vectors and delivery routes needed to drive exogenous transgene incorporation that may support the treatment of acute and chronic kidney diseases.

Full text

Frontiers in Medicine 01 frontiersin.org
Still finding ways to augment the
existing management of acute and
chronic kidney diseases with
targeted gene and cell therapies:
Opportunities and hurdles
PeterR.Corridon
1,2, 3*
1 Department of Immunology and Physiology, College of Medicine and Health Sciences, Khalifa
University, Abu Dhabi, United Arab Emirates, 2 Biomedical Engineering, Healthcare Engineering
Innovation Center, Khalifa University, Abu Dhabi, United Arab Emirates, 3 Center for Biotechnology,
Khalifa University, Abu Dhabi, United Arab Emirates
The rising global incidence of acute and chronic kidney diseases has increased
the demand for renal replacement therapy. This issue, compounded with the
limited availability of viable kidneys for transplantation, has propelled the search
for alternative strategies to address the growing health and economic burdens
associated with these conditions. In the search for such alternatives, significant
eorts have been devised to augment the current and primarily supportive
management of renal injury with novel regenerative strategies. For example,
gene- and cell-based approaches that utilize recombinant peptides/proteins,
gene, cell, organoid, and RNAi technologies have shown promising outcomes
primarily in experimental models. Supporting research has also been conducted to
improve our understanding of the critical aspects that facilitate the development
of ecient gene- and cell-based techniques that the complex structure of the
kidney has traditionally limited. This manuscript is intended to communicate
eorts that have driven the development of such therapies by identifying the
vectors and delivery routes needed to drive exogenous transgene incorporation
that may support the treatment of acute and chronic kidney diseases.
KEYWORDS
acute kidney disease, chronic kidney disease, gene therapy, cell therapy, renal
1. Introduction
Renal dysfunction can beacute, chronic, or end-stage, manifesting in several forms. e
most prevalent cases arise from congenital disorders (1, 2); nephrotoxicity (3); ischemia–
reperfusion injury (4, 5); systolic hypotension and hemorrhage (6); hypertension (7); trauma
(8); essential mineral deciencies (9); malignancies (10); diabetes (11, 12); and viral infections,
as observed with the COVID-19 pandemic (13, 14). Paradoxically, hospitalization and the
complex relationship between various forms of kidney injuries are additional factors that can
contribute to renal dysfunction. For decades, clinicians have been aware of the risk of patients,
with and without underlying kidney injury, developing hospital-acquired kidney malfunction
(15). ey have also been aware of the complex connection between acute kidney injury (AKI)
and chronic kidney disease (CKD), whereby they are closely linked and likely promote one
another. For instance, CKD is a reputed risk factor for developing AKI during hospitalization,
OPEN ACCESS
EDITED BY
Shan Mou,
Shanghai Jiao Tong University,
China
REVIEWED BY
Darukeshwara Joladarashi,
Temple University,
UnitedStates
*CORRESPONDENCE
Peter R. Corridon
peter.corridon@ku.ac.ae
SPECIALTY SECTION
This article was submitted to
Nephrology,
a section of the journal
Frontiers in Medicine
RECEIVED 12 January 2023
ACCEPTED 17 February 2023
PUBLISHED 07 March 2023
CITATION
Corridon PR (2023) Still finding ways to
augment the existing management of acute
and chronic kidney diseases with targeted gene
and cell therapies: Opportunities and hurdles.
Front. Med. 10:1143028.
doi: 10.3389/fmed.2023.1143028
COPYRIGHT
© 2023 Corridon. 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.
TYPE Mini Review
PUBLISHED 07 March 2023
DOI 10.3389/fmed.2023.1143028

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 02 frontiersin.org
while there is a growing body of evidence illustrating how AKI
accelerates the progression of CKD in critically ill patients (16),
particularly hospitalized COVID-19 patients (17).
From a global perspective, it is estimated that AKI aects
approximately 13 million people annually, contributing to nearly 1.7
million annual deaths (18). Traditionally, AKI is a critical stage in
injury progression because of its reversibility (19). In comparison,
CKD aects over one-tenth of the general population worldwide (20),
and eventually, these conditions contribute to 5–8 million patients
with end-stage renal disease (ESRD) requiring renal replacement
therapy (21). AKI is a critical stage in injury progression because of
its reversibility (21). Beyond this stage, treatment options are limited
to renal replacement therapy, as the dysfunction has progressed to
either CKD or, unfortunately, ESRD. It was previously thought that
AKI, a sudden reduction in renal function, was fully reversible in all
patients (22). Nevertheless, recent research has gone against this
notion based on studies conducted on individuals with reduced
ltration capacities who are more prone to ESRD progression and
mortality than a reversal of the condition (23, 24).
ese facts highlight signicant clinical problems that arise from
acute and chronic disorders. Furthermore, from a nancial
perspective, these patients oen require long-term hospitalization,
which imposes substantial burdens on the healthcare systems related
to the etiologies of these disorders and their complex and debilitating
interconnected nature. Likewise, these conditions lead to enhanced
levels of morbidity and reductions in quality of life. Overall,
morbidity and mortality are expected to rise exponentially with the
growing rates of diabetes and cardiovascular diseases. Given that
current treatments are mainly preventive strategies and early
detection and intervention can bedicult in asymptomatic patients
with these conditions, there is a denite need for alternative strategies
to address the growing prevalence and subtle progression of renal
dysfunction and ultimately reduce the need for renal replacement
therapy (5, 25–28).
In the search for such strategies, signicant eorts are being
devised to augment the present-day management of kidney disease
using novel regenerative strategies. For example, gene- and cell-based
approaches that utilize recombinant peptides/proteins, gene, cell,
organoid, and RNAi technologies have shown promising outcomes
primarily in experimental models (25). Accompanying eorts have
also been devised to facilitate the development of ecient gene- and
cell-based techniques. is article is intended to convey eorts that
have advanced these alternative forms of therapy by highlighting
vectorization and mechanisms that can elicit genetic modications
that may support the treatment of acute and chronic kidney diseases.
2. Eorts to devise eective genetic
alterations in the kidney
2.1. Recombinant peptides and proteins
Various methods have been proposed to deliver exogenous genes
to mammalian cells. For the kidney, attempts have been made to
protect and repair renal function by targeting single genetic loci with
puried protein products, plasmids, recombinant growth factors, and
viruses encoding peptides and proteins. Intravenous doses of human
growth factor (HGF), which has anti-brotic properties, have
promoted kidney repair in rodents with CKD (29, 30). Injections of
IL-18BP, a recombinant interleukin, improved renal function,
restored tubular morphology, and decreased tubular necrosis and
apoptosis in small animal models (31). Cell-based approaches
conducted with intrarenal injections of human placenta-derived stem
cells have also ameliorated damage in ischemia–reperfusion settings
of AKI (32).
Single intravenous doses of plasmids encoding human growth
factor (HGF) have also been shown to improve tissue regeneration
and protect tubular epithelial cells from injury and apoptosis during
acute renal failure (33). In such earlier studies, HGF also helped
preserve renal structure in chronic injury models by activating matrix
degradation and reducing brosis (34–36). Researchers have tested
growth hormone-releasing hormone (GHRH) plasmid-based therapy
in feline and canine chronic injury models. GHRH-treated animals
displayed better levels of erythropoiesis, urea and creatinine
clearances compared to controls (37), as well as more recent ndings
related to its therapeutic eect in CKD patients (38).
It has been well-established that adenovirus and adeno-associated
virus vectors are two of the most ecient systems for transducing
non-dividing cells (39) and have been used to target a variety of
genetic loci. Other experimental studies have used adeno-based
vectors for gene transfer. Lately, such vectors have displayed the long
noncoding RNA-H19-derived attenuation of acute ischemic kidney
injury (40) and the mediation of AKI to CKD progression (41). ese
vectors have also helped preserve renal microvascular morphology
and suppress the progression of AKI via the upregulation of vascular
endothelial growth factor (VEGF) and angiopoietin (42).
Interestingly, the inhibition of VEGF also promoted structural and
functional improvements in diabetes-induced chronic kidney disease
(43, 44). ese ndings support the long-derived notion that
repairing ischemic and toxic renal injuries depended critically on
regulating a redundant, interactive network of cytokines and growth
factors (45). us, it would beof value to devise a system that could
reliably modulate gene expression levels to return kidney function to
near-normal baseline levels without inducing viral-derived toxicity.
However, despite its benets regarding kidney function recovery,
recombinant agents have short half-lives and require large doses (46).
Further studies are needed to demonstrate consistent safety and
eectiveness levels before these experimental techniques become
clinical practice (47).
2.2. Cell and organoid transplantation
Cell therapy is another option to improve tissue/organ
regeneration. Research eorts initially focused on cell transfer for
bone marrow and organ transplantation, blood transfusion, and in
vitro fertilization (48). Nowadays, this technique is being developed
to facilitate the repair/replacement of damaged and lost
compartments in solid organs. is regenerative strategy transplants
cells, which deliver genes of interest, to targeted organs. To achieve
this purpose, investigators use the following cells: stem or progenitor
cells; mature, functional cells from humans or animals; and
genetically modied and transdierentiated cells (48–51). More
recently, organoids, transdierentiated three-dimensional cell

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 03 frontiersin.org
clusters, arose as another promising option to enhance or restore
kidney function (52–54).
Papazova et al. published a meta-analysis of CKD and cell
therapies (55). is analysis demonstrated that more than half of all
cell-based studies focused on the therapeutic eects of single
intravenous doses of mesenchymal stem cells. About a third of the
studies investigated the preventive benets of such therapies, while
half of the studies focused on their therapeutic benets. For instance,
in AKI animal models, mesenchymal stem cells improved renal
function (56–58). Even though the specic mechanisms of action are
still under investigation, these cells helped reduce renal brosis,
improve remodeling, and promote neoangiogenesis (59). Kelly etal.
also helped restore renal function using undierentiated
reprogrammed cells to generate sera amyloid A proteins in ischemia–
reperfusion, plus gentamicin- and cisplatin-based nephrotoxicity
acute injury rat models (60).
Additional eorts have also reported the successful dierentiation
of embryonic and induced pluripotent stem cells into tubular,
glomerular, and whole nephron organoids (61–68). A greater
understanding of the roles of key signaling pathways has also allowed
investigators to dierentiate stem cell niches into various lineages.
Webelieve that shortly, organoids derived from patients’ cells will
beable to repopulate decellularized renal scaolds and printed tissues
or even beinjected back into the patients to restore their native
dysfunction (69–71). Nevertheless, many technical (72–78) and
ethical (79–87) issues still need to besolved in this eld. It is well-
established that embryonic stem cell technology oers hope for new
therapies, yet societal and moral incongruences limit their use.
Teratoma, a hallmark of pluripotency (89–91), is a signicant concern
aer implantation. e ability to culture and manipulate human stem
cells indenitely while simultaneously governing their dierentiation
characteristics oers excellent possibilities for the future of medicine
(92–94).
2.3. RNA interference therapy
Another option within the growing arsenal of gene and cell
therapy applications is RNA interference (RNAi). e discovery of
mammalian RNAi is one of the most promising therapeutic strategies
because it enables the silencing of any gene (95). RNAi is an
advantageous technique, as it is easier to silence decient and
non-functional genes than replace them (96). Moreover, RNAi is the
most practical approach thus far, as it is relatively low cost, highly
specic, and can inhibit multiple genes of various pathways
simultaneously (97). is technology can help identify complex
genetic loci essential to human pathology.
RNAi is an endogenous process that allows cells to regulate their
genetic activity. is process remains central to gene expression and
the defense against mutagenesis generated from viral genes and
transposons (98). e primary methods that induce exogenous
RNAi-based gene silencing utilize micro-RNA (miRNA), small
interfering RNA (siRNA), and small hairpin RNA (shRNA) systems.
Since Napoli and Jorgensen rst reported on this phenomenon in
1990 (99), there has been a growing interest in using RNAi technology
to improve renal health (95). is interest has directed RNAi-based
research focused on improving the study and management of kidney
disease by identifying miRNA targets and AKI biomarkers. It has also
prompted interest in improving the delivery of exogenous silencing
mediators and siRNA and shRNA targets to either reduce or protect
against renal injury. Currently, lipid nanoparticles are the most
frequently used formulation to mediate silencing (100), and further
work has been proposed to determine in vivo silencing eciencies
and investigate other small RNAs that can aect post-transcriptional
gene silencing (101, 102).
From a diagnostic standpoint, several studies have provided
fundamental insight into renal injury biomarkers. Valadi et al.
showed that miRNAs recovered from urinary exosomes provide
information about the kidney in standard and injury settings (103).
Zhou et al. showed that miR-27b and miR-192 in these urinary
vesicles could dierentiate between glomerular and tubular damage
(104). Also, from a therapeutic standpoint, exosomes containing
miRNAs can enter recipient cells by membrane surface proteins. is
phenomenon oers a new mechanism for cell–cell communication
and gene delivery (105–111). In a study by Cantaluppi et al.,
microvesicles enriched with pro-angiogenic miR-126 and miR-296
were injected into the vein, enhanced tubular cell proliferation, and
reduced apoptosis and leukocyte inltration (112). In AKI settings,
such silencing has demonstrated that the caspase-3 siRNA improved
ischemic reperfusion (IR) injury with reduced caspase-3 expression
and apoptosis, better renal oxygenation and acid–base homeostasis,
and the silencing IKKβ using siRNA diminished inammation and
protected the kidneys against IR injury (113). Whereas, in a
glomerulonephritic chronic injury model, MAPK1 suppression
remarkably improved kidney function, reduced proteinuria, and
ameliorated glomerular sclerosis (113).
RNAi therapy could bea valuable surrogate for treating patients
with AKI by reducing the uptake of nephrotoxins, ameliorating
immunologic response mechanisms, and downregulating harmful
disease mediators (114–116). Such characteristics have prompted
interest in the knockdown of dynamin-2 (Dyn2) and low-density
lipoprotein-related protein 2 (LRP2). Dyn2 is a critical component of
the endocytic pathway (117–119), and its knockdown blocks clathrin-
coat-dependent endocytosis and coat-independent uid phase probe
uptake in several epithelial cell lines (120). In animal models,
silencing LRP2 reduced gentamicin toxicity in proximal tubule
epithelial cells (121–123). In a rat model of kidney transplantation,
caudal vein administration of siRNAs, which targeted connective
tissue growth factor (CTGF), decreased renal brosis (124). CTGF is
an essential pro-brotic cofactor that is downstream from TGF-β.
Electroporation also enhanced the delivery of siRNA targeted to
TGF-β1, signicantly reducing glomerular matrix deposition and
proteinuria four and 6 weeks aer anti-y-1 administration
(124, 125).
In other studies, which have investigated the renotherapeutic
potential of siRNA technology (126), siRNA sequences were
systemically delivered to inhibit the expression of p53. is strategy
signicantly reduced ischemia-induced p53 upregulation and helped
attenuate ischemic and cisplatin-induced AKI (127, 128). e
oligonucleotides used to facilitate RNAi contained stabilizing
modications with a relatively low anity for albumin and other
plasma proteins. Such modications diminished their hepatic
distribution and degradation in serum and facilitated their renal
clearance and endocytic tubular uptake (128). is fact limits the

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 04 frontiersin.org
class of therapeutic siRNAs for such procedures because of the
natural tendency of systemically delivered materials to accumulate
within the liver.
In comparison, the expression of transgenic shRNA targeting the
proapoptotic BIM gene prevented the development of polycystic
kidney disease in BCl-2 decient mice (129). However, the mortality
rate in this study was high. Additional research is required to identify
whether the high mortality rate was due to the sequence of the shRNA.
3. Mechanisms for exogenous
transgene expression in mammalian
cells
One major challenge to developing gene- and cell-based strategies
is our need to understand their mechanisms of action. Regardless of
the performance of recombinant peptides, DNA vectors, stem cells,
and RNAi agents, mechanisms related to each approach still need to
be uncovered (47, 69, 130–135). is gap in knowledge makes it
dicult to optimize these techniques. Nevertheless, the basic
principles for successful transgene expression have been documented
(130–134, 136–142). All such therapies rely on eciently delivering
exogenous genes to widespread cellular targets. e techniques
discussed earlier have achieved this by directly using DNA/RNA
strands or inserting these molecules into gene transport vehicles.
Once the genetic materials enter the nuclei, they either aid or inhibit
the expression of the gene product(s) of interest in transformed cells
and their progeny.
Likewise, the overall ecacy of RNAi in inducing gene silencing in
any cell depends on the ability of the dsRNA reagent to access the
subcellular compartment containing the RNA-induced silencing
complex (RISC) and other components of the RNAi machinery (143,
144). is subcellular compartment is in the perinuclear region of the
cytoplasm. However, if cell transplantation mediates transgene
expression, the gene delivery process will rely on integrating the
delivered cells, native cellular division, and intercellular communication.
Furthermore, the goal is to facilitate gene expression/inhibition once
exogenous cells are integrated into tissues and organs (145, 146).
For instance, previous work suggests that the eectiveness of gene
therapies using adenoviral (147) and siRNA (148) vectors depends on
the dose and timing of transgene administration. Such dependence
drives variations in drug concentrations at the respective sites of the
gene expression and silencing machinery.
It is, therefore, essential to understanding how eective
concentrations within the cytoplasm aect therapeutic potency based
on dosing and timing of transgene administrations. is factor is a
topic of practical importance, as the mechanism(s) will determine the
intracellular fate of exogenous transgenes from non-viral, viral, and
cellular sources and aid the development of eectual medical strategies
that can control the duration and extent of induced genetic traits.
Alternatively, for approaches that focus on whole organ engineering
and re-engineering, additional insights are needed into the
mechanisms behind the successful repopulation of tissue and organ
templates (65). Researchers must also determine the characteristics
required to facilitate exogenous genetic and cellular harmony for
viable transplantable kidneys before these ndings can translate into
clinical practice.
4. Key aspects to facilitate
advancements in renal genetic
medicine
4.1. The development of ecient delivery
techniques
Over the past 30 years, many methods have been proposed to
deliver exogenous genes and cells to target organs (32, 39, 46, 97, 100,
102, 130, 142, 149–157). From a fundamental viewpoint, these
techniques seek to provide inexpensive and rapid alternatives to
pronuclear microinjection-derived transgenic models and platforms
for translational studies (121). However, a limiting step in this process
is the need for more reliable delivery systems. Several reports have
indicated inconsistent outcomes regarding the eectiveness of existing
gene and cell transfer techniques. Studies in the kidney have illustrated
this variability (155, 156, 158–164). In general, an in vivo gene and cell
transfer system’s success relies on various factors. e factors include:
• the ability to deliver vectors to the target cells/organ;
• the time the target cell/organs take to express the exogenous
materials; and
• the number of cells/organs that express the required phenotype.
Other essential factors are the resulting expression levels, cellular
turnover rates, the reproducibility of the process, and the severity of
the injury that may result from it (95, 130). us, most existing
strategies remain experimental (165–168).
Researchers must consider organ morphology and function
variations as crucial elements to improve the overall ecacy of
delivery strategies (169, 170). us, ecient gene and cellular
therapies for treating kidney diseases remain challenging (47, 171–
175). e structure of the renal vasculature and its unique
characteristics are prominent limiting factors. Systems focusing on
proximal tubular epithelial cellular uptake could behelpful (175–177).
However, a potential drawback to this technique is the variations in
the glomerular permeability of dierent molecules (178–183).
Likewise, the unknown degree to which these cells are accessible for
gene delivery at the basolateral surface via the peritubular capillaries
provides another level of complication. Studies using adenovirus
vectors have demonstrated the need to improve our understanding of
renal physiology and our ability to manipulate it.
Intra-arterial kidney injections, pre-chilled for extended periods,
facilitated transgene expression within the cortical vasculature (184).
Combining the pre-chilling treatment with vasodilators provided gene
transfer in the outer medulla’s inner and outer strips (184). Other
studies have successfully presented adenoviral vector delivery to rat
glomerular and tubular compartments by infusions into the right
renal artery (185, 186). is technique provided high levels of
transgene expression for 2–4 weeks without causing signicant
damage (187, 188). Analogous concentrations of the same adenovirus
vector were suspended in dierent volumes and delivered to the
kidney via arterial injections and pelvic catheter infusions. is
approach facilitated transgene expression in distinct kidney regions
(188, 189). Aer injecting vectors into the aorta at a location proximal
to the le renal artery, the investigators observed transgene expression
only in proximal tubular cells.

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 05 frontiersin.org
Tail vein and retrograde ureteral adenovirus infusions that target
aquaporin water channels also reported dierent expression levels,
which depended on the transgene infusion site (130, 156). Aquaporin
1 transgenes were expressed in apical and basolateral membranes of
proximal tubule epithelial cells in the renal cortex but not in the
glomerulus, loop of Henle, or collecting duct. Conversely, ureteral and
renal papilla transgene expression was reported through ureteral
infusions. e researchers also reported less intense and patchy
expression in cortical collecting ducts. Ashworth et al. (190) and
Tanner etal. (161) explored the direct transfer of adenovirus vectors
that carried transgenes into individual nephron segments using
micropuncture techniques. ey observed site-specic transgene
expression within the injected tubules or vascular welling points.
ese results also demonstrated the utility of intravital uorescent
multiphoton microscopy to monitor protein expression in live animals
directly. However, one limitation of the approach was that the injection
sites were the only places where the investigators found
transgene expression.
ese studies further highlight the challenge of introducing genes
into multiple renal cell types due to the intricate anatomy of the
kidney, even when using the same type of vector. Results depend on
the transgene infusion site, volume, and rate, as well as the organ
temperature and the use of vasodilators. Hydroporation may address
these challenges by increasing vascular permeability and thus
eciently delivering exogenous substances throughout the kidney.
Hydrodynamic uid delivery impacts uid pressures within thin,
stretchable capillaries (191, 192). e enhanced uid ow generated
from pressurized injections produces rapid and high uctuations in
blood circulation. eoretically, it increases the permeability of the
capillary endothelium and epithelial junctions by generating transient
pores in plasma membranes that facilitate the cellular internalization
of macromolecules of interest (47, 191, 193). e unique anatomy of
the kidney provides various innate delivery pathways (artery, vein, and
ureter) that may beideal for hydrodynamic gene delivery. In our
recent reports, this delivery method provided ecient and lengthy
plasmid and viral expression in live rat kidneys (130, 142, 194) and
facilitated protection against moderate forms of ischemia–reperfusion
injury (154, 195–197). A summary of delivery methods and associated
vectors is presented in Table1.
4.2. Exogenous transgene vectors
e gene of interest is infused either systemically or directly
into the kidney. Apart from the artery, vein, and ureter, direct
infusions into the renal capsule and parenchyma using
micro-needles (161, 190) or blunt-tip needles (157, 198) have also
been proposed, along with indirect tail vein (191, 196, 199) and
peritoneum (200, 201) gene delivery schemes. As indicated before,
the success of these methods varies per the anatomical location of
the targeted cells and the types of vectors used to support gene
expression. ese vectors include PRC-amplied DNA fragments;
plasmid DNA; liposomes; polycations; viral vectors; and stem cells
(130). If transformed cells act as gene vectors to promote transgene
expression, they may beengineered with various anchoring or
binding proteins/peptides to assist their integration into the tissue
of interest (202). is process mimics endogenous viral capsid
components, which mediate receptor binding and support entry
into mammalian cells. As observed in some injured kidney animal
models, local healing/regeneration factors facilitate the
incorporation of exogenous renal cells delivered intravenously (55).
An outline of transgene vector incorporation into the renal
epithelium is presented in Figure1.
Apart from achieving successful genetic modications, wemust
also focus on exogenous transgene delivery and expression eects.
Such considerations relate to the levels of cellular toxicity and injury
that may occur during and aer the transfer process. Endo- and
exonucleases eciently degrade DNA fragments (203, 204).
However, an overload of exogenous DNA fragmentation may
stimulate Ca
2+
endonuclease activity, degrade endogenous DNA,
and mediate cell death (205). Similarly, plasmid DNA, prepared
from bacteria, may induce unmethylated CpG motif toxicity that
can trigger lower respiratory tract inammatory responses (206).
Oligonucleotide therapies have also been shown to stimulate
immune system responses and induce hepatotoxicity and
nephrotoxicity (207). Virus-induced toxic and immunogenic
responses from high titers, protein overexpression, and capsid
protein infections are also topics of signicant concern (208). Long-
term mutagenesis may also bean issue. Reports have shown such
events using recombinant adenovirus systems (209, 210).
Specically, slow-transforming insertional mutagenesis may arise
from retroviruses that incorporate into an organism’s genome (211),
and in vivo stem cell quiescence can tamper with DNA repair
mechanisms to further support mutagenesis (212).
5. Conclusion
ere is a dire need to improve the clinical management of acute
and chronic renal diseases. Preliminary outcomes in experimental
models with kidney dysfunction managed by gene-based and cell-
based approaches are promising. Recent ndings echo the traditional
TABLE1 An overview of delivery methods and associated vectors.
Infusion Site Infusion Method Infusion Compound Auxiliary Gene Enhancer
Tail vein Systemic injection (normal volume and
pressure)
Plasmid and viral vectors, and cells None reported
Renal artery, renal vein, renal
pelvis, and ureter
Low pressure injections
Hydrodynamic injections
DNA particles, liposomes, polycations, stem
cells, and viral vectors
Electroporation, microbubble cavitation,
ultrasound cavitation, ultrasound and
microbubble coupled cavitation
Renal capsule Micropuncture and blunt needle
injections
Viral vectors None reported

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 06 frontiersin.org
B
C
D
A
FIGURE1
A schematic overview of the renal gene- and cell-based approaches highlights vectorization, delivery mode, and pathways supporting transgene
incorporation and expression.

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 07 frontiersin.org
need to address several challenges before these therapies become
viable clinical options. Existing techniques provide a wide range of
success rates and, in some instances, also induce harmful side eects.
us, further research is needed to develop methods to induce
transient or permanent modications with minimal physiological
interference or damage as weaim to improve the treatment of acute
and chronic kidney diseases.
Author contributions
e author conrms being the sole contributor of this work and
has approved it for publication.
Funding
is study was supported in part by the Khalifa University’s
College of Medicine and Health Sciences and Grant Number:
FSU-2020-25 and funding from RC2-2018-022 (HEIC) awarded to PC.
Acknowledgments
e author would like to thank Maja Corridon for reviewing
the manuscript.
Conflict of interest
e author declares that the research was conducted in the
absence of any commercial or nancial relationships that could
beconstrued as a potential conict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their aliated 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.
References
1. Isert, S, Müller, D, and umfart, J. Factors associated with the development of
chronic kidney disease in children with congenital anomalies of the kidney and urinary
tract. Front Pediatr . (2020) 8:298. doi: 10.3389/fped.2020.00298
2. Bergmann, C, Guay-Woodford, LM, Harris, PC, Horie, S, Peters, DJM, and
Torres, VE. Polycystic kidney disease. Nat Rev Dis Primers. (2018) 4:50. doi: 10.1038/
s41572-018-0047-y
3. al-Naimi, MS, Rasheed, HA, Hussien, NR, al-Kuraishy, HM, and al-Gareeb, AI.
Nephrotoxicity: role and signicance of renal biomarkers in the early detection of acute
renal injury. J Adv Pharm Technol Res. (2019) 10:95–9. doi: 10.4103/japtr.JAPTR_336_18
4. Burek, M, Burmester, S, Salvador, E, Möller-Ehrlich, K, Schneider, R, Roewer, N,
et al. Kidney ischemia/reperfusion injury induces changes in the drug transporter
expression at the blood–brain barrier in vivo and invitro. Front Physiol. (2020)
11:569881. doi: 10.3389/fphys.2020.569881
5. Pantic, I., Cumic, J, Dugalic, S, Petroianu, GA, and Corridon, PR, Gray level co-
occurrence matrix and wavelet analyses reveal discrete changes in proximal tubule cell
nuclei aer mild acute kidney injury. (2022), Res Square [Preprint].
6. Qureshi, AI, Huang, W, Lobanova, I, Hanley, DF, Hsu, CY, Malhotra, K, et al.
Systolic blood pressure reduction and acute kidney injury in Intracerebral hemorrhage.
Stroke. (2020) 51:3030–8. doi: 10.1161/STROKEAHA.120.030272
7. Jankowski, J, Floege, J, Fliser, D, Böhm, M, and Mar x, N. Cardiovascular disease in
chronic kidney disease. Circulation. (2021) 143:1157–72. doi: 10.1161/
CIRCULATIONAHA.120.050686
8. Jheong, J-H, Hong, S-K, and Kim, T-H. Acute kidney injury aer trauma: risk factors
and clinical outcomes. J Acute Care Surg. (2020) 10:90–5. doi: 10.17479/jacs.2020.10.3.90
9. Lombardi, Y, Ridel, C, and Touzot, M. Anaemia and acute kidney injury: the tip of
the iceberg? Clin Kidney J. (2020) 14:471–3. doi: 10.1093/ckj/sfaa202
10. Malyszko, J, Tesarova, P, Capasso, G, and Capasso, A. e link between kidney
disease and cancer: complications and treatment. Lancet. (2020) 396:277–87. doi:
10.1016/S0140-6736(20)30540-7
11. Forst, T, Mathieu, C, Giorgino, F, Wheeler, DC, Papanas, N, Schmieder, RE, et al.
New strategies to improve clinical outcomes for diabetic kidney disease. BMC Med.
(2022) 20:337. doi: 10.1186/s12916-022-02539-2
12. Alicic, R, and Nicholas, SB. Diabetic kidney disease Back in focus: management
eld guide for health care professionals in the 21st century. Mayo Clin Proc. (2022)
97:1904–19. doi: 10.1016/j.mayocp.2022.05.003
13. Adapa, S, Chenna, A, Balla, M, Merugu, GP, Koduri, NM, Daggubati, SR, et al.
COVID-19 pandemic causing acute kidney injury and impact on patients with chronic
kidney disease and renal transplantation. J Clin Med Res. (2020) 12:352–61. doi:
10.14740/jocmr4200
14. Geetha, D, Kronbichler, A, Rutter, M, Bajpai, D, Menez, S, Weissenbacher, A, et al.
Impact of the COVID-19 pandemic on the kidney community: lessons learned and
future directions. Nat Rev Nep hrol. (2022) 18:724–37. doi: 10.1038/s41581-022-00618-4
15. Hsu, RK, and Hsu, C-y. CKD increases risk of acute kidney injury during
hospitalization. Nat Clin Pract Nephrol. (2008) 4:408–8. doi: 10.1038/ncpneph0850
16. Hsu, RK, and Hsu, CY. e role of acute kidney injury in chronic kidney disease.
Semin Nephrol. (2016) 36:283–92. doi: 10.1016/j.semnephrol.2016.05.005
17. Bell, JS, James, BD, al-Chalabi, S, Sykes, L, Kalra, PA, and Green, D. Community-
versus hospital-acquired acute kidney injury in hospitalised COVID-19 patients. BMC
Nephrol. (2021) 22:269. doi: 10.1186/s12882-021-02471-2
18. Minja, NW, Akrabi, H, Yeates, K, and Kilonzo, KG. Acute kidney injury and
associated factors in intensive care units at a ter tiary Hospital in Northern Tanzania. Can
J Kidney Health Dis. (2021) 8:20543581211027971. doi: 10.1177/20543581211027971
19. Tanemoto, F, and Mimura, I. erapies targeting epigenetic alterations in acute
kidney injury-to-chronic kidney disease transition. Pharmaceuticals. (2022) 15:123. doi:
10.3390/ph15020123
20. Kovesdy, CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int
Suppl. (2022) 12:7–11. doi: 10.1016/j.kisu.2021.11.003
21. Lv, JC, and Zhang, LX. Prevalence and disease burden of chronic kidney disease.
Adv Exp Med Biol. (2019) 1165:3–15. doi: 10.1007/978-981-13-8871-2_1
22. Goyal, A., Daneshpajouhnejad, Parnaz, Hashmi, Muhammad F., Bashir, Khalid, and
John, Bini K. (2022). Acute kidney injury (nursing) in StatPearls: Treasure Island (FL), 68, 159.
23. Palevsky, PM. Endpoints for clinical trials of acute kidney injury. Nephron. (2018)
140:111–5. doi: 10.1159/000493203
24. Muroya, Y, He, X, Fan, L, Wang, S, Xu, R, Fan, F, et al. Enhanced renal ischemia-
reperfusion injury in aging and diabetes. Am J Physiol Ren Physiol. (2018) 315:F1843–
f1854. doi: 10.1152/ajprenal.00184.2018
25. Corridon, PR, Wang, X, Shakeel, A, and Chan, V. Digital technologies: advancing
individualized treatments through gene and Cell therapies, Pharmacogenetics, and
disease detection and diagnostics. Biomedicine. (2022) 10:2445. doi: 10.3390/
biomedicines10102445
26. Pantic, IV, Shakeel, A, Petroianu, GA, and Corridon, PR. Analysis of vascular
architecture and parenchymal damage generated by reduced blood perfusion in
Decellularized porcine kidneys using a gray level co-occurrence matrix. Front Cardio
Med. (2022) 9:797283. doi: 10.3389/fcvm.2022.797283
27. Pantic, I, Paunovic, J, Cumic, J, Valjarevic, S, Petroianu, GA, and Corridon, PR.
Articial neural networks in contemporary toxicology research. Chem Biol Interact.
(2023) 369:110269. doi: 10.1016/j.cbi.2022.110269
28. Davidovic, LM, Cumic, J, Dugalic, S, Vicentic, S, Sevarac, Z, and Petroianu, G.
Gray-level Co-occurrence matrix analysis for the detection of discrete, ethanol-induced,
structural changes in cell nuclei: an articial intelligence approach. Microsc. Microanal.
(2022) 28:265–271. doi: 10.1017/S1431927621013878
29. Oka, M, Sekiya, S, Sakiyama, R, Shimizu, T, and Nitta, K. Hepatocyte growth
factor–secreting Mesothelial cell sheets suppress progressive brosis in a rat model of
CKD. J AmSoc Nephrol. (2019) 30:261–76. doi: 10.1681/ASN.2018050556
30. Flaquer, M, Franquesa, M, Vidal, A, Bolaños, N, Torras, J, Lloberas, N, et al.
Hepatocyte growth factor gene therapy enhances inltration of macrophages and may
induce kidney repair in db/db mice as a model of diabetes. Diabetologia. (2012)
55:2059–68. doi: 10.1007/s00125-012-2535-z

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 08 frontiersin.org
31. Hirooka, Y, and Nozaki, Y. Interleukin-18in inammatory kidney disease. Front
Med. (2021) 8:8. doi: 10.3389/fmed.2021.639103
32. Kim, JH, Yang, H, Kim, MW, Cho, KS, Kim, DS, Yim, HE, et al. e delivery of the
recombinant protein cocktail identied by stem cell-derived Secretome analysis
accelerates kidney repair aer renal ischemia-reperfusion injury. Front Bioeng
Biotechnol. (2022) 10:10. doi: 10.3389/ioe.2022.848679
33. Dai, C, Yang, J, and Liu, Y. Single injection of naked plasmid encoding hepatocyte
growth factor prevents cell death and ameliorates acute renal failure in mice. J Am Soc
Nephrol. (2002) 13:411–22. doi: 10.1681/ASN.V132411
34. Mihajlovic, M, Wever, KE, van der Made, TK, de Vries, RBM, Hilbrands, LB, and
Masereeuw, R. Are cell-based therapies for kidney disease safe? A systematic review of
preclinical evidence. Pharmacol er. (2019) 197:191–211. doi: 10.1016/j.
pharmthera.2019.01.004
35. Liu, Y, Rajur, K, Tolbert, E, and Dworkin, LD. Endogenous hepatocyte growth
factor ameliorates chronic renal injury by activating matrix degradation pathways.
Kidne y Int. (2000) 58:2028–43. doi: 10.1111/j.1523-1755.2000.00375.x
36. Zhou, D, Tan, RJ, Fu, H, and Liu, Y. Wnt/β-catenin signaling in kidney injury and
repair: a double-edged sword. Lab Investig. (2016) 96:156–67. doi: 10.1038/
labinvest.2015.153
37. Brown, PA, Bodles-Brakhop, AM, Pope, MA, and Draghia-Akli, R. Gene therapy
by electroporation for the treatment of chronic renal failure in companion animals. BMC
Biotechnol. (2009) 9:4. doi: 10.1186/1472-6750-9-4
38. Rieger, AC, Bagno, LL, Salerno, A, Florea, V, Rodriguez, J, Rosado, M, et al. Growth
hormone-releasing hormone agonists ameliorate chronic kidney disease-induced heart
failure with preserved ejection fraction. Proc Natl Acad Sci U S A. (2021)
118:e2019835118. doi: 10.1073/pnas.2019835118
39. Wang, AY, Peng, PD, Ehrhardt, A, Storm, TA, and Kay, MA. Comparison of
adenoviral and adeno-associated viral vectors for pancreatic gene delivery invivo. Hum
Gene er. (2004) 15:405–13. doi: 10.1089/104303404322959551
40. Haddad, G, Kölling, M, Wegmann, UA, Dettling, A, Seeger, H, Schmitt, R, et al.
Renal AAV2-mediated overexpression of long non-coding RNA H19 attenuates
ischemic acute kidney injury through sponging of microRNA-30a-5p. J AmSoc Nephrol.
(2021) 32:323–41. doi: 10.1681/ASN.2020060775
41. Dong, X, Cao, R, Li, Q, and Yin, L. e long noncoding RNA-H19 mediates the
progression of brosis from acute kidney injury to chronic kidney disease by regulating
the miR-196a/Wnt/β-catenin signaling. Nephron. (2022) 146:209–19. doi:
10.1159/000518756
42. Qin, Z, Li, X, Yang, J, Cao, P, Qin, C, Xue, J, et al. VEGF and Ang-1 promotes
endothelial progenitor cells homing in the rat model of renal ischemia and reperfusion
injury. Int J Clin Exp Pathol. (2017) 10:11896–908.
43. Tanabe, K, Maeshima, Y, Sato, Y, and Wada, J. Antiangiogenic therapy for diabetic
nephropathy. Biomed Res Int. (2017) 2017:5724069–12. doi: 10.1155/2017/5724069
44. Tao, Q-R, Chu, YM, Wei, L, Tu, C, and Han, YY. Antiangiogenic therapy in
diabetic nephropathy: a double-edged sword. Mol Med Rep. (2021) 23:260. doi: 10.3892/
mmr.2021.11899
45. Torras, J, Cruzado, JM, Herrero-Fresneda, I, and Grinyo, JM. Gene therapy for
acute renal failure. Contrib Nephrol. (2008) 159:96–108. doi: 10.1159/000125614
46. AlQahtani, AD, O’Connor, D, Domling, A, and Goda, SK. Strategies for the
production of long-acting therapeutics and ecient drug delivery for cancer treatment.
Biomed Pharmacother. (2019) 113:108750. doi: 10.1016/j.biopha.2019.108750
47. Rubin, JD, and Barry, MA. Improving molecular therapy in the kidney. Mol Diagn
er. (2020) 24:375–96. doi: 10.1007/s40291-020-00467-6
48. Hunt, CJ. Cryopreservation of human stem cells for clinical application: a review.
Transfus Med Hemother. (2011) 38:107–23. doi: 10.1159/000326623
49. Shakeel, A, and Corridon, PR. Mitigating challenges and expanding the future of
vascular tissue engineering—are wethere yet? Front Physiol. (2023) 13:1079421. doi:
10.3389/fphys.2022.1079421
50. Wang, X, Chan, V, and Corridon, PR. Decellularized blood vessel development:
current state-of-the-art and future directions. Front Bioeng Biotechnol. (2022) 10:951644.
doi: 10.3389/ioe.2022.951644
51. Wang, X, Chan, V, and Corridon, PR. Acellular tissue-engineered vascular gras
from polymers: methods, achievements, characterization, and challenges. Polymers.
(2022) 14:4825. doi: 10.3390/polym14224825
52. Geuens, T, van Blitterswijk, CA, and LaPointe, VLS. Overcoming kidney organoid
challenges for regenerative medicine. NPJ Regen Med. (2020) 5:8. doi: 10.1038/
s41536-020-0093-4
53. Khoshdel-Rad, N, Ahmadi, A, and Moghadasali, R. Kidney organoids: current
knowledge and future directions. Cell Tissue Res. (2022) 387:207–24. doi: 10.1007/
s00441-021-03565-x
54. Liu, M, Cardilla, A, Ngeow, J, Gong, X, and Xia, Y. Studying kidney diseases using
Organoid models. Front Cell Develop Biol. (2022) 10:845401. doi: 10.3389/
fcell.2022.845401
55. Papazova, DA, Oosterhuis, NR, Gremmels, H, van Koppen, A, Joles, JA, and
Verhaar, MC. Cell-based therapies for experimental chronic kidney disease: a systematic
review and meta-analysis. Dis Mod el Mech. (2015) 8:281–93. doi: 10.1242/dmm.017699
56. Wang, J, Lin, Y, Chen, X, Liu, Y, and Zhou, T. Mesenchymal stem cells: a new
therapeutic tool for chronic kidney disease. Front Cell Develop Biol. (2022) 10:910592.
doi: 10.3389/fcell.2022.910592
57. Eirin, A, and Lerman, LO. Mesenchymal stem/stromal cell–derived extracellular
vesicles for chronic kidney disease: are wethere yet? Hypertension. (2021) 78:261–9. doi:
10.1161/HYPERTENSIONAHA.121.14596
58. Wong, CY. Current advances of stem cell-based therapy for kidney diseases. World
J Stem Cells. (2021) 13:914–33. doi: 10.4252/wjsc.v13.i7.914
59. Missoum, A. Recent updates on Mesenchymal stem cell based therapy for acute
renal failure. Curr Uro l. (2019) 13:189–99. doi: 10.1159/000499272
60. Kelly, KJ, Kluve-Beckerman, B, Zhang, J, and Dominguez, JH. Intravenous cell
therapy for acute renal failure with serum amyloid a protein-reprogrammed cells. Am J
Physiol Ren Physiol. (2010) 299:F453–64. doi: 10.1152/ajprenal.00050.2010
61. Fatehullah, A, Tan, SH, and Barker, N. Organoids as an invitro model of human
development and disease. Nat Cell Biol. (2016) 18:246–54. doi: 10.1038/ncb3312
62. Little, MH. Generating kidney tissue from pluripotent stem cells. Cell Death Dis.
(2016) 2:16053. doi: 10.1038/cddiscovery.2016.53
63. Morizane, R, Lam, AQ, Freedman, BS, Kishi, S, Valerius, MT, and Bonventre, JV.
Nephron organoids derived from human pluripotent stem cells model kidney
development and injury. Nat Biotechnol. (2015) 33:1193–200. doi: 10.1038/nbt.3392
64. Garreta, E, Nauryzgaliyeva, Z, and Montserrat, N. Human induced pluripotent
stem cell-derived kidney organoids toward clinical implementations. Curr Opinion
Biomed Eng. (2021) 20:100346. doi: 10.1016/j.cobme.2021.100346
65. Corridon, PR. Intravital microscopy datasets examining key nephron segments of
transplanted decellularized kidneys. Sci Data. (2022) 9:561. doi: 10.1038/
s41597-022-01685-9
66. Pantic, IV, Shakeel, A, Petroianu, GA, and Corridon, PR. Analysis of vascular
architecture and parenchymal damage generated by reduced blood perfusion in
Decellularized porcine kidneys using a gray level co-occurrence matrix. Front Cardiovasc
Med. (2022) 9:797283. doi: 10.3389/fcvm.2022.797283
67. Ciampi, O, Bonandrini, B, Derosas, M, Conti, S, Rizzo, P, Benedetti, V, et al.
Engineering the vasculature of decellularized rat kidney scaolds using human induced
pluripotent stem cell-derived endothelial cells. Sci Rep. (2019) 9:8001. doi: 10.1038/
s41598-019-44393-y
68. de Haan, MJA, Witjas, FMR, Engelse, MA, and Rabelink, TJ. Have wehit a wall
with whole kidney decellularization and recellularization: a review. Curr O pinion Biomed
Eng. (2021) 20:100335. doi: 10.1016/j.cobme.2021.100335
69. Corridon, PR, Ko, IK, Yoo, JJ, and Atala, A. Bioarticial kidneys. Curr Stem Cell
Rep. (2017) 3:68–76. doi: 10.1007/s40778-017-0079-3
70. Corridon, PR. In vitro investigation of the impact of pulsatile blood ow on the
vascular architecture of decellularized porcine kidneys. Sci Rep. (2021) 11:16965. doi:
10.1038/s41598-021-95924-5
71. Khan, R, Khraibi, A, Dumée, LF, and Corridon, PR. From waste to wealth:
Repurposing slaughterhouse waste for xenotransplantation. Front. Bioeng. Biotechnol.
(2023). doi: 10.3389/ioe.2023.1091554
72. Becerra, J, Santos-Ruiz, L, Andrades, JA, and Marí-Bea, M. e stem cell niche
should bea key issue for cell therapy in regenerative medicine. Stem Cell Rev Rep. (2011)
7:248–55. doi: 10.1007/s12015-010-9195-5
73. Haworth, R, and Sharpe, M. e issue of immunology in stem cell therapies: a
pharmaceutical perspective. Regen Med. (2015) 10:231–4. doi: 10.2217/rme.14.50
74. Jalil, RA, Neng, LC, and Kodis, T. Challenges in deriving and utilizing stem cell-
derived endothelial cells for regenerative medicine: a key issue in clinical therapeutic
applications. J Stem Cells. (2011) 6:93–9.
75. Lepperdinger, G, Brunauer, R, Jamnig, A, Laschober, G, and Kassem, M.
Controversial issue: is it safe to employ mesenchymal stem cells in cell-based therapies?
Exp Gerontol. (2008) 43:1018–23. doi: 10.1016/j.exger.2008.07.004
76. Lin, SZ. Era of stem cell therapy for regenerative medicine and cancers: an
introduction for the special issue of pan Pacic symposium on stem cells and cancer
research. Cell Transplant. (2015) 24:311–2. doi: 10.3727/096368915X686814
77. Sell, S. Adult stem cell plasticity: introduction to the rst issue of stem cell reviews.
Stem Cell Rev. (2005) 1:001–8. doi: 10.1385/SCR:1:1:001
78. Wade, N. An old question becomes new again: stem cell issue causes debate over
the exact moment life begins. N Y Times Web. (2001):A20.
79. Brown, M. No ethical bypass of moral status in stem cell research. Bioethics. (2013)
27:12–9. doi: 10.1111/j.1467-8519.2011.01891.x
80. Cohen, CB, Brandhorst, B, Nagy, A, Leader, A, Dickens, B, Isasi, RM, et al. e use
of fresh embryos in stem cell research: ethical and policy issues. Cell Stem Cell. (2008)
2:416–21. doi: 10.1016/j.stem.2008.04.002
81. Cote, DJ, Bredenoord, AL, Smith, TR, Ammirati, M, Brennum, J, Mendez, I, et al.
Ethical clinical translation of stem cell interventions for neurologic disease. Neurology.
(2017) 88:322–8. doi: 10.1212/WNL.0000000000003506
82. Habets, MG, van Delden, JJ, and Bredenoord, AL. e inherent ethical challenge
of rst-in-human pluripotent stem cell trials. Regen Med. (2014) 9:1–3. doi: 10.2217/
rme.13.83

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 09 frontiersin.org
83. Lo, B, and Parham, L. Ethical issues in stem cell research. Endocr Rev. (2009)
30:204–13. doi: 10.1210/er.2008-0031
84. Manzar, N, Manzar, B, Hussain, N, Hussain, MFA, and Raza, S. e ethical
dilemma of embryonic stem cell research. Sci Eng Ethics. (2013) 19:97–106. doi: 10.1007/
s11948-011-9326-7
85. Mauron, A, and Jaconi, ME. Stem cell science: current ethical and policy issues.
Clin Pharmacol er. (2007) 82:330–3. doi: 10.1038/sj.clpt.6100295
86. Schuklenk, U. How not to win an ethical argument: embryo stem cell research
revisited. Bioethics. (2008) 22:ii–iii. doi: 10.1111/j.1467-8519.2008.00640.x
87. Suckiel, E. Human embryonic stem cell research: a critical survey of the ethical
issues. Adv Pediatr Infect Dis. (2008) 55:79–96. doi: 10.1016/j.yapd.2008.07.017
88. Cho, SJ, Kim, SY, Jeong, HC, Cheong, H, Kim, D, Park, SJ, et al. Repair of ischemic
injury by pluripotent stem cell based cell therapy without teratoma through selective
photosensitivity. Stem Cell Reports. (2015) 5:1067–80. doi: 10.1016/j.stemcr.2015.10.004
89. Tang, C, Weissman, IL, and Drukker, M. e safety of embryonic stem cell therapy
relies on teratoma removal. Oncotarget. (2012) 3:7–8. doi: 10.18632/oncotarget.434
90. Zhang, W. Teratoma formation: a tool for monitoring pluripotency in stem cell
research. StemBook. (2014). doi: 10.3824/stembook.1.53.1
91. de Los Angeles, A, Ferrari, F, Xi, R, Fujiwara, Y, Benvenisty, N, Deng, H, et al.
Hallmarks of pluripotency. Nature. (2015) 525:469–78. doi: 10.1038/nature15515
92. Dhawan, AP, D'Alessandro, B, and Fu, X. Optical imaging modalities for
biomedical applications. IEEE Rev Biomed Eng. (2010) 3:69–92. doi: 10.1109/
RBME.2010.2081975
93. Zakrzewski, W, Dobrzyński, M, Szymonowicz, M, and Rybak, Z. Stem cells: past,
present, and future. Stem Cell Res er. (2019) 10:68. doi: 10.1186/s13287-019-1165-5
94. Mousaei Ghasroldasht, M, Seok, J, Park, HS, Liakath Ali, FB, and al-Hendy, A.
Stem cell therapy: from idea to clinical practice. Int J Mol Sci. (2022) 23:2850. doi:
10.3390/ijms23052850
95. Lien, YH, and Lai, LW. Renal gene transfer: nonviral approaches. Mol Biotechnol.
(2003) 24:283–94. doi: 10.1385/MB:24:3:283
96. Agrawal, N, Dasaradhi, PVN, Mohmmed, A, Malhotra, P, Bhatnagar, RK, and
Mukherjee, SK. RNA interference: biology, mechanism, and applications. Microbiol Mol
Biol Rev. (2003) 67:657–85. doi: 10.1128/MMBR.67.4.657-685.2003
97. Chen, X, Mangala, LS, Rodriguez-Aguayo, C, Kong, X, Lopez-Berestein, G, and
Sood, AK. RNA interference-based therapy and its delivery systems. Cancer Metastasis
Rev. (2018) 37:107–24. doi: 10.1007/s10555-017-9717-6
98. Gupta, S, Verfaillie, C, Chmielewski, D, Kren, S, Eidman, K, Connaire, J, et al.
Isolation and characterization of kidney-derived stem cells. J AmSoc Nephrol. (2006)
17:3028–40. doi: 10.1681/ASN.2006030275
99. Sen, GL, and Blau, HM. A brief history of RNAi: the silence of the genes. FASEB
J. (2006) 20:1293–9. doi: 10.1096/.06-6014rev
100. Bondue, T, van den Heuvel, L, Levtchenko, E, and Brock, R. e potential of
RNA-based therapy for kidney diseases. Pediatr Nephrol. (2023) 38:327–44. doi: 10.1007/
s00467-021-05352-w
101. Kameda, S, Maruyama, H, Higuchi, N, Iino, N, Nakamura, G, Miyazaki, J, et al.
Kidney-targeted naked DNA transfer by retrograde injection into the renal vein in mice.
Biochem Biophys Res Commun. (2004) 314:390–5. doi: 10.1016/j.bbrc.2003.12.107
102. Lam, JK, Chow, MYT, Zhang, Y, and Leung, SWS. siRNA versus miRNA as
therapeutics for gene silencing. Mol er Nucleic Acids. (2015) 4:e252. doi: 10.1038/
mtna.2015.23
103. orling, CA, Dancik, Y, Hupple, CW, Medley, G, Liu, X, Zvyagin, AV, et al.
Multiphoton microscopy and uorescence lifetime imaging provide a novel method in
studying drug distribution and metabolism in the rat liver inv ivo. J Biomed Opt. (2011)
16:086013. doi: 10.1117/1.3614473
104. Schena, FP, Serino, G, and Sallustio, F. MicroRNAs in kidney diseases: new
promising biomarkers for diagnosis and monitoring. Nephrol Dial Transplant. (2014)
29:755–63. doi: 10.1093/ndt/g223
105. Saal, S, and Harvey, SJ. MicroRNAs and the kidney: coming of age. Curr Opin
Nephrol Hypertens. (2009) 18:317–23. doi: 10.1097/MNH.0b013e32832c9da2
106. Aslan, C, Kiaie, SH, Zolbanin, NM, Lotnejad, P, Ramezani, R, Kashanchi, F, et al.
Exosomes for mRNA delivery: a novel biotherapeutic strategy with hurdles and hope.
BMC Biotechnol. (2021) 21:20. doi: 10.1186/s12896-021-00683-w
107. Zhang, Y, Liu, Q, Zhang, X, Huang, H, Tang, S, Chai, Y, et al. Recent advances in
exosome-mediated nucleic acid delivery for cancer therapy. J Nanobiotechnol. (2022)
20:279. doi: 10.1186/s12951-022-01472-z
108. Herrmann, IK, Wood, MJA, and Fuhrmann, G. Extracellular vesicles as a next-
generation drug delivery platform. Nat Nanotechnol. (2021) 16:748–59. doi: 10.1038/
s41565-021-00931-2
109. Lv, LL, Wu, WJ, Feng, Y, Li, ZL, Tang, TT, and Liu, BC. erapeutic application
of extracellular vesicles in kidney disease: promises and challenges. J Cell Mol Med.
(2018) 22:728–37. doi: 10.1111/jcmm.13407
110. Xiang, H, Zhang, C, and Xiong, J. Emerging role of extracellular vesicles in
kidney diseases. Front Pharmacol. (2022) 13:985030. doi: 10.3389/fphar.2022.985030
111. Corrêa, RR, Juncosa, EM, Masereeuw, R, and Lindoso, RS. Extracellular vesicles
as a therapeutic tool for kidney disease: current advances and perspectives. Int J Mol Sci.
(2021) 22:5787. doi: 10.3390/ijms22115787
112. Cantaluppi, V, Gatti, S, Medica, D, Figliolini, F, Bruno, S, Deregibus, MC, et al.
Microvesicles derived from endothelial progenitor cells protect the kidney from
ischemia-reperfusion injury by microRNA-dep endent reprogramming of resident renal
cells. Kidne y Int. (2012) 82:412–27. doi: 10.1038/ki.2012.105
113. Yang, C, Zhang, C, Zhao, Z, Zhu, T, and Yang, B. Fighting against kidney diseases
with small interfering RNA: opportunities and challenges. J Transl Med. (2015) 13:39.
doi: 10.1186/s12967-015-0387-2
114. Miller, RP, Tadagavadi, RK, Ramesh, G, and Reeves, WB. Mechanisms of
Cisplatin nephrotoxicity. Toxins. (2010) 2:2490–518. doi: 10.3390/toxins2112490
115. Pabla, N, and Dong, Z. Cisplatin nephrotoxicity: mechanisms and renoprotective
strategies. Kidne y Int. (2008) 73:994–1007. doi: 10.1038/sj.ki.5002786
116. Peres, LA, and da Cunha, AD Jr. Acute nephrotoxicity of cisplatin: molecular
mechanisms. J Bras Nefrol. (2013) 35:332–40. doi: 10.5935/0101-2800.20130052
117. BOSCH, B, GRIGOROV, B, SENSERRICH, J, CLOTET, B, DARLIX, J,
MURIAUX, D, et al. A clathrin-dynamin-dependent endocytic pathway for the uptake
of HIV-1 by direct T cell-T cell transmission. Antivir Res. (2008) 80:185–93. doi:
10.1016/j.antiviral.2008.06.004
118. Marina-García, Ń, Franchi, L, Kim, YG, Hu, Y, Smith, DE, Boons, GJ, et al.
Clathrin- and dynamin-dependent endocytic pathway regulates muramyl dipeptide
internalization and NOD2 activation. J Immunol. (2009) 182:4321–7. doi: 10.4049/
jimmunol.0802197
119. Wiejak, J, Surmacz, L, and Wyroba, E. Dynamin- and clathrin-dependent
endocytic pathway in unicellular eukaryote paramecium. Biochem Cell Biol. (2004)
82:547–58. doi: 10.1139/o04-098
120. McFarland, MJ, Bardell, TK, Yates, ML, Placzek, EA, and Barker, EL. RNA
interference-mediated knockdown of dynamin 2 reduces endocannabinoid uptake into
neuronal dCAD cells. Mol Pharmacol. (2008) 74:101–8. doi: 10.1124/mol.108.044834
121. Hall, AM, Rhodes, GJ, Sandoval, RM, Corridon, PR, and Molitoris, BA. In vivo
multiphoton imaging of mitochondrial structure and function during acute kidney
injury. Kidney Int. (2013) 83:72–83. doi: 10.1038/ki.2012.328
122. Mahadevappa, R, Nielsen, R, Christensen, EI, and Birn, H. Megalin in acute
kidney injury: foe and friend. Am J Physiol Ren Physiol. (2014) 306:F147–54. doi:
10.1152/ajprenal.00378.2013
123. Nagai, J, Saito, M, Adachi, Y, Yumoto, R, and Takano, M. Inhibition of gentamicin
binding to rat renal brush-border membrane by megalin ligands and basic peptides. J
Control Release. (2006) 112:43–50. doi: 10.1016/j.jconrel.2006.01.003
124. Stokman, G, Qin, Y, Rácz, Z, Hamar, P, and Price, LS. Application of siRNA in
targeting protein expression in kidney disease. Adv Drug Deliv Rev. (2010) 62:1378–89.
doi: 10.1016/j.addr.2010.07.005
125. Ren, Y, du, C, Yan, L, Wei, J, Wu, H, Shi, Y, et al. CTGF siRNA ameliorates tubular
cell apoptosis and tubulointerstitial brosis in obstructed mouse kidneys in a Sirt1-
independent manner. Drug Des Devel er. (2015) 9:4155–71. doi: 10.2147/DDDT.
S86748
126. ompson, JD, Kornbrust, DJ, Foy, JWD, Solano, ECR, Schneider, DJ,
Feinstein, E, et al. Toxicological and pharmacokinetic properties of chemically modied
siRNAs targeting p53 RNA following intravenous administration. Nucleic Acid er.
(2012) 22:255–64. doi: 10.1089/nat.2012.0371
127. Imamura, R, Isaka, Y, Sandoval, RM, Ori, A, Adamsky, S, Feinstein, E, et al.
Intravital two-photon microscopy assessment of renal protection ecacy of siRNA for
p53 in experimental rat kidney transplantation models. Cell Transplant. (2010)
19:1659–70. doi: 10.3727/096368910X516619
128. Molitoris, BA, Dagher, PC, Sandoval, RM, Campos, SB, Ashush, H, Fridman, E,
et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney
injury. J AmSoc Nephrol. (2009) 20:1754–64. doi: 10.1681/ASN.2008111204
129. Bouillet, P, Robati, M, Bath, M, and Strasser, A. Polycystic kidney disease
prevented by transgenic RNA interference. Cell Death Dier. (2005) 12:831–3. doi:
10.1038/sj.cdd.4401603
130. Corridon, PR, Rhodes, GJ, Leonard, EC, Basile, DP, Gattone, VH II, Bacallao, RL,
et al. A method to facilitate and monitor expression of exogenous genes in the rat kidney
using plasmid and viral vectors. Am J Physiol Ren Physiol. (2013) 304:F1217–29. doi:
10.1152/ajprenal.00070.2013
131. Duvshani-Eshet, M, Haber, T, and Machluf, M. Insight concerning the
mechanism of therapeutic ultrasound facilitating gene delivery: increasing cell
membrane permeability or interfering with intracellular pathways? Hum Gene er.
(2014) 25:156–64. doi: 10.1089/hum.2013.140
132. Felgner, JH, Kumar, R, Sridhar, CN, Wheeler, CJ, Tsai, YJ, Border, R, et al.
Enhanced gene delivery and mechanism studies with a novel series of cationic lipid
formulations. J Biol Chem. (1994) 269:2550–61. doi: 10.1016/S0021-9258(17)41980-6
133. Grandinetti, G, Smith, AE, and Reineke, TM. Membrane and nuclear
permeabilization by polymeric pDNA vehicles: ecient method for gene delivery or
mechanism of cytotoxicity? Mol Pharm. (2012) 9:523–38. doi: 10.1021/mp200368p
134. Wickham, T. A novel approach and a novel mechanism for stealthing gene
delivery vehicles. Mol er. (2000) 2:103–4. doi: 10.1006/mthe.2000.0112

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 10 frontiersin.org
135. Davis, L, and Park, F. Gene therapy research for kidney diseases. Physiol
Genomics. (2019) 51:449–61. doi: 10.1152/physiolgenomics.00052.2019
136. Ang, D, Nguyen, QV, Kayal, S, Preiser, PR, Rawat, RS, and Ramanujan, RV.
Insights into the mechanism of magnetic particle assisted gene delivery. Acta Biomater.
(2011) 7:1319–26. doi: 10.1016/j.actbio.2010.09.037
137. Choi, HS, Kim, HH, Yang, JM, and Shin, S. An insight into the gene delivery
mechanism of the arginine peptide system: role of the peptide/DNA complex size.
Biochim Biophys Acta. (2006) 1760:1604–12. doi: 10.1016/j.bbagen.2006.09.011
138. Elnaggar, R, Hanawa, H, Liu, H, Yoshida, T, Hayashi, M, Watanabe, R, et al. e
eect of hydrodynamics-based delivery of an IL-13-Ig fusion gene for experimental
autoimmune myocarditis in rats and its possible mechanism. Eur J Immunol. (2005)
35:1995–2005. doi: 10.1002/eji.200425776
139. Liu, H, Hanawa, H, Yoshida, T, Elnaggar, R, Hayashi, M, Watanabe, R, et al. Eect
of hydrodynamics-based gene delivery of plasmid DNA encoding interleukin-1 receptor
antagonist-Ig for treatment of rat autoimmune myocarditis: possible mechanism for
lymphocytes and noncardiac cells. Circulation. (2005) 111:1593–600. doi: 10.1161/01.
CIR.0000160348.75918.CA
140. McKay, T, Reynolds, P, Jezzard, S, Curiel, D, and Coutelle, C. Secretin-mediated
gene delivery, a specic targeting mechanism with potential for treatment of biliary and
pancreatic disease in cystic brosis. Mol er. (2002) 5:447–54. doi: 10.1006/
mthe.2002.0560
141. Simeoni, F, Morris, MC, Heitz, F, and Divita, G. Insight into the mechanism of
the peptide-based gene delivery system MPG: implications for delivery of siRNA into
mammalian cells. Nucleic Acids Res. (2003) 31:2717–24. doi: 10.1093/nar/gkg385
142. Corridon, PR, Karam, SH, Khraibi, AA, Khan, AA, and Alhashmi, MA. Intravital
imaging of real-time endogenous actin dysregulation in proximal and distal tubules at
the onset of severe ischemia-reperfusion injury. Sci Rep. (2021) 11:8280. doi: 10.1038/
s41598-021-87807-6
143. Filipowicz, W. RNAi: the nuts and bolts of the RISC machine. Cells. (2005)
122:17–20. doi: 10.1016/j.cell.2005.06.023
144. Pratt, AJ, and MacRae, IJ. e RNA-induced silencing complex: a versatile gene-
silencing machine. J Biol Chem. (2009) 284:17897–901. doi: 10.1074/jbc.R900012200
145. Zhang, X, Edwards, JP, and Mosser, DM. e expression of exogenous genes in
macrophages: obstacles and opportunities. Method s Mol Biol. (2009) 531:123–43. doi:
10.1007/978-1-59745-396-7_9
146. Arrighi, N. (ed.). “3 - Stem Cells at the Core of Cell erapy,” in Stem Cells.
Amsterdam: Elsevier. (2018). 73–100.
147. Crystal, RG. Adenovirus: the rst eective invivo gene delivery vector. Hum
Gene er. (2014) 25:3–11. doi: 10.1089/hum.2013.2527
148. Manfredsson, FP, Lewin, AS, and Mandel, RJ. RNA knockdown as a potential
therapeutic strategy in Parkinson's disease. Gene er. (2006) 13:517–24. doi: 10.1038/
sj.gt.3302669
149. Katz, MG, Fargnoli, AS, Williams, RD, and Bridges, CR. Gene therapy delivery
systems for enhancing viral and nonviral vectors for cardiac diseases: current concepts
and future applications. Hum Gene er. (2013) 24:914–27. doi: 10.1089/hum.2013.2517
150. Nayerossadat, N, Maedeh, T, and Ali, PA. Viral and nonviral delivery systems for
gene delivery. Adv Biomed Res. (2012) 1:27. doi: 10.4103/2277-9175.98152
151. Kamimura, K, Suda, T, Zhang, G, and Liu, D. Advances in gene delivery systems.
Pharmaceut Med. (2011) 25:293–306. doi: 10.2165/11594020-000000000-00000
152. Bhattacharya, S, Saini, M, Bisht, D, Rana, M, Bachan, R, Gogoi, SM, et al.
Lentiviral-mediated delivery of classical swine fever virus Erns gene into porcine
kidney-15 cells for production of recombinant ELISA diagnostic antigen. Mol Biol Rep.
(2019) 46:3865–76. doi: 10.1007/s11033-019-04829-0
153. Huang, S, Ren, Y, Wang, X, Lazar, L, Ma, S, Weng, G, et al. Application of
ultrasound-targeted microbubble destruction–mediated exogenous gene transfer in
treating various renal diseases. Hum Gene er. (2018) 30:127–38. doi: 10.1089/
hum.2018.070
154. Kolb, AL, Corridon, PR, Zhang, S, Xu, W, Witzmann, FA, Collett, JA, et al.
Exogenous gene transmission of Isocitrate dehydrogenase 2 mimics ischemic
preconditioning protection. J Am Soc Nephrol. (2018) 29:1154–64. doi: 10.1681/
ASN.2017060675
155. Nakamura, A, Imaizumi, A, Niimi, R, Yanagawa, Y, Kohsaka, T, and Johns, EJ.
Adenoviral delivery of the beta2-adrenoceptor gene in sepsis: a subcutaneous approach
in rat for kidney protection. Clin Sci (Lond). (2005) 109:503–11. doi: 10.1042/
CS20050088
156. Verkman, AS, and Yang, B. Aquaporin gene delivery to kidney. Ki dney Int . (2002)
61:S120–4. doi: 10.1046/j.1523-1755.2002.0610s1120.x
157. Imai, E, and Isaka, Y. Strategies of gene transfer to the kidney. Ki dney Int . (1998)
53:264–72. doi: 10.1046/j.1523-1755.1998.00768.x
158. Boletta, A, Benigni, A, Lutz, J, Remuzzi, G, Soria, MR, and Monaco, L. Nonviral
gene delivery to the rat kidney with polyethylenimine. Hum Gene er. (1997)
8:1243–51. doi: 10.1089/hum.1997.8.10-1243
159. Kapturczak, MH, Chen, S, and Agarwal, A. Adeno-associated virus vector-
mediated gene delivery to the vasculature and kidney. Acta Biochim Pol. (2005) 52:293–9.
doi: 10.18388/abp.2005_3442
160. Ramirez-Gordillo, D, Trujillo-Provencio, C, Knight, VB, and Serrano, EE.
Optimization of gene delivery methods in Xenopus laevis kidney (A6) and Chinese
hamster ovary (CHO) cell lines for heterologous expression of Xenopus inner ear genes.
In Vitro Cell Dev Biol Anim. (2011) 47:640–52. doi: 10.1007/s11626-011-9451-2
161. Tanner, GA, Sandoval, RM, Molitoris, BA, Bamburg, JR, and Ashworth, SL.
Micropuncture gene delivery and intravital two-photon visualization of protein
expression in rat kidney. Am J Physiol Ren Physiol. (2005) 289:F638–43. doi: 10.1152/
ajprenal.00059.2005
162. Wang, Y, Cui, H, Li, K, Sun, C, Du, W, Cui, J, et al. A magnetic nanoparticle-based
multiple-gene delivery system for transfection of porcine kidney cells. PLoS One. (2014)
9:e102886. doi: 10.1371/journal.pone.0102886
163. Xing, Y, Pua, EC, Lu, X, and Zhong, P. Low-amplitude ultrasound enhances
hydrodynamic-based gene delivery to rat kidney. Biochem Biophys Res Commun. (2009)
386:217–22. doi: 10.1016/j.bbrc.2009.06.020
164. Zhu, G, Nicolson, AG, Zheng, XX, Strom, TB, and Sukhatme, VP. Adenovirus-
mediated beta-galactosidase gene delivery to the liver leads to protein deposition in
kidney glomeruli. Kidney Int. (1997) 52:992–9. doi: 10.1038/ki.1997.421
165. Friedmann, T. A new serious adverse event in a gene therapy study. Mol er.
(2007) 15:1899–900. doi: 10.1038/sj.mt.6300328
166. Gonçalves, GAR, and Paiva, RMA. Gene therapy: advances, challenges and
perspectives. Einstein. (2017) 15:369–75. doi: 10.1590/s1679-45082017rb4024
167. Tremblay, JP, Annoni, A, and Suzuki, M. ree decades of clinical gene therapy:
from experimental technologies to viable treatments. Mol er. (2021) 29:411–2. doi:
10.1016/j.ymthe.2021.01.013
168. Goswami, R, Subramanian, G, Silayeva, L, Newkirk, I, Doctor, D, and Chawla, K.
Gene therapy leaves a vicious cycle. Front Oncol. (2019) 9:297. doi: 10.3389/fonc.2019.00297
169. Cai, N, Lai, AC-K, Liao, K, Corridon, PR, Graves, DJ, and Chan, V. Recent
advances in uorescence recovery aer photobleaching for decoupling transport and
kinetics of biomacromolecules in cellular physiology. Poly mers. (2022) 14:1913. doi:
10.3390/polym14091913
170. Shaya, J, Corridon, PR, al-Omari, B, Aoudi, A, Shunnar, A, Mohideen, MIH, et al.
Design, photophysical properties, and applications of uorene-based uorophores in
two-photon uorescence bioimaging: a review. J Photochem Photobiol C: Photochem Rev.
(2022) 52:100529. doi: 10.1016/j.jphotochemrev.2022.100529
171. Hickson, LJ, Eirin, A, and Lerman, LO. Challenges and opportunities for stem
cell therapy in patients with chronic kidney disease. Kidney Int. (2016) 89:767–78. doi:
10.1016/j.kint.2015.11.023
172. Moore, MAS, Leonard, JP, Flasshove, M, Bertino, J, Gallardo, H, and Sadelain, M.
Gene therapy- the challenge for the future. Ann Oncol. (1996) 7:53–8. doi: 10.1093/
annonc/7.suppl_2.53
173. Oshimura, M, Kazuki, Y, and Uno, N. Challenge toward gene-therapy using iPS
cells for Duchenne muscular dystrophy. Rinsho Shinkeigaku. (2012) 52:1139–42. doi:
10.5692/clinicalneurol.52.1139
174. Sousa, F, Passarinha, L, and Queiroz, JA. Biomedical application of plasmid DNA
in gene therapy: a new challenge for chromatography. Biotechnol Genet Eng Rev. (2010)
26:83–116.
175. Stokman, MF, Renkema, KY, Giles, RH, Schaefer, F, Knoers, NVAM, and van
Eerde, AM. e expanding phenotypic spectra of kidney diseases: insights from genetic
studies. Nat Rev Nephrol. (2016) 12:472–83. doi: 10.1038/nrneph.2016.87
176. Chen, P, Chen, BK, Mosoian, A, Hays, T, Ross, MJ, Klotman, PE, et al. Virological
synapses allow HIV-1 uptake and gene expression in renal tubular epithelial cells. J
AmSoc Nephrol. (2011) 22:496–507. doi: 10.1681/ASN.2010040379
177. Gusella, GL, Fedorova, E, Marras, D, Klotman, PE, and Klotman, ME. In vivo
gene transfer to kidney by lentiviral vector. Ki dney Int. (2002) 61:S32–6. doi: 10.1046/j.
1523-1755.2002.0610s1032.x
178. Deen, WM. What determines glomerular capillary permeability? J Clin Invest.
(2004) 114:1412–4. doi: 10.1172/JCI23577
179. Deen, WM, Lazzara, MJ, and Myers, BD. Structural determinants of glomerular
permeability. Am J Physiol Ren Physiol. (2001) 281:F579–96. doi: 10.1152/
ajprenal.2001.281.4.F579
180. Drumond, MC, and Deen, WM. Structural determinants of glomerular hydraulic
permeability. Am J Phys. (1994) 266:F1–F12. doi: 10.1152/ajprenal.1994.266.1.F1
181. Ishida, R, Kami, D, Kusaba, T, Kirita, Y, Kishida, T, Mazda, O, et al. Kidney-
specic Sonoporation-mediated gene transfer. Mol er. (2016) 24:125–34. doi: 10.1038/
mt.2015.171
182. L i, P, Gao, Y, Zhang, J, Liu, Z, Tan, K, Hua, X, et al. Renal interstitial permeability
changes induced by microbubble-enhanced diagnostic ultrasound. J Drug Target. (2013)
21:507–14. doi: 10.3109/1061186X.2013.776053
183. Reiser, J, Gupta, V, and Kistler, AD. Toward the development of podocyte-specic
drugs. Kidney Int. (2010) 77:662–8. doi: 10.1038/ki.2009.559
184. Appledorn, DM, Seregin, S, and Amaltano, A. Adenovirus vectors for renal-
targeted gene delivery. Contrib Nephrol. (2008) 159:47–62. doi: 10.1159/000125581
185. Ye, X, Jerebtsova, M, Liu, XH, Li, Z, and Ray, PE. Adenovirus-mediated gene
transfer to renal glomeruli in rodents. Kidney Int. (2002) 61:S16–23. doi:
10.1046/j.1523-1755.2002.0610s1016.x

Corridon 10.3389/fmed.2023.1143028
Frontiers in Medicine 11 frontiersin.org
186. Ye, X, Liu, XH, Li, Z, and Ray, PE. Ecient gene transfer to rat renal glomeruli
with recombinant adenoviral vectors. Hum Gene er. (2001) 12:141–8. doi:
10.1089/104303401750061203
187. Imai, E. Gene therapy approach in renal disease in the 21st century. Nephrol
Dial Transplant. (2001) 16:26–34. doi: 10.1093/ndt/16.suppl_5.26
188. Moullier, P, Friedlander, G, Calise, D, Ronco, P, Perricaudet, M, and Ferry, N.
Adenoviral-mediated gene transfer to renal tubular cells invivo. Kidney Int. (1994)
45:1220–5. doi: 10.1038/ki.1994.162
189. Brunetti-Pierri, N, Stapleton, GE, Palmer, DJ, Zuo, Y, Mane, VP, Finegold, MJ,
et al. Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into
non-human primates for liver-directed gene therapy. Mol er. (2007) 15:732–40.
doi: 10.1038/sj.mt.6300102
190. Ashworth, SL, Sandoval, RM, Tanner, GA, and Molitoris, BA. Two-photon
microscopy: visualization of kidney dynamics. Kidney Int. (2007) 72:416–21. doi:
10.1038/sj.ki.5002315
191. Suda, T, and Liu, D. Hydrodynamic gene delivery: its principles and
applications. Mol er. (2007) 15:2063–9. doi: 10.1038/sj.mt.6300314
192. Collett, JA, Corridon, PR, Mehrotra, P, Kolb, AL, Rhodes, GJ, Miller, CA, et al.
Hydrodynamic isotonic uid delivery ameliorates moderate-to-severe ischemia-
reperfusion injury in rat kidneys. J AmSoc Nephrol. (2017) 28:2081–92. doi: 10.1681/
ASN.2016040404
193. Zhang, G, Gao, X, Song, YK, Vollmer, R, Stolz, DB, Gasiorowski, JZ, et al.
Hydroporation as the mechanism of hydrodynamic delivery. Gene er. (2004)
11:675–82. doi: 10.1038/sj.gt.3302210
194. Oyama, N, Kawaguchi, M, Itaka, K, and Kawakami, S. Ecient messenger
RNA delivery to the kidney using renal pelvis injection in mice. Pharmaceutics.
(2021) 13:1810. doi: 10.3390/pharmaceutics13111810
195. Corridon, P. Hydrodynamic delivery of mitochondrial genes invivo protects
against moderate ischemia-reperfusion injury in the rat kidney. FASEB J. (2014) 28.
doi: 10.1096/fasebj.28.1_supplement.690.17
196. Woodard, LE, Cheng, J, Welch, RC, Williams, FM, Luo, W, Gewin, LS, et al.
Kidney-specic transposon-mediated gene transfer invivo. Sci Rep. (2017) 7:44904.
doi: 10.1038/srep44904
197. Corridon, PR. Enhancing the expression of a key mitochondrial enzyme at the
inception of ischemia-reperfusion injury can boost recovery and halt the progression
of acute kidney injury. Front Physiol. (2023). doi: 10.3389/fphys.2023.1024238
198. Imai, E. Gene therapy for the treatment of renal disease: prospects for the future.
Curr Opin Nephrol Hypertens. (1997) 6:496–503. doi: 10.1097/00041552-199709000-00015
199. Bonamassa, B, Hai, L, and Liu, D. Hydrodynamic gene delivery and its
applications in pharmaceutical research. Pharm Res. (2011) 28:694–701. doi: 10.1007/
s11095-010-0338-9
200. Rocca, CJ, Ur, SN, Harrison, F, and Cherqui, S. rAAV9 combined with renal vein
injection is optimal for kidney-targeted gene delivery: conclusion of a comparative study.
Gene er. (2014) 21:618–28. doi: 10.1038/gt.2014.35
201. Zincarelli, C, Soltys, S, Rengo, G, and Rabinowitz, JE. Analysis of AAV serotypes 1-9
mediated gene expression and tropism in mice aer systemic injection. Mol er. (2008)
16:1073–80. doi: 10.1038/mt.2008.76
202. Yao, J, Fan, Y, Li, Y, and Huang, L. Strategies on the nuclear-targeted delivery of
genes. J Drug Target. (2013) 21:926–39. doi: 10.3109/1061186X.2013.830310
203. Lovett, ST. e DNA exonucleases of Escherichia coli. EcoSal Plus. (2011) 4. doi:
10.1128/ecosalplus.4.4.7
204. Dermić, D. Functions of multiple exonucleases are essential for cell viability, DNA
repair and homologous recombination in recD mutants of Escherichia coli. Genetics. (2006)
172:2057–69. doi: 10.1534/genetics.105.052076
205. Villalba, M, Ferrari, D, B ozza, A, del Senno, L, and di Virgilio, F. Ionic regulation of
endonuclease activity in PC12 cells. Biochem J. (1995) 311:1033–8. doi: 10.1042/bj3111033
206. Schwartz, DA, Quinn, TJ, orne, PS, Sayeed, S, Yi, AK, and Krieg, AM. CpG motifs
in bacterial DNA cause inammation in the lower respiratory tract. J Clin Invest. (1997)
100:68–73. doi: 10.1172/JCI119523
207. Frazier, KS. Antisense oligonucleotide therapies: the promise and the challenges
from a toxicologic pathologist's perspective. Toxicol Pathol. (2015) 43:78–89. doi:
10.1177/0192623314551840
208. Tenenbaum, L, Lehtonen, E, and Monahan, PE. Eva luation of risks related to the use
of adeno-associated virus-based vectors. Curr Gene er. (2003) 3:545–65. doi:
10.2174/1566523034578131
209. omas, CE, Ehrhardt, A, and Kay, MA. Progress and problems with the use of viral
vectors for gene therapy. Nat Rev Genet. (2003) 4:346–58. doi: 10.1038/nrg1066
210. Maggio, I, Holkers, M, Liu, J, Janssen, JM, Chen, X, and Gonçalves, MAFV.
Adenoviral vector delivery of RNA-guided CRISPR/Cas9 nuclease complexes induces
targeted mutagenesis in a diverse array of human cells. Sci Rep. (2014) 4:5105. doi: 10.1038/
srep05105
211. Uren, AG, Kool, J, Berns, A, and van Lohuizen, M. Retroviral insertional
mutagenesis: past, present and future. Oncogene. (2005) 24:7656–72. doi: 10.1038/sj.
onc.1209043
212. Li, T, Zhou, ZW, Ju, Z, and Wang, ZQ. DNA damage response in hematopoietic stem
cell ageing. Genomics Prot Bioinfom. (2016) 14:147–54. doi: 10.1016/j.gpb.2016.04.002