Recent advances in gene therapy for neurological disorders: A comprehensive overview

INTRODUCTION

Neurological issues embody a huge spectrum of conditions affecting the imperative and peripheral worried systems, often leading to revolutionary cognitive and motor deficits. These issues, together with Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), multiple sclerosis, and amyotrophic lateral sclerosis (ALS), present a growing global burden due to growing old populations and limited healing alternatives.^[1,2] Most neurodegenerative diseases are driven through complex genetic mutations, protein mis-folding, oxidative stress, and chronic neuro irritation, culminating in synaptic disorder and neuronal loss.^[3] Conventional treatment approaches primarily manage clinical symptoms but demonstrate limited effectiveness in slowing the progression of neurodegenerative diseases. In evaluation, gene therapy introduces the potential to without delay correct or modulates disease causing genetic alterations.^[4] With advances in genome editing and vector layout, both viral vectors including adeno-associated viruses (AAVs) and lentiviruses and non-viral systems have emerged as promising equipment for targeted transport [Figure 1] to neural tissues.^[5,6] This review objective was to explore the evolving landscape of gene therapy in neurodegenerative diseases. It discusses disease particular pathophysiology, healing targets, transport systems, medical trial effects, and the demanding situations worried in translating experimental methods into viable medical treatments.^[7]

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Figure 1:

Direct and indirect method for gene therapy.

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OVERVIEW OF GENE THERAPY APPROACHES

Gene therapy entails the introduction, alteration, or silencing of genetic material to treat or prevent ailment. Inside the context of neurological disorders, it gives the potential to deal with root reasons through targeting particular mutations, regulating gene expression, or restoring useful proteins.^[8] Broadly, gene therapy strategies are categorized into two sorts: Gene substitute and gene silencing. Gene substitute introduces useful copies of faulty or lacking genes, regularly used in monogenic disorders. Gene silencing, through ribonucleic acid interference (RNAi) or antisense oligonucleotides (ASOs), is employed to reduce the expression of poisonous or overactive genes.^[9] The achievement of gene therapy relies on heavily on the capacity to supply healing material throughout the blood-brain barrier (BBB) and into particular neural cellular sorts. Current advancements in delivery vectors and genome enhancing gear inclusive of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 have notably improved the precision and performance of these strategies.^[10]

VIRAL VECTORS IN GENE THERAPY

Viral vectors have emerged as the cornerstone of gene delivery structures due to their high transduction efficiency and capability to integrate or express transgenes in target cells. Among them, AAVs are the most broadly utilized in neurological gene therapy due to their low immunogenicity, sustained gene expression, and capability to cross the BBB.^[11] AAVs have been efficiently implemented in preclinical and medical research for disorders together with spinal muscular atrophy (SMA) and PD.^[12] Lentiviral vectors, derived from human immunodeficiency virus, offer the gain of stable integration into the host genome, making them appropriate for long-term expression in dividing and non-dividing cells.^[13] However, worries regarding insertional mutagenesis and capability oncogenicity require cautious vector engineering and safety checks. Different viral structures encompass adenoviruses and herpes simplex viruses, which offer larger packaging capacities but often trigger more potent immune responses, restricting their medical utility.^[14] Persevered studies focus on enhancing viral capsids to improve tropism, lessen toxicity, and beautify specificity for neural tissues.^[15]

NON-VIRAL DELIVERY SYSTEMS

While viral vectors are powerful, they pose limitations consisting of immunogenicity, restrained cargo potential, and production complexity. As an end result, non-viral transport structures have gained interest as safe and more secure and greater versatile alternatives for gene therapy in neurological problems.^[16] These consist of lipid-based nanoparticles, polymeric carriers, dendrimers, and exosome-based transport systems. Lipid nanoparticles have been considerably explored due to their biocompatibility, ease of customization, and potential to encapsulate nucleic acids such as messenger ribonucleic acids (mRNA), small interfering ribonucleic acids (siRNA), or plasmid deoxyribonucleic acid (DNA).^[17] Their success in mRNA-based COVID-19 vaccines has elevated interest in their use for brain-targeted cures. Modifying surface ligands or using BBB penetrating peptides enhances their transport performance to neural tissues. Polymeric carriers, consisting of polyethyleneimine and poly (lactic-co-glycolic acid), provide benefits in gene loading and sustained release, although toxicity remains a problem at higher molecular weights.^[18] Dendrimers, with their branched structures and tunable surface groups, show promise in targeted brain transport with decreased systemic facet outcomes.^[19] Exosomes naturally going on extracellular vesicles are increasingly explored as gene transport vehicles due to their innate potential to pass the BBB and their minimal immunogenicity.^[20] Engineering these vesicles to carry therapeutic ribonucleic acids (RNAs) or proteins might also pave the way for personalized, cell loose remedies in neurodegenerative diseases [Figure 2].

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Figure 2:

Basic gene therapy.

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GENE EDITING TECHNOLOGIES IN NEUROLOGICAL DISORDERS

Gene modifying has transformed the panorama of molecular medication through enabling particular modification of disease-associated genetic sequences. In neurological problems, where pathogenic mutations often underlie disease development, focused modifying tools provide the capability for long-lasting therapeutic results.^[21] CRISPR/Cas9 is the most broadly studied gene modifying machine due to its programmability and excessive efficiency. It makes use of a guide RNA to direct the Cas9 nuclease to precise DNA sequences, enabling site-specific se double strand breaks and subsequent restore or gene disruption.^[22] CRISPR-based totally processes have been explored in models of Huntington’s disorder, ALS, and Alzheimer’s disorder to silence poisonous genes or correct mutations.^[23] Other gene-modifying structures encompass zinc finger nucleases and transcription activator like effector nucleases, which give excessive specificity but are greater complicated to engineer compared to CRISPR structures.^[24] Recent improvements such as base editors and high editors provide even greater precision through enabling nucleotide conversions without inducing double-strand breaks, lowering the threat of off-target results.^[25] Those tools, while blended with advanced transport structures, hold the promise of growing 1 time remedies for inherited and acquired neurological situations.

EPIGENETIC MECHANISMS AND RNA-BASED THERAPIES

Epigenetic changes play a critical role in regulating gene expression without changing the underlying DNA sequence. In neurological problems, dysregulation of DNA methylation, histone changes, and non-coding RNA expression has been connected to disease onset and development.^[26] These reversible changes offer promising objectives for healing intervention. Long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and ASOs have emerged as powerful tools to modulate gene expression on the transcriptional and put post-transcriptional stages.^[27] ASOs are quick, synthetic strands of nucleotides designed to bind specific RNA transcripts and regulate their feature through degradation or splicing correction. Food and Drug Administration authorized ASO treatment plans, including nusinersen for SMA, have paved the way for similar techniques in neurodegenerative diseases.^[28] MiRNAs adjust a couple of genes concurrently and are concerned in neuronal differentiation, synaptic plasticity, and neuro infection. Healing modulation of miRNA stages either thru mimics or inhibitors has proven promise in preclinical models of AD and PD.^[29] In addition, lncRNAs are gaining interest for his or her roles in chromatin remodeling and transcriptional control, although their healing application remains under investigation. Focused on those epigenetic regulators might also offer novel, final tuned tactics for correcting aberrant gene expression in complicated neurological problems.^[30]

CHALLENGES AND LIMITATIONS IN GENE THERAPY

In spite of its transformative capability, gene therapy in neurological disease faces numerous technical, biological, and moral challenges. Significant obstacles are the BBB, which limits the efficient transport of healing agents to the central nervous system.^[31] While sure viral vectors such as AAV9 and modified non-viral carriers can pass the BBB, achieving regular, focused distribution remains difficult. Immunogenicity is another problem, especially with viral vectors, which may additionally trigger host immune responses that lessen healing efficacy or cause unfavorable results.^[32] Repeat dosing can be complicated using the development of neutralizing antibodies. In addition, off-target results in gene modifying mainly with CRISPR/Cas9 pose dangers of unintended genomic alterations and lengthy term toxicity.^[33] Production complexity, scalability, and regulatory hurdles further complicate clinical translation. Generating excessive purity vectors at scale while retaining consistency and affordability remains a bottleneck, mainly for uncommon or customized neurological disorder.^[34] Furthermore, moral concerns associated with germline modifying, long-term tracking, and equitable access to gene therapies continues to initiate debate.^[35] Addressing these limitations through improved vector engineering, specific targeting techniques, and robust safety critiques is crucial for the successful integration of gene therapy into routine neurological care.

GENE THERAPY IN AD

AD is the most common form of dementia, characterized by modern cognitive decline, synaptic disorder, and neuronal loss. Its pathology is essentially related to the accumulation of amyloid-b (ab) plaques and hyper phosphorylated tau protein, in conjunction with neuroinflammatory responses and oxidative stress.^[36] Gene therapy strategies in AD focus on a couple of molecular targets. One method aims to lessen ab production by down regulating b-secretase or improving the clearance of ab through overexpression of neprilysin and insulin degrading enzyme.^[37] AAV-mediated delivery of those genes has proven efficacy in decreasing plaque burden and enhancing cognition in animal models. Another target is tau pathology, wherein gene silencing techniques such as ASOs or RNAi were used to lessen the expression of tau mRNA.^[38] In addition, gene transfer of neurotrophic elements, along with nerve growth factor or brain-derived neurotrophic component, has verified ability in selling neuronal survival and synaptic plasticity.^[39] Latest improvements also include CRISPR/Cas9 mediated genome editing to accurate presenilin or amyloid precursor protein (APP) mutations in familial ad models.^[40] Regardless of encouraging preclinical information, translating those findings into clinical programs stays challenging due to delivery issues, off target outcomes, and the complex, multifactorial nature of sporadic AD.

GENE THERAPY IN PD

PD is a progressive neurodegenerative disease normally affecting dopaminergic neurons within the substantia nigra, leading to motor symptoms along with tremor, bradykinesia, and stress. The pathogenesis includes a-synuclein aggregation, mitochondrial disorder, and impaired dopamine synthesis.^[41] Gene therapy for PD targets to restore dopamine levels, defend dopaminergic neurons, or regulate disease development. One nicely studied strategy includes the AAV-mediated delivery of the fragrant L-amino acid decarboxylase (AADC) gene, which complements dopamine synthesis through enhancing the conversion of levodopa to dopamine within the striatum.^[42] Clinical trials have proven motor improvements and decreased medicinal drug dependency in patients receiving AADC gene therapy. Another approach targets neuroprotection through the delivery of genes encoding neurotrophic factor, such as glial cell line-derived neurotrophic factor or neurturin, which sell the survival and function of dopaminergic neurons.^[43] While early trials tested safety, efficacy consequences had been combined due to challenges in accomplishing sufficient gene expression in target areas. Rising strategies include RNAi to lessen a-synuclein expression and CRISPR/Cas9-based editing of PD-associated mutations along with leucine rich repeat kinase 2 (LRRK2) and synuclein alpha (SNCA).^[44,45] Those tactics show promise in preclinical models but require further refinement earlier than clinical software. “Numerous ongoing clinical trials are exploring the use of gene therapy for AD, targeting APP and presenilin 1 (PSEN1) mutations [Table 1].”

GENE THERAPY IN HD

HD is an autosomal dominant neurodegenerative disease as a result of an improved cytosine-adenine-guanine (CAG) (trinucleotide repeat) in the huntingtin (HTT) gene, main to the manufacturing of a toxic mutant HTT (mHTT) protein. Clinically, HD is marked through innovative motor dysfunction, psychiatric disturbances, and cognitive decline.^[46] Gene therapy in HD primarily focuses on silencing or reducing the expression of the mutant HTT gene. One widely studied method includes the usage of RNAi strategies, consisting of siRNAs and quick hairpin RNAs, to selectively degrade HTT mRNA.^[47] ASOs focused on HTT have additionally improved to scientific trials, with some applicants demonstrating reductions in mHTT protein degrees in cerebrospinal fluid.^[48] AAV-based gene delivery structures had been used to deliver gene silencing tools directly into the striatum, displaying reduced mHTT degrees and progressed behavioral consequences in animal models.^[49] More currently, CRISPR/Cas9 era has been implemented to excise or disrupt the improved CAG repeats in the HTT gene, presenting a potential 1-time therapeutic strategy.^[50] Despite those advances, demanding situations remain in reaching allele specificity, minimizing off-target results, and ensuring long-term protection and efficacy particularly for therapies requiring irreversible gene adjustments.

GENE THERAPY IN ALS

ALS is a fatal neurodegenerative disease characterized through the modern loss of upper and lower motor neurons, leading to muscle weakness, paralysis, and respiratory failure. Although most of the people of ALS cases are sporadic, about 10% are familiar, often regarding mutations in genes which include superoxide dismutase 1 (SOD1), C9orf72, fused in sarcoma (FUS), and TARDBP.^[51] Gene therapy approaches in ALS purpose to target those genetic mutations and mitigates downstream poisonous results. One of the maximum superior techniques entails ASOs designed to reduce mutant SOD1 mRNA. Tofersen, an ASO targeting SOD1, has demonstrated reduced protein levels and slowed disease progression in early medical trials.^[52] For C9orf72-related ALS, that is related to hexanucleotide repeat expansions, gene silencing the usage of RNAi or ASOs is under investigation research to lower the manufacturing of poisonous RNA foci and dipeptide repeat proteins.^[53] Similarly, CRISPR/Cas9-based gene enhancing has shown promise in correcting or disrupting pathogenic sequences in preclinical models.^[54]

Demanding situations in ALS gene therapy include the fast disease progression, heterogeneous genetic background, and the need for vast delivery to both spinal cord and cortical motor neurons. Nonetheless, advancements in vector design and delivery techniques continue to improve therapeutic potential.^[55]

GENE THERAPY IN SMA

SMA is a genetic neuromuscular disease due to mutations or deletions within the survival motor neuron (SMN1) gene, leading to a deficiency of SMN protein. This results in progressive degeneration of motor neurons within the spinal cord and muscular atrophy, particularly in infants and young children.^[56] Gene therapy for SMA has made exquisite scientific progress. The maximum prominent breakthrough is onasemnogene abeparvovec (Zolgensma^®), an AAV9-based totally gene therapy that can provide a practical replica of the SMN1 gene. This single-dose intravenous treatment has tested sizable improvements in motor feature and survival in toddlers with SMA Type 1.^[57] Every other essential therapeutic strategy entails ASOs along with nusinersen (Spinraza^®), which modulate the splicing of the SMN2 gene to growth production of practical SMN protein.^[58] Not like Zolgensma, that’s a 1-time therapy, Spinraza calls for repeated intrathecal management. Moreover, small molecule splicing modulators like risdiplam were evolved as oral alternatives, further diversifying the treatment landscape.^[59] The success of SMA treatment options has not handiest advanced results for affected patients but additionally set up a foundation for similar approaches in different monogenic neurological problems.^[60]

GENE THERAPY IN LYSOSOMAL STORAGE DISORDERS (LSDS)

LSDs constitute a group of uncommon inherited metabolic situations as a result of mutations in genes encoding lysosomal enzymes or delivery proteins. These mutations result in the accumulation of under graded substrates, leading to cellular disorder and, in many cases, progressive neurodegeneration.^[61] Examples of neuronopathic LSDs consist of Tay Sachs disorder, Gaucher disorder type2, and metachromatic leukodystrophy. Gene therapy in LSDs primarily ambitions was to repair purposeful enzyme hobby in affected tissues, particularly the central frightened gadget (CNS). AAV-based vectors have proven achievement in delivering corrective genes to the brain, either through intrathecal or intracerebroventricular routes, to bypass the BBB and reach neuronal targets.^[62] In metachromatic leukodystrophy, lentiviral mediated hematopoietic stem cell gene therapy (consisting of Libmeldy^®) has established long-term clinical benefits by enabling permitting sustained enzyme expression from genetically modified autologous cells.^[63] Similar strategies are being evaluated for Krabbe disorder and mucopolysaccharidoses, in which CNS manifestations are extreme and poorly addressed using traditional enzyme replacement therapy.^[64] Demanding situations continue to be in accomplishing large brain distribution, controlling immune responses to the added enzymes, and addressing the high cost of gene treatment options. Despite the fact that, early clinical successes sign a transformative era for treating LSDs with neurological involvement.^[65]

DISCUSSION

The application of gene therapy in neurological disorder has advanced significantly over the past decade, transferring from theoretical models to clinical translation. This progress has been driven by improved understanding of disease genetics, improvements in vector design, and the improvement of extra specific genome editing tools which include CRISPR/Cas9. A note able trend is the diversification of therapeutic strategies from gene replacement and silencing to RNA modulation and epigenetic regulation every tailor made to unique disease mechanisms and genetic profiles.^[66] Monogenic disorder such as SMA and certain lysosomal storage diseases have seen the earliest successes, in large part due to their properly described genetic reasons and the ability to interfere early in disease development. In comparison, complex polygenic disorder which includes AD and PD poses more demanding situations due to their multifactorial nature, incomplete pathophysiological expertise, and the need for big CNS delivery.^[67] Notwithstanding encouraging effects in animal models and early phase trials, numerous limitations preclude broader clinical implementation. These include immunogenicity of viral vectors, difficulty crossing the BBB, limited transduction performance, and ability long-term safety issues which include insertional mutagenesis or off target consequences.^[68] Moreover, moral and regulatory concerns surrounding genome editing in particular inside the human germline should be carefully addressed.^[69] Transferring ahead, combining gene therapy with different rising modalities such as nanomedicine, synthetic intelligence guided focused on, and patient unique triggered pluripotent stem cells can also provide synergistic advantages. As transport structures and safety profiles keep improving, gene therapy holds the potential to become a standard aspect of precision medication for neurological diseases.^[70] “Recent improvements have led to a surge in patents associated with gene editing technologies in neurodegeneration [Table 2], indicating substantial commercial and therapeutic interest.”

CONCLUSION

Gene therapy has emerged as a transformative approach in the therapy of neurological disorders, imparting the potential for disease modification and, in a few cases, long-term remission. Advances in vector technology, genome editing tools, and RNA-based totally therapeutics have enabled the development of targeted interventions tailored to the genetic and molecular profiles of diverse situations. Successes in disorders such as SMA and metachromatic leukodystrophy have proven the feasibility and scientific effect of these healing procedures. However, the translation of gene therapy into great scientific use remains constrained through enormous demanding situations. These include technical boundaries in delivery across the BBB, vector immunogenicity, protection issues with gene editing, and variability in therapy response. In addition, ethical, regulatory, and financial issues should be addressed to make certain equitable access and long-term monitoring of gene therapy recipients. Regardless of these hurdles, ongoing studies and innovation maintain to refine healing strategies and amplify their applicability. As our understanding of neurogenetics deepens and technology mature, gene therapy is poised to come to be a fundamental thing of personalized therapy for neurological diseases shifting the paradigm from symptom management to actual disease modification and, potentially, cure.