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Diagram depicts the HTT gene domains in the DNA segment (CAG trinucleotide repeat) and its prevalence in adult and juvenile stages. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
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Neurological and neuropsychiatric disorders are the main risks for the health care system, exhibiting a huge socioeconomic load. The available range of pharmacotherapeutics mostly provides palliative consequences and fails to treat such conditions. The molecular etiology ofvarious neurological and neuropsychiatric disorders is mostly associated wit...
Context in source publication
Context 1
... are most likely to develop the disorder, almost always, with patients having up to 120 CAG repeats. Moreover, with the passage of altered HTT gene from one generation to the next, there is an increase in the size of the CAG repeat. Since CAG is a codon for glutamine, the mutation results in an abnormal expansion of the polyglutamine tract in HD (Fig. ...
Citations
... However, AAVs have size limitations. 247, 251 Dual AAVs have been explored to deliver Cas-9 encoding DNA and sgRNA separately to address the issue. 247,252,253 Lentivirusmediated CRISPR/Cas9 offers high infection efficiency even in non-dividing cells, 254,255 making it ideal for gene modification in tissues such as the liver and brain. ...
The genome editing technology based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 (CRISPR/Cas9), is revolutionizing research, particularly in the context of human neurodegenerative disorders. This review examines recent advancements in CRISPR/Cas9 and its potential to address the protein misfolding mechanisms underlying these diseases. Proteins, the fundamental units of life, can misfold due to various changes, resulting in aggregation and contributing to devastating illnesses such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. Understanding the pathology of these disorders and the methods used for their detection is vital for developing effective treatments. CRISPR/Cas9 offers a powerful tool for combating neurodegenerative disorders at the molecular level. Its groundbreaking gene-editing capabilities are advancing preclinical and animal studies, paving the way for potential human trials and innovative therapeutic strategies. This review explores the complex challenge of protein misfolding and highlights how CRISPR technology could provide a crucial breakthrough in the fight against neurodegenerative disorders. It offers a synthesis of CRISPR advancements for neurodegenerative disorders. However, it is essential to be aware of the review’s limitations, including potential selection bias, the risk of oversimplification, and possible obsolescence in rapidly changing research fields. Despite these considerations, the transformative promise of CRISPR in understanding and potentially treating neurodegenerative diseases warrants continued research and thorough analysis.
... 1. Delivery methods: Ensuring the ef icient and targeted delivery of therapeutic genes to the relevant cells or tissues without causing off-target effects or triggering immune responses is a signi icant challenge [52]. ...
... Overcoming safety concerns, such as the risk of immunogenic reactions, off-target effects, and the potential for long-term adverse events. Additionally, ensuring sustained and effective expression of the therapeutic gene poses a critical challenge [52,53]. ...
... 6. Biomarker development: Developing effective biomarkers to assess the effectiveness of gene therapy and monitor long-term outcomes is an essential aspect of addressing challenges in this ield [52]. Addressing these challenges is vital for the successful development and widespread application of gene therapy for genetic disorders. ...
Neurodegenerative disorders (NDDs) pose a significant global health challenge, impacting millions with a gradual decline in neurons and cognitive abilities. Presently, available NDD therapies focus on symptom management rather than altering the disease trajectory. This underscores the critical necessity for groundbreaking treatments capable of addressing the root causes of neurodegeneration, offering both neuroprotection and neuro-restoration. This in-depth review delves into the forefront of emerging NDD therapies, encompassing gene therapy, stem cell therapy, immunotherapy, and neurotrophic factors. It sheds light on their potential advantages, hurdles, and recent advancements gleaned from both preclinical and clinical studies. Additionally, the document outlines existing NDD treatments, spanning pharmacological and non-pharmacological interventions, along with their inherent limitations. The overarching conclusion emphasizes the immense potential of emerging therapies in NDD treatment, yet underscores the imperative for continued research and optimization to ensure their safety, efficacy, and specificity.
... One of the emerging approaches in treating genetic disorders involves gene editing [100][101][102]. This technique uses a biological system, such as CRISPR/Cas9, to precisely excise a specific gene segment and employ a biological vector to insert a desired sequence [103][104][105][106]. These treatments are ideal, as they are permanent, unlike the multimodal management that is currently being utilized [107]. ...
Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Recent research has increasingly focused on the genetic underpinnings of ASD, with the Neurexin 1 (NRXN1) gene emerging as a key player. This comprehensive systematic review elucidates the contribution of NRXN1 gene variants in the pathophysiology of ASD. Methods: The protocol for this systematic review was designed a priori and was registered in the PROSPERO database (CRD42023450418). A risk of bias analysis was conducted using the Joanna Briggs Institute (JBI) critical appraisal tool. We examined various studies that link NRXN1 gene disruptions with ASD, discussing both the genotypic variability and the resulting phenotypic expressions. Results: Within this review, there was marked heterogeneity observed in ASD genotypic and phenotypic manifestations among individuals with NRXN1 mutations. The presence of NRXN1 mutations in this population emphasizes the gene’s role in synaptic function and neural connectivity. Conclusion: This review not only highlights the role of NRXN1 in the pathophysiology of ASD but also highlights the need for further research to unravel the complex genetic underpinnings of the disorder. A better knowledge about the multifaceted role of NRXN1 in ASD can provide crucial insights into the neurobiological foundations of autism and pave the way for novel therapeutic strategies.
... Although transgenic technology may introduce many genes and their regulatory components, gene editing enables more precise and focused modifications to be applied to certain genes or Genomic regions. Precision: Compared to transgenic technologies, gene editing is typically thought to be more accurate (Mani et al., 2023). The transgenic technique involves adding new genes into the genome at random sites, whereas gene editing methods like CRISPR-Cas9 may target particular genes or regions within the genome with great accuracy (Wang et al., 2022). ...
The increasing world population has created an alarming situation to meet the demand for food. Ultimately wheat yield is
required to be increased proportionally to the world’s population. An estimated increase of 05 tonnes per hectare is direly
needed from the current production of 3.3 tonnes by the end of 2050. To achieve this goal it is required to adopt new, emerging,
and efficient breeding techniques which caused a recent breakthrough in wheat genome sequencing and provided sufficient
information for the traits which are directly related to quality and yield of crops. This review provides a comprehensive
overview of tools and techniques which are widely used for discovering the functionality of genes that results in specific
phenotypes of Wheat. It gives a deep historical account of the development of wheat transformation techniques and provides
an idea about in which way these techniques have been adapted to produce gain-of-function phenotypes through gene
overexpression, loss-of-function phenotypes through the expression of antisense RNAs (RNA interference or RNAi). Recently,
gene structure and expression manipulation using site-specific nucleases such as CRISPR/Cas9 for genome editing. The review
summarizes recent successes in the application of wheat genetic manipulation to enhance yield, improve wheat's nutritional
and health-promoting qualities, and boost the crop's resistance to various biotic and abiotic stresses
... Physical methods of gene delivery such as microinjection, electroporation, needle injection, and gene gun, which are highly efficient in transferring genes through the passage of extracellular and intracellular barriers, have limited use due to low cell viability and the cell senescence risk (Anguela and High 2019). Therefore, there has always been an attempt to find new non-viral strategies based on natural and synthetic substances to replace them (Anguela and High 2019;Mani et al. 2023). Nonviral nucleic acid vectors which have been frequently investigated in recent years are lipid/polymeric-based systems and inorganic materials-based systems (Dunbar et al. 2018). ...
... It has been a long time since polymeric materials act as a strong driving force in various industries (Chen et al. 2020). The outstanding and flexible mechanical properties of polymer materials have led to their wide use in the design and manufacture of biomedical products in various fields such as artificial organs, implants, dental materials, and drug delivery (Mani et al. 2023). ...
... Although PEIs have unique properties as gene carriers, in many cases, their engineering and modifying are necessary to provide desired properties such as biodegradability and biocompatibility (Cho et al. 2022). Because their molecular weight is directly related to toxicity, some PEIs derivatives with lower molecular weight have been reported to reduce the toxicity profile, but in most cases, these have also limited transfection efficiency (Mani et al. 2023). So, such applied strategies that may affect the crucial factors involved in gene delivery, such as binding capability toward DNA, uptake, and endosomal escape, should be balanced between transfection efficacy and eliminate their undesirable features (Yang et al. 2022a). ...
A new era of medical technology in cancer treatment is a directly specific modification of gene expression in tumor cells by nucleic acid delivery. Currently, the main challenge to achieving this goal is to find a non-toxic, safe, and effective strategy for gene transfer to cancer cells. Synthetic composites based on cationic polymers have historically been favored in bioengineering due to their ability to mimic bimolecular structures. Among them, polyethylenimines (PEIs) with superior properties such as a wide range of molecular weight and a flexible structure may propel the development of functional combinations in the biomedical and biomaterial fields. Here, in this review, we will focus on the recent progressions in the formulation optimization of PEI-based polyplex in gene delivery to treat cancer. Also, the effect of PEI's intrinsic characteristics such as structure, molecular weight, and positive charges which influence the gene delivery efficiency will be discussed.
... The cure for AD is still a challenge though there are many promising approaches with phytomedicines and gene therapy that have been developed, they are yet under exploration for targeting the wholistic AD pathological sites [5,6]. ...
Background:
Alzheimer's disease (AD) is the most common type of neurodegenerative dementia affecting people in their later years of life. The AD prevalence rate has significantly increased due to a lack of early detection technology and low therapeutic efficacy. Despite recent scientific advances, some aspects of AD pathological targets still require special attention. Certain traditionally consumed phytocompounds have been used for thousands of years to treat such pathologies. The standard extract of Gingko biloba (EGB761) is a combination of 13 macro phyto-compounds and various other micro phytocompounds that have shown greater therapeutic potential against the pathology of AD.
Objective:
Strong physiological evidence of cognitive health preservation has been observed in elderly people who keep an active lifestyle. According to some theories, consuming certain medicinal extracts helps build cognitive reserve. We outline the research employing EGB761 as a dual target for AD.
Methods:
This study investigates various inhibitory targets against AD using computational approaches such as molecular docking, network pharmacology, ADMET (full form), and bioactivity prediction of the selected compounds.
Results:
After interaction studies were done for all the phytoconstituents of EGB761, it was concluded that all four of the phytocompounds (kaempferol, isorhamnetin, quercetin, and ginkgotoxin) showed the maximum inhibitory activity against acetylcholinesterase (AChE) and GSK3β.
Conclusion:
The highly active phytocompounds of EGB761, especially quercetin, kaempferol, and isorhamnetin, have better activity against AChE and GSK3β than its reported synthetic drug, according to molecular docking and network pharmacology research. These compounds may act on multiple targets in the protein network of AD. The AChE theory was primarily responsible for EGB761's therapeutic efficacy in treating AD.
... The gene-editing approach in the gene therapy category has proved to be more promising than the other subsets. This approach can be utilized for various purposes such as gene regulation/repair, total dormancy of toxic genes, etc., though its onsite efficacy and site-specific deliveries are unsolved queries to date leading to its deferred clinical application [109]. In traditional approaches, the defective genes were reinstated with the rectified ones through the various vector types and induced the new gene sets inside the cells to elicit the production of appropriate functional proteins as mentioned in Table 1 [110]. ...
The vast use of corticosteroids (CCSs) globally has led to an increase in CCS-induced neuropsychiatric disorders (NPDs), a very common manifestation in patients after CCS consumption. These neuropsychiatric disorders range from depression, insomnia, and bipolar disorders to panic attacks, overt psychosis, and many other cognitive changes in such subjects. Though their therapeutic importance in treating and improving many clinical symptoms overrides the complications that arise after their consumption, still, there has been an alarming rise in NPD cases in recent years, and they are seen as the greatest public health challenge globally; therefore, these potential side effects cannot be ignored. It has also been observed that many of the neuronal functional activities are regulated and controlled by genomic variants with epigenetic factors (DNA methylation, non-coding RNA, and histone modeling, etc.), and any alterations in these regulatory mechanisms affect normal cerebral development and functioning. This study explores a general overview of emerging concerns of CCS-induced NPDs, the effective molecular biology approaches that can revitalize NPD therapy in an extremely specialized, reliable, and effective manner, and the possible gene-editing-based therapeutic strategies to either prevent or cure NPDs in the future.
Neurodegenerative diseases such as Alzheimer's disease (AD) are still an important issue for scientists because it is difficult to cure with the available molecular medications and conventional treatments. Due to the complex nature of the brain structures and heterogeneous morphological and physiological properties of neuronal cells, interventions for cerebral-related disorders using surgical approaches, and classical and ongoing treatments remain hard for physicians. Furthermore, the development of newly designed medications attempts to target AD are not successful in improving AD, because abnormalities of tau protein, aggregation of amyloid β (Aβ) peptide, inflammatory responses, etc lead to advanced neurodegeneration processes that conventional treatments cannot stop them. In recent years, novel diagnostic strategies and therapeutic approaches have been developed to identify and cure early pathological events of AD. Accordingly, many gene-based therapies have been developed and introduce the therapeutic potential to prevent and cure AD. On the other hand, genetic investigations and postmortem assessments have detected a large number of factors associated with AD pathology. Also, genetically diverse animal models of AD help us to detect and prioritize novel resilience mechanisms. Hence, gene therapy can be considered an effective and powerful tool to identify and treat human diseases. Ultimately, gene study and gene-based therapy with a critical role in the detection and cure of various human disorders will have a fundamental role in our lives forever. This scientific review paper discusses the present status of different therapeutic strategies, particularly gene-based therapy in treating AD, along with its challenges.
Delivery of genetic material to cells is an integral tool to analyze and reveal the genetic interventions in normal cellular processes and differentiation, disease development and for gene therapy. It has profound applications in pharmaceutical, agricultural, environmental and biotechnological sectors. The major methods relied for gene delivery or transfection requires either viral vectors or xenogenic carrier molecules, which renders probabilistic carcinogenic, immunogenic and toxic effects. A newly evolved physical method, Cold atmospheric plasma induced transfection neither needs vector nor carriers. The 4th state of matter 'Plasma' is a quasineutral ionized gas-containing ions, neutral atoms, electrons and reactive radical molecules; and possess electric and magnetic field, along with emanating photons and UV radiations. Plasma produced at atmospheric pressure conditions, and having room temperature is conferred as Low temperature plasma or Cold atmospheric plasma. Selective and controlled application of cold atmospheric plasma on tissues creates temporary, restorable pores on cell membranes that could be diligently manipulated for gene delivery. Research in this regard attained pace since 2016. Cold atmospheric plasma induces transfection by lipid peroxidation, electroporation, and clathrin dependent endocytosis in cell membranes, by virtue of its reactive radicals and electric field. Plasma formed reactive radicals, especially 'OH' penetrates to the cell membrane and cleaves the phosphate head group of membrane lipids, peroxidize and detaches fatty acid tails. This decreases membrane thickness, increases membrane fluidity and permeability. Simultaneously plasma formed ions, electrons and reactive radicals accumulate over cells, generating local electric field and neutralize the negative charge of cell membrane. This induces stress on cell membrane and disrupts its structural integrity, by infringing the dynamic equilibrium between surface tension, spatial repulsion and linear tension between the head groups of phospholipids, generating minute pores. Neutralization of membrane charge promote foreign, external plasmid and gene movement towards cells and its enhanced binding with ligands and receptors on cell membrane, instigating clathrin dependent endocytosis. In vitro and in vivo studies have successfully delivered plasmids, linear DNA, siRNA and miRNA to several established cell lines like, HeLa, PC12, CHL, HUVEC, Jurkat, MCF, SH-SY5Y, HT, B16F10, HaCaT, LP-1, etc., and live C57BL/6 and BALB/c mice, using cold atmospheric plasma. This review delineates the cell surface mechanism of plasma-induced transfection, critically summarizes the research progress in this context, plasma devices used, and the inimitable features of this method. Metabolic activity, cell function, and viability are not adversely affected by this process; moreover, the cell permeating plasma-formed reactive radicals are effectively defended by cellular antioxidant mechanisms like superoxide dismutase, glutathione reductase and cytokines, alleviating its toxicity. A deeper understanding on mechanism of plasma action on cells, its aftermath, and the research status in this field would provide a better insight on future avenues of research.
As a result of the catastrophic rise in the incidence and transmission of neurodegenerative disorders (CNS), around 24.3% of the world's population was predicted to have Alzheimer's disease (AD), or Parkinson's disease (PD) in 2015. A wide range of drugs have been created over the last three to four decades to address different neurological conditions. Many of the drugs listed for treating cerebral diseases cannot reach the brain because of the blood–brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB), which are biological barriers to the brain. As a result, their effectiveness in treating cerebral disorders is reduced. Phytopharmaceuticals are generally preferred over chemically generated medicines because to their slightly greater patient compliance and lower negative effects. However, special administration techniques that have the ability to drastically change the ADME properties of these potential drugs are required for them to reach their maximum therapeutic index. The intranasal medication delivery channel via an olfactory neural pathway has successfully demonstrated the high efficacy and minimal side effects of the direct targeting technique for the delivery of drugs in the brain in neurological disorders. There are numerous natural compounds that have been studied for the treatment of neuronal disorders and their effective delivery to the targeted site of the brain, including crude extracts of Curcuma longa, Centella Asiatica, Gingko Biloba, Theobroma cacao, Withania somnifera, Bacopa monnieri, etc. and pure substances like—Bilobalide, Quercetin, (-)-Epigal. In comparison to their conventional forms, the therapeutic efficacy, stability, and release kinetics of these extracts/phytocompounds’ nanoformulations are produced and evaluated. And in mouse models of AD produced by commercial medicines, the results of these nanoformulations showed considerably greater neuroprotective efficacy. This shows that the formulations based on natural compounds have the potential to improve the pathological condition of AD and may be pursued as a prospective candidate for clinical research to determine its effectiveness in humans.KeywordsNanomedicineNovel drug delivery systemsOlfactory pathwaysTherapeutic indexBlood–brain barrier (BBB)Blood-cerebrospinal fluid barrier (BCSFB)
