NANOMEDICINE FOR HUNTINGTON’S DISEASE: A REVIEW OF CURRENT STRATEGIES, CHALLENGES, AND FUTURE DIRECTIONS

NANOMEDICINE FOR HUNTINGTON’S DISEASE: A REVIEW OF CURRENT STRATEGIES, CHALLENGES, AND FUTURE DIRECTIONS

M. V. Neethu *, Shubham Sharma, Neha Narwal, Sapna Kumari and V. M. Anjumol

Mets College of Pharmaceutical Sciences & Research, Kuruvilassery P.O, Mala, Thrissur, Kerala, India.

ABSTRACT: Mutations in the HTT gene cause Huntington's disease (HD), a hereditary neurological disorder. These mutations lead to the accumulation of the mutant huntingtin protein, which results in neuronal dysfunction and progressively worsening mental, cognitive, and physical symptoms. In Western populations, the prevalence of HD ranges from 10.6 to 13.7 cases per 100,000. Huntington's disease does not yet have a cure; the main treatments for its symptoms are cognitive and psychiatric issues, chorea, psychosis, and dystonia. Among the therapeutic issues that need to be addressed are poor drug distribution across the blood-brain barrier (BBB) and off-target effects caused by the BBB's restricted permeability. Nanotechnology provides novel methods and insights that can improve therapy effectiveness, neuroprotection, and customized drug delivery. This review article discusses Huntington's disease's aetiology, epidemiology, pathophysiology, symptoms, current treatments, nanotherapy, and ongoing clinical studies. Despite numerous challenges, this review highlights the advancements in nanotechnology for HD therapy, the possibility of overcoming present barriers, improving patient outcomes, and the need for additional research to fully understand long-term health effects.

Keywords: Huntington’s disease, Neurodegenerative disorder, Drug delivery, Barrier, Nanotechnology, Neuroprotection

INTRODUCTION: In contrast to the focused neuronal damage brought on by metabolic or chemical insults, neurodegenerative illnesses are characterized by the gradual degeneration of particular groups of susceptible neurons. The presence of proteins with aberrant conformations is a crucial feature of these diseases ¹.

Neurodegenerative diseases pose a serious threat to future generations and are a major worldwide health problem because of their genetic inheritance patterns. These neurodegenerative disorders include amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) ².

Huntington's disease is caused by a mutation in the HTT gene and is inherited autosomally dominantly. Patients and their families are profoundly impacted by this serious neurological condition. It usually first appears in early or mid-adulthood and gets worse with time. A variety of symptoms, such as behavioural abnormalities, cognitive decline, and motor dysfunction, are indicative of HD. An enlarged CAG trinucleotide sequence in the huntingtin protein-encoding HTT gene is the primary cause. This expansion causes the protein's polyglutamine tracts to become abnormally lengthy in afflicted individuals. These structural changes weaken the stability of proteins and increase their propensity to misfold and break down, which ultimately results in neuronal death and functional degradation ^2-4.

Nanotechnology is enabling a breakthrough in the treatment of neurodegenerative illnesses. Small size, increased surface area, improved BBB penetration, and well-defined particle size and shape are characteristics that set nanoparticles apart. Immunomodulation, autophagy induction, Huntington gene (HTT) suppression, HTT protein modification or inactivation, and N-methyl-d-aspartate (NMDA) extra synaptic receptor inhibition are among the nanoparticle-based treatments for HD ⁵. Nanotherapeutics have the potential to treat HD because of their capacity to precisely target and distribute therapeutic compounds. Nanocarriers can transport therapeutic payloads directly to the affected regions of the HD brain by successfully bridging the blood-brain barrier. With the aid of nanotherapeutics, diagnostics drug research may transition from conventional to personalised treatment ⁶.

Epidemiology: The prevalence of Huntington’s disease (HD) ranges between 10.6 and 13.7 cases per 100,000 individuals in Western countries ⁷. One study reported that 3,763 individuals carry a 25% or 50% risk of developing HD, and 631 individuals have already been diagnosed. Based on this data, there could currently be around 4,700 individuals living with HD in Canada, with another 14,000 people at 50% risk. In the United States, the estimates suggest up to 43,000 diagnosed cases and approximately 123,000 individuals at 50% risk. This marks the first comprehensive study on HD epidemiology in Canada in over 30 years. Typically, HD results in death within 15–20 years after symptom onset ^{8, 9}.

There is more than a tenfold regional variance in the global prevalence of HD. Even while Asian populations have a noticeably lower frequency, inconsistent case identification or diagnostic criteria may account for some of the difference. The prevalence of HD, a neurodegenerative disease that is extremely incapacitating, is roughly 0.40 per 100,000 in Asia as opposed to 5.70 per 100,000 in North America, Europe, and Australia. Regional variations in the occurrence of this inherited illness are largely due to variances in genetic haplotypes ⁹.

Causes: Using brain slices taken from people with different stages of Huntington's disease, researchers found an unexpected trend: as the disease progressed, the number of brain cells decreased exponentially, perhaps due to hereditary variables associated with neurodegeneration. The huntingtin (Htt) protein has an abnormally expanded polyglutamine (polyQ) tract as a result of the underlying genetic mutation that causes HD. The mutant Htt acquires toxic characteristics from this enlarged polyQ stretch, which aids in the advancement of neurodegeneration ⁹. The mutant huntingtin protein (mHTT) misfolds in HD patients because of its extended polyglutamine sequence. This causes soluble HTT monomers to transform into oligomeric forms. The nucleus and cytoplasm also contain these oligomers, which serve as starting locations for the development of mHTT fibrils and bigger aggregates ⁸. Neurodegeneration has been seen in animal models that express untranslated CAG-repeat RNA, and extensive research has shown that mHTT is toxic ^10-17. This suggests that mHTT RNA itself may have a pathogenic role ¹².

Every single incidence of HD is caused by a genetic mutation that causes the HTT protein to abnormally expand a polyQ region. This enlargement gives HTT neurotoxic properties and raises the probability of HTT aggregation within cells ^{18, 19}. In addition, a variety of motor symptoms including chorea, myoclonus, stiffness, tremors, and dystonia have been documented in individuals with the C9orf72 expansion ¹⁹. It is also common to associate HD etiology with the C9ORF72 gene's hexanucleotide repeat expansion ^19-24. It is well-known that oxidative stress and mitochondrial dysfunction play a crucial role in neuronal damage in Huntington's disease. Oxidative DNA damage and genomic instability at the huntingtin gene locus induce somatic CAG repeat expansion, one of the key drivers to HD development ²⁵.

Pathogenesis: There are a number of pathways by which a huntingtin gene mutation causes neuronal malfunction and eventual death. Disruption of cellular homeostasis, neural transport, gene transcription, protein synthesis, mitochondrial integrity, and synaptic function are among the immediate impacts of the mutant huntingtin (mHTT) fragment at locus one, along with its potential to form hazardous aggregates ^26-28. Autophagy eliminates damaged organelles and protein aggregates, while the ubiquitin-proteasome pathway eliminates faulty proteins. These two systems are the main means by which cells breakdown proteins. Multiple biological systems may be affected by Huntington's disease (HD), according to research in both animal models and human tissues ^28-34.

Both transcript variants encode the identical HTT protein; however, they differ in their 3′ untranslated regions (UTRs) by approximately 3 kb, resulting from alternative splicing of the HTT gene. The longer variation is mostly found in the brain, while the shorter transcript is expressed more widely. Postmortem HD brain samples and HD mice models have both shown the presence of truncated exon 1 transcripts, with the greatest expression detected in tissues with substantial CAG repeat expansions ^35-37. The nuclear pore complex (NPC) is a trio of nucleoporins (NUPs) that traverse the nuclear envelope and are essential for the transport of proteins and RNA from the nucleus to the cytoplasm. A major component of NPCs, NUP62, is mutated recessively in infants, leading to bilateral striatal necrosis. This suggests that malfunction of NPCs may contribute to the tissue-specific vulnerability observed in HD ^{38, 39}. In a mouse model of demyelination, the nuclear export inhibitor KPT-350 showed protective effects, and in a fruit fly model with 30 GGGGCC repetitions in C9orf72, a similar chemical likewise decreased neuronal damage ^39-44.

The expansion of polyglutamine (polyQ) is involved in a wide variety of illnesses, however it is most commonly linked to a hazardous gain-of-function mechanism in neurological disorders. A subtype of spinocerebellar ataxia (SCA) has recently been discovered and is one of eight such variants. Another variant is associated with an expansion of CAG repeats in the THAP11 gene. Atrophy of the spinal cord and bulbar muscles, dentatorubral-pallidoluysian atrophy (DRPLA), and Huntington disease type 2 are further disorders linked to polyQ ^45-47. Alterations in HTT gene function are associated with pathological abnormalities in the cortex and striatum. The striatum has no capacity to produce its own brain-derived neurotrophic factor (BDNF) and must rely on its supply from the cortex for its survival. For BDNF synthesis and transport from the cortex to the striatum, the HTT protein is critical ^48-51.

Transcriptional Dysregulation: A major factor in the development of Huntington's disease (HD) is deregulation of transcription. Important transcriptional regulators, such as p53, CREB-binding protein (CBP), and the cAMP response element-binding (CREB) protein, are disrupted by the mutant huntingtin protein (htt) ^52-58. On the other hand, wild-type htt helps regulate genes by bringing NRSE-binding transcription factors from the cytoplasm into the nucleus. The expression of genes containing NRSE is critical for the preservation of striatal neurons, and these factors play a pivotal role in this process ⁵⁹.

Additionally, mutant htt interacts with molecular chaperones including the Hsp70 and Hsp40 families in polyQ-expanded proteins and colocalizes with protein aggregates. Impaired capacity to regulate aberrant protein folding results from a decrease in the number of available soluble forms of these chaperones when they get encased in aggregates ^60-63.

Astrocytes and Microglial Dysfunction: Microglial dysfunction and astrocytes greatly affect Huntington's disease (HD)-related neuronal loss. Stimulating molecules via NF-κB signalling causes microglia to survey and increases PU1 and CCAT binding. Activated microglia can experience several polarisation states often known as M1 and M2 and these cells can move between them. Thought to be the principal initiators of the innate and adaptive immunological responses of the brain, M1 microglia are also linked to the inflammatory reaction. These phagocytic cells release cytotoxic compounds like quinolinic acid, ROS, and nitric oxide (NO), hence aggravating invasive infections ^{59, 64-70}.

Defective Synaptic Transmission: Effective axonal transport is necessary for proper translocation to neuronal membranes, which facilitates synaptic transmission. Huntington's disease (HD) lowers synaptic excitability because neither GABAA (γ-aminobutyric acid type A) nor AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors are supplied. HAP1 disrupts the connection between these receptors and the kinesin motor factor KIF5 by binding mutant huntingtin (htt) to this factor ^{59, 71-75}.

Excitotoxicity and Medium Spiny Neurons (MSNs) Degeneration: The most obvious reduction is seen in MSNs located in the striatum. Furthermore, it has been demonstrated that glutamatergic inputs, which cause aberrant firing and neurotransmission, are particularly advantageous to MSNs. In a process known as excitotoxicity, glutamate can kill striatal neurones by activating NMDA receptors ^76-80.

Pathogenic mHTT and Experimental Models for HD: The protein misfolds due to the enlarged polyQ region at the N-terminus of HTT, resulting in aberrant accumulations and aggregates. Inclusion bodies, which are present in the cytoplasm or nucleus, signify aggregated mHTT. A number of HD experimental models, such as those made from transgenic animals and human embryonic stem cells, have been created and studied in order to further HD research. These models display either full-length HTT or N-terminal segments of mHTT. Induced pluripotent stem cells produced from HD patients are also utilised ^{70, 81}.

Symptoms: People have lower self-esteem, fear, and feelings of guilt. Apathy, not anxiety or depression, is the only emotional state associated with the progression of the illness ²⁸. Although the central nervous system (CNS) is the primary cause of Huntington's disease clinical symptoms, other factors such as hormone imbalances, weight loss, muscular atrophy, and metabolic abnormalities may also be important. Huntington's disease is thought to have a prodromal phase that begins long before a motor diagnosis can be made and is associated with neurobiological alterations such as striatal atrophy. Chora is typically the first motor symptom to be clinically detected, but bradykinesia and incoordination (or motor dysfunction) are typically more incapacitating ^{7, 82, 83}. Psychiatric disorders such as obsessive-compulsive disorder, sadness, anxiety, and irritability are linked to HD ^{83, 84}. Chora is one of the motor abnormalities caused by Huntington's disease, which disrupts the striatal output routes ^85-87. Additionally, apathy and weight loss have been connected to Huntington's disease ^{2, 28, 88}.

Current Therapy: Due to the likelihood that the HD mutation is more prevalent and can mask Alzheimer's disease symptoms, neuropathological confirmation is essential for a conclusive diagnosis of co-existing Alzheimer’s disease ²⁸. Clinical evaluation of Huntington's disease utilizes the Unified Huntington’s Disease Rating Scale, which assesses motor deficits, behavioural symptoms, and cognitive impairments ^89-91. Recent advancements, such as the use of cryo-electron microscopy, have resolved the structure of the HTT protein, offering new insights into both the pathological mechanisms of HD and the normal biological functions of HTT ⁹².

Current therapeutic research in HD primarily focuses on targeting several mechanisms, including excitotoxicity, dopamine dysregulation, caspase activation, mutant huntingtin (mHTT) aggregation, mitochondrial abnormalities, transcriptional dysregulation, and dietary influences ⁹³. One promising approach under clinical investigation is antisense oligonucleotide (ASO) therapy. Small molecule splicing modulators, RNA interference (RNAi), and ASOs are being explored for their RNA-targeting capabilities. A phase 1b/2a clinical trial is presently evaluating ASOs in HD patients ^94-96. Tetrabenazine, a dopamine-depleting agent, is considered effective for managing chorea, although it may be associated with significant adverse effects. Newer antipsychotics such as aripiprazole and olanzapine are being utilized for managing chorea and psychosis, offering improved safety profiles compared to older medications ^97-99. Deutetrabenazine, a deuterated analog of tetrabenazine, has shown enhanced pharmacokinetics with a longer half-life and reduced variability. Findings from the FIRST-HD trial demonstrate that deutetrabenazine effectively reduces chorea and improves motor symptoms over a 12-week period ^100-103.

Various biomarkers are implicated in HD pathophysiology, including oxidative stress markers like 8-OHdG; metabolic markers such as creatine kinase and branched-chain amino acids; cholesterol derivatives like 24-OH cholesterol; and immune mediators such as clusterin, complement proteins, and interleukins 6 and 8. Other indicators include transcriptional changes, endocrine hormones (e.g., cortisol, leptin, and ghrelin), brain-derived neurotrophic factor (BDNF), and adenosine 2A receptors ^104-108. Imaging and structural biomarkers useful for early HD detection and progression tracking include striatal volume, cortical thickness, subcortical white matter volume, total brain and ventricular size, functional MRI, PET scans using fluorodeoxyglucose, and magnetic resonance spectroscopy measuring lactate levels ^108-112. In addition, early detection may benefit from quantitative motor assessments, neurophysiological evaluations (e.g., transcranial magnetic stimulation), and precise eye movement analyses ^{113, 114}.

An increase in BDNF levels was found to be concentration-dependent in striatal tissues of both N171-82Q HD mouse models and wild-type striatal cells, suggesting that glatiramer acetate could emerge as a future HD treatment option ^115-117. In a randomized controlled trial, the antipsychotic sulpiride demonstrated effectiveness in reducing chorea symptoms ^{98, 118}. Cholinesterase inhibitors such as galantamine, donepezil, and rivastigmine have shown positive results in two randomized trials for HD treatment ¹¹⁹. Pharmacological options also include SSRIs like citalopram, fluoxetine, paroxetine, and sertraline, along with dual-action antidepressants such as mirtazapine and venlafaxine. Antipsychotic medications are used to address psychosis and aggressive behavior, while drugs like methylphenidate, atomoxetine, modafinil, amantadine, bromocriptine, and bupropion have been explored for managing apathy, although robust evidence from randomized trials remains limited ¹²⁰.

Caspases 1 and 2 are recognized as key contributors in HD pathology. Minocycline has shown therapeutic promise by reducing the expression of inducible nitric oxide synthase, inhibiting the upregulation of caspase-1 and caspase-3 mRNA, and slowing disease progression ¹²¹. Amantadine has been found effective for treating HD-related chorea ^122-124, and for idiopathic dystonia, treatments may involve botulinum toxin, benzodiazepines, and baclofen ¹²¹. Another trial also supports the use of amantadine for controlling chorea in HD ¹²⁴. In the 3-nitropropionic acid (3NP) model of HD, memantine has shown neuroprotective effects by decreasing striatal damage, reducing Bax expression, increasing Bcl-xl, preserving body weight, and minimizing lesion volume, likely through inhibition of calpain activity ^{125, 126}. Congo red has shown potential for symptom relief in HD by modifying protein misfolding and aggregation, thereby reducing toxic oligomers and enhancing motor performance ^{127, 128}. The rapamycin analog CCI-779, which inhibits mTOR, promotes autophagy, counteracts polyglutamine toxicity, and reduces protein aggregate formation, making it a promising therapeutic candidate for HD management ^129-132.

TABLE 1: CURRENT TREATMENT OPTIONS AVAILABLE FOR HUNTINGTON DISEASE

Nanotherapy: Due to their high surface area-to-mass ratio, nanoparticles possess unique optical, magnetic, and biological properties within biological systems. They can be broadly categorized as organic (e.g., liposomes) or inorganic (e.g., gold nanoparticles). Polymeric nanoparticles, made from biodegradable and biocompatible polymers, are particularly effective in protecting drugs from degradation. Additionally, nanoparticles enable the delivery of poorly water-soluble drugs with low bioavailability ¹⁴⁰. These nanocarriers can transport a range of therapeutic agents including siRNAs, stem cells, neurotrophic factors, and pharmaceuticals. Various nanoparticle types such as solid lipid, polymeric, lipid-based, liposomal, and metal/metal oxide nanoparticles are being explored for treating Huntington’s disease (HD). Integrating nanomaterials with stem cell systems enhances neural stem cell (NSC) expansion, targeted delivery of bioactive molecules, and allows for noninvasive, long-term monitoring of cell movements post-implantation. Merging nanotechnology, stem cell therapy, and molecular biology may improve the efficacy of these treatments while addressing existing limitations ¹⁴¹. W20-SPIONs have been able to cross the blood-brain barrier and specifically bind to oligomeric regions, producing MRI signals in transgenic mice, and thereby differentiating between Parkinson’s and Huntington’s disease. This makes them promising diagnostic tools for HD ¹⁴². Since mitochondrial dysfunction plays a central role in HD, nanoparticle-based theranostic systems are being explored as potential therapeutic interventions ¹⁴³. The CRISPR/Cas system also holds promise in gene editing strategies aimed at treating monogenic disorders like HD, especially through targeting repeated RNA sequences (e.g., CAGN repeats) using R-Cas9 ¹⁴⁴.

In HD rat models, intravenous administration of human immature dental pulp stem cells (hIDPSCs) helped restore BDNF, DARPP32, and D2R levels, enhancing neurogenesis and neuroprotection ¹⁴⁵. Targeting multiple cellular, epigenetic, and genetic mechanisms may offer more comprehensive symptom relief. For instance, human striatal organoids (hStrOs) derived from hiPSCs mimic early brain development and integrate effectively into host neuronal circuits post-transplantation ^{146, 147}. Co-transplantation of hStrOs with human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) mitigates immune rejection and mechanical trauma by leveraging the immunomodulatory and neurotrophic functions of hUC-MSCs ^{147, 148}. Theranostic approaches that combine drug-free photothermal therapy with advanced imaging to monitor aggregate ablation support the potential of aggregate-disrupting strategies in treating neurodegenerative diseases like HD ¹⁴⁹.

Pre-treatment with sesamol (5, 10, and 20 mg/kg) improved oxidative damage markers, behaviour, and mitochondrial enzyme activities. At higher doses, sesamol increased cell survival, indicating its potential therapeutic role in HD due to its antioxidant properties ¹⁵⁰. Selenium nanoparticles (Nano-Se) were found to reduce neuronal death and behavioural impairment at low doses in HD models, including in C. elegans, highlighting their therapeutic promise ¹⁵¹. In HD animal models, hybrid-g7-NPs-chol, containing deuterium-labeled cholesterol, delivered cholesterol in a controlled, inflammation-free manner, restoring natural cholesterol synthesis and improving motor and cognitive deficits ¹⁵². Dual dosing of hybrid-g7-NPs-chol produced lasting improvements in cognition, behaviour, and brain pathology ¹⁵³.

A promising delivery strategy includes nasal administration of chitosan nanoparticles loaded with anti-HTT siRNA, effectively suppressing mutant HTT expression and contributing to HD management ¹⁵⁴. In a 3NP-induced HD rat model, solid lipid nanoparticles loaded with rosmarinic acid (SLNPRT) showed significant behavioural improvements and antioxidant effects, pointing to their therapeutic value ¹⁵⁵. Both rat striatal cells (ST14A-HTT120Q) and human HD fibroblasts displayed reduced HTT expression after treatment with CDsiRNA nanoparticle complexes. In the R6/2 HD mouse model, a single injection of these nanoparticles resulted in prolonged gene silencing, and multiple injections further improved motor functions ^156-158.

Engineered γ-Fe₂O₃ poly(trehalose) nanoparticles were 1,000–10,000 times more effective than plain trehalose in preventing extracellular fibril formation, inhibiting mHTT aggregation in neurons, and reducing aggregates in HD mouse brains ¹⁵⁹. In 3NP-induced HD models, curcumin encapsulated in solid lipid nanoparticles (CSLNs) significantly decreased mitochondrial swelling, reactive oxygen species, protein carbonyls, and lipid peroxidation, while enhancing antioxidant enzyme activity such as superoxide dismutase and glutathione ^160-164. Similarly, low doses of thymoquinone in suspension lipid nanoparticles (TQ-SLN) were effective in reversing behavioural, biochemical, and histopathological changes in HD models ^165-167.

Chitosan nanoparticles enhanced with ginger extract showed efficacy in 3NP-induced HD rat models by improving cognitive and motor functions (e.g., grip strength, gait, memory) and by reducing oxidative stress markers like malondialdehyde and protein carbonyls. These effects were accompanied by increases in antioxidants such as glutathione, catalase, and superoxide dismutase. Inhibition of acetylcholine esterase was also associated with improved cognition ¹⁶⁸. Ginger, known for its neuroprotective properties, has limited bioavailability and brain penetration, but nanoparticle formulations can overcome these barriers. Finally, PLGA nanoparticles carrying PGQ9P2, QBP1, and NT17 peptides were shown to significantly reduce polyglutamine aggregation in neuronal models (Neuro 2A, PC12) and enhance motor performance post-treatment ¹⁶⁹.

TABLE 2: THE NANOTECHNOLOGY-BASED OPTIONS AVAILABLE FOR HUNTINGTON DISEASE

Future-outlook: Nanotherapeutics offer promising advantages in treating Huntington’s disease (HD) by enabling targeted drug delivery across the blood–brain barrier (BBB), directly reaching the affected brain regions. This approach enhances therapeutic outcomes and reduces adverse effects. Additionally, nanotherapeutics are being explored as diagnostic tools in HD management. The rapid growth in this field opens up numerous possibilities for transforming HD treatment. However, current challenges remain, such as the absence of FDA-approved nanotherapeutic options for HD and the necessity for comprehensive safety evaluations. By targeting key pathological factors such as mHTT DNA, mHTT RNA, mutant protein, mitochondrial dysfunction, defective autophagy, cell death pathways, and histone methylation, nanotherapeutic platforms help mitigate HD progression ⁶. To validate the impact of nanoparticles in human systems, clinical studies are essential. Since most investigations focus on how nanoparticles influence metabolic activity, it is crucial to conduct in vivo studies to better understand their physical, chemical, and metabolic characteristics. Further insights into the mechanisms that allow nanoparticles to traverse physiological barriers in-vivo will be instrumental in refining their design. Establishing standardized criteria to assess the biodegradability of nanoparticles in vivo is also critical. Therefore, fundamental research is required before nanotechnology can be routinely applied in clinical practice. Expanding interdisciplinary research will contribute to the development of an integrated nanotechnology-based therapeutic strategy for neurodegenerative diseases (NDs) ¹⁴³. Future efforts should prioritize the integration of multimodal data and rigorous clinical validation to enhance model performance. Leveraging machine learning for HD diagnosis holds potential for earlier interventions, individualized therapies, and improved outcomes for patients and their families ¹⁷¹. Gene therapy is a promising avenue for future HD treatments, with the goal of directly correcting or silencing the mutant HTT gene or associated DNA damage response (DDR) mechanisms. A combined strategy involving gene and cell therapy entails replacing damaged neurons with striatal organoids derived from iPSCs, either from healthy donors or gene-corrected HD patients. To reduce immune responses and injection-related inflammation during transplantation, mesenchymal stem cells (MSCs) are co-transplanted. These MSCs also facilitate BDNF production, which may support neuronal survival and recovery. Additionally, microglial repopulation creates a more favorable environment for the engraftment and differentiation of transplanted cells. Going forward, research should focus on establishing the safety, therapeutic efficacy, and clinical utility of these organoid-based therapies in animal models of HD ¹⁴⁷. The Huntington's Disease Integrated Staging System (HD-ISS) provides a framework for classifying individuals based on clinical, biological, and functional indicators. Starting from Stage 0 which includes individuals genetically predisposed to HD but showing no clinical manifestations the HD-ISS outlines a progressive staging model: Stage 1 (biological markers of disease), Stage 2 (appearance of clinical symptoms), and Stage 3 (functional decline). Each stage is defined by precise, evidence-based thresholds, facilitating accurate staging for research and clinical monitoring ⁸³.

TABLE 3: ONGOING CLINICAL RESEARCH CONTINUES TO TACKLE THE VARIOUS CHALLENGES ASSOCIATED WITH HD TREATMENT. A SUMMARY OF THESE CLINICAL INVESTIGATIONS IS PROVIDED IN

CONCLUSION: Nanotherapeutics possess the capability to cross the blood–brain barrier (BBB) effectively, allowing for the direct delivery of therapeutic agents to the regions of the brain affected by Huntington’s disease (HD), thereby reducing side effects and improving treatment outcomes ⁶. While current therapies primarily address symptoms, RNA interference (RNAi)-based nanotherapeutics have emerged as innovative tools for modulating stem cell behavior both in-vitro and in-vivo. Compared to traditional techniques such as lipoplex transfection, electroporation, and lentiviral methods, nano- and microcarriers used for nucleotide delivery offer considerable advantages ¹⁷². Due to their unique physicochemical properties, nanoparticles are highly suitable for targeted drug delivery and offer neuroprotective potential. Their ability to traverse the BBB supports the development of precision medicine approaches ¹⁷³. Nanocarriers functionalized with targeting elements such as proteins, peptides, aptamers, or cell membrane-derived vesicles can actively engage antigen-presenting cells (APCs), enhancing delivery specificity ¹⁷⁴. Furthermore, exosomes present dual utility: they can be used as carriers in gene-silencing therapies and also serve as biomarker sources for early-stage disease detection, thereby contributing to our understanding of HD pathogenesis ¹⁷⁵. With promising results demonstrated in preclinical settings, strategies involving genetic, epigenetic, and stem cell-based interventions hold great potential for future clinical applications. Continued development of these therapeutic avenues could ultimately pave the way for a cure for this devastating neurodegenerative condition ¹⁷⁶.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: Nil

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     How to cite this article:

     Neethu MV, Sharma S, Narwal N, Kumari S and Anjumol VM: Nanomedicine for huntington’s disease: a review of current strategies, challenges, and future directions. Int J Pharm Sci & Res 2026; 17(1): 75-90. doi: 10.13040/IJPSR.0975-8232.17(1).75-90.

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