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Cell therapy products (CTP) derived from pluripotent stem cells (iPSCs) may constitute a renewable, specifically differentiated source of cells to potentially cure patients with neurodegenerative disorders. However, the immunogenicity of CTP remains a major issue for therapeutic approaches based on transplantation of non-autologous stem cell-derived neural grafts. Despite its considerable side-effects, long-term immunosuppression, appears indispensable to mitigate neuro-inflammation and prevent rejection of allogeneic CTP. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to access CTP with enhanced immunological compatibility, ultimately reducing the need for immunosuppression. In the present work, we challenge this paradigm by grafting autologous, MHC-matched and mis-matched neuronal grafts in a primate model of Huntington’s disease. Unlike previous reports in unlesioned hosts, we show that in the absence of immunosuppression MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain. Matching iPSC donors’ and patients’ HLA haplotypes has been proposed as a way to generate cell therapy products with enhanced immunological compatibility. Here the authors show that MHC matching alone is insufficient to grant long-term survival of neuronal grafts in the lesioned brain of non-human primates.

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. While traditionally viewed through the lens of neuronal dysfunction, emerging evidence highlights the critical role of endothelial dysfunction in HD pathogenesis. This review provides a comprehensive overview of endothelial dysfunction in HD, drawing on findings from both animal models and human studies. Key features of endothelial dysfunction in HD include impaired angiogenesis, altered cerebral blood flow, compromised neurovascular coupling and cerebrovascular reactivity, and increased blood–brain barrier permeability. Genetic factors such as the mutant huntingtin protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Brain-derived neurotrophic factor (BDNF), and the adenosine A2A receptor (ADORA2A) interact to influence endothelial function in complex ways. Various therapeutic approaches targeting endothelial dysfunction, including antioxidants, nitric oxide enhancers, calcium channel blockers, statins, and metformin, have shown promise in preclinical HD models but face translational challenges, particularly regarding optimal timing of intervention and patient stratification. The implications of these findings suggest that reconceptualizing HD as a neurovascular disorder, rather than purely neuronal, could lead to more effective treatment strategies. Future research priorities should include: (1) developing validated vascular biomarkers for disease progression, (2) advancing neuroimaging techniques to monitor endothelial dysfunction in real-time. These directions will be crucial for bridging the current gap between preclinical promise and clinical success in vascular-targeted HD therapeutics.

Dominant negative genetic disorders, in which a mutant allele of a gene causes disease in the presence of a second, normal copy, have been challenging since there is no cure and treatments are only to alleviate the symptoms. Current therapies involving pharmacological and biological drugs are not suitable to target mutant genes selectively due to structural indifference of the normal variant of their targets from the disease-causing mutant ones. In instances when the target contains single nucleotide polymorphism (SNP), whether it is an enzyme or structural or receptor protein are not ideal for treatment using conventional drugs due to their lack of selectivity. Therefore, there is a need to develop new approaches to accelerate targeting these previously inaccessible targets by classical therapeutics. Although there is a cooling trend by the pharmaceutical industry for the potential of RNA interference (RNAi), RNAi and other RNA targeting drugs (antisense, ribozyme, etc.) still hold their promise as the only drugs that provide an opportunity to target genes with SNP mutations found in dominant negative disorders, genes specific to pathogenic tumor cells, and genes that are critical for mediating the pathology of various other diseases. Because of its exquisite specificity and potency, RNAi has attracted a considerable interest as a new class of therapeutic for genetic diseases including amyotrophic lateral sclerosis, Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), spinocerebellar ataxia, dominant muscular dystrophies, and cancer. In this review, progress and challenges in developing RNAi therapeutics for genetic diseases will be discussed.

Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium–chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl−) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl− currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse’s spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington’s disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2’s growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.

Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.

Huntington’s disease (HD) is a fatal autosomal dominantly inherited brain disease caused by excessively expanded CAG repeats in gene which encodes huntingtin protein. These abnormally encoded huntingtin proteins and their truncated fragments result in disruption of cellular quality mechanism ultimately triggering neuronal death. Despite great efforts, a potential causative agent leading to genetic mutation in HTT , manifesting the neurons more prone to oxidative stress, cellular inflammation, energy depletion and apoptotic death, has not been established yet. Current scenario concentrates on symptomatic pathologies to improvise the disease progression and to better the survival. Most of the therapeutic developments have been converged to rescue the protein homeostasis. In HD, abnormal expansion of glutamine repeats in the protein huntingtin leads to toxic aggregation of huntingtin which in turn impairs the quality control mechanism of cells through damaging the machineries involved in removal of aggregated abnormal protein. Therapeutic approaches to improve the efficiency of aggregate clearance through quality control mechanisms involve protein folding machineries such as chaperones and protein degradation machineries such as proteasome and autophagy. Also, to reduce protein aggregation by enhancing proper folding, to degrade and eliminate the aggregates are suggested to negatively regulate the HD progression associated with the disruption of protein homeostasis. This review focuses on the collection of therapeutic strategies targeting enhancement of protein quality control activity to delay the HD pathogenesis.

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself.In this Review, Tabrizi et al. discuss new insights into the molecular pathogenesis of Huntington disease and outline potential therapeutic strategies, which could include the modulation of DNA repair processes.

Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.

Positron emission tomography with O-15-labeled water was used to study at rest the neurophysiological effects of bilateral external globus pallidus (GPe) deep brain stimulation in patients with Huntington's disease (HD). Five patients were compared with a control group in the on and off states of the stimulator. External globus pallidus stimulation decreased neuronal activity and modulated cerebral connectivity within the basal ganglia-thalamocortical circuitry, the sensorimotor, and the default-mode networks. These data indicate that GPe stimulation modulates functional integration in HD patients in accordance with the basal ganglia-thalamocortical circuit model.

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine repeat in the Huntingtin gene (HTT). Although suppressing the expression of mutant HTT (mHTT) has been explored as a therapeutic strategy to treat Huntington's disease, considerable efforts have gone into developing allele-specific suppression of mHTT expression, given that loss of Htt in mice can lead to embryonic lethality. It remains unknown whether depletion of HTT in the adult brain, regardless of its allele, could be a safe therapy. Here, we report that permanent suppression of endogenous mHTT expression in the striatum of mHTT-expressing mice (HD140Q-knockin mice) using CRISPR/Cas9-mediated inactivation effectively depleted HTT aggregates and attenuated early neuropathology. The reduction of mHTT expression in striatal neuronal cells in adult HD140Q-knockin mice did not affect viability, but alleviated motor deficits. Our studies suggest that non-allele-specific CRISPR/Cas9-mediated gene editing could be used to efficiently and permanently eliminate polyglutamine expansion-mediated neuronal toxicity in the adult brain.