Advances in gene and cellular therapeutic approaches for Huntington’s disease

Abstract

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the abnormal expansion of CAG trinucleotide repeats in the Huntingtin gene (HTT) located on chromosome 4. It is transmitted in an autosomal dominant manner and is characterized by motor dysfunction, cognitive decline, and emotional disturbances. To date, there are no curative treatments for HD have been developed; current therapeutic approaches focus on symptom relief and comprehensive care through coordinated pharmacological and nonpharmacological methods to manage the diverse phenotypes of the disease. International clinical guidelines for the treatment of HD are continually being revised in an effort to enhance care within a multidisciplinary framework. Additionally, innovative gene and cell therapy strategies are being actively researched and developed to address the complexities of the disorder and improve treatment outcomes. This review endeavours to elucidate the current and emerging gene and cell therapy strategies for HD, offering a detailed insight into the complexities of the disorder and looking forward to future treatment paradigms. Considering the complexity of the underlying mechanisms driving HD, a synergistic treatment strategy that integrates various factors—such as distinct cell types, epigenetic patterns, genetic components, and methods to improve the cerebral microenvironment—may significantly enhance therapeutic outcomes. In the future, we eagerly anticipate ongoing innovations in interdisciplinary research that will bring profound advancements and refinements in the treatment of HD.

Keywords

Huntington’s disease (HD) / Huntingtin gene (HTT) / gene therapy / cell therapy / interdisciplinary research

References

[1] Aditi K, Singh A, Shakarad MN et al. Management of altered metabolic activity in. Exp Biol Med (Maywood) 2022;247:152–164.

[2] Agarwal K. Revolutionizing gene therapy: biomaterials as enabling tools for targeted delivery and enhanced efficacy. Int J Multidiscip Res 2023;5:6647.

[3] Agustín-Pavón C, Mielcarek M, Garriga-Canut M et al. Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Mol Neurodegener 2016;11:64.

[4] Aldous SG, Smith EJ, Landles C et al. A CAG repeat threshold for therapeutics targeting somatic instability in Huntington’s disease. Brain 2024;147:1784–1798.

[5] Alpaugh M, Galleguillos D, Forero J et al. Disease-modifying effects of ganglioside GM1 in Huntington’s disease models. EMBO Mol Med 2017;9:1537–1557.

[6] An MC, Zhang N, Scott G et al. Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 2012;11:253–263.

[7] Anand RP, Layer JV, Heja D et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature 2023;622:393–401.

[8] Anbari F, Khalili MA, Bahrami AR et al. Intravenous transplantation of bone marrow mesenchymal stem cells promotes neural regeneration after traumatic brain injury. Neural Regen Res 2014;9:919–923.

[9] Anonymous. Lipophilic siRNA conjugates yield durable silencing in extrahepatic tissues. Nat Biotechnol 2022;40:1439–1440.

[10] Anzalone AV, Randolph PB, Davis JR et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019;576:149–157.

[11] Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol 2020;38:824–844.

[12] Aylward EH, Nopoulos PC, Ross CA et al. PREDICT-HD Investigators and Coordinators of Huntington Study Group. Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry 2011;82:405–410.

[13] Bachoud-Lévi AC. on behalf the Multicentric Intracerebral Grafting in Huntington’s Disease Group. Human fetal cell therapy in Huntington’s disease: A Randomized, Multicenter, Phase II Trial. Mov Disord 2020;35:1323–1335.

[14] Bachoud-Lévi AC, Rémy P, Nguyen JP et al. Motor and cognitive improvements in patients with Huntington’s disease after neural transplantation. Lancet 2000;356:1975–1979.

[15] Bachoud-Lévi AC, Gaura V, Brugières P et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol 2006;5:303–309.

[16] Bachoud-Lévi AC, Massart R, Rosser A. Cell therapy in Huntington’s disease: taking stock of past studies to move the field forward. Stem Cells 2021;39:144–155.

[17] Badano JL, Teslovich TM, Katsanis N. The centrosome in human genetic disease. Nat Rev Genet 2005;6:194–205.

[18] Barker RA, Mason SL, Harrower TP et al. NEST-UK collaboration. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J Neurol Neurosurg Psychiatry 2013;84:657–665.

[19] Belgrad J, Khvorova A. More than 185 CAG repeats: a point of no return in Huntington’s disease biology. Brain 2024;147:1601–1603.

[20] Beers B, Bredlau A-L, Bhattacharyya A et al. J06 pivot-HD: A phase 2, randomised, placebo-controlled study to evaluate the safety and efficacy of ptC518 in subjects with huntington’s disease. J Neurol Neurosurg Psychiatry. 2022;93:A96.

[21] Benraiss A, Wang S, Herrlinger S et al. Human glia can both induce and rescue aspects of disease phenotype in Huntington disease. Nat Commun 2016;7:11758.

[22] Bhattacharyya KB. The story of George Huntington and his disease. Ann Indian Acad Neurol 2016;19:25–28.

[23] Birolini G, Valenza M, Ottonelli I et al. Insights into kinetics, release, and behavioral effects of brain-targeted hybrid nanoparticles for cholesterol delivery in Huntington’s disease. J Control Release 2021;330:587–598.

[24] Boak L, Mccolgan P. Understanding the treatment and post-treatment effects of tominersen in the Phase III GENERATION HD1 study. CHDI Foundation Annual Therapeutics Conference, 2022.

[25] Bohlen CJ, Friedman BA, Dejanovic B et al. Microglia in brain development, homeostasis, and neurodegeneration. Annu Rev Genet 2019;53:263–288.

[26] Brown KM, Nair JK, Janas MM et al. Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates. Nat Biotechnol 2022;40:1500–1508.

[27] Cantley W. A new approach to HTT lowering using a C16-siRNA conjugate. CHDI Foundation Annual Therapeutics Conference, 2023.

[28] Caron NS, Southwell AL, Brouwers CC et al. Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease. Nucleic Acids Res 2020;48:36–54.

[29] Carter T. Targeting the brain with novel AAV capsid variants to reduce mutant HTT and MSH3 with siRNA-based gene therapy for Huntington’s disease. CHDI Foundation Annual Therapeutics Conference, 2023.

[30] Caviston JP, Zajac AL, Tokito M et al. Huntingtin coordinates the dynein-mediated dynamic positioning of endosomes and lysosomes. Mol Biol Cell 2011;22:478–492.

[31] Chan ST, Mercaldo ND, Ravina B et al. Association of dilated perivascular spaces and disease severity in patients with huntington disease. Neurology 2021;96:e890–e894.

[32] Chen Z, Palmer TD. Cellular repair of CNS disorders: an immunological perspective. Hum Mol Genet 2008;17:R84–R92.

[33] Chen YC, Ma NX, Pei ZF et al. A NeuroD1 AAV-Based Gene Therapy for functional brain repair after ischemic injury through in vivo astrocyte-to-neuron conversion. Mol Ther 2020;28:217–234.

[34] Chen X, Saiyin H, Liu Y et al. Human striatal organoids derived from pluripotent stem cells recapitulate striatal development and compartments. PLoS Biol 2022;20:e3001868.

[35] Cho IK, Hunter CE, Ye S et al. Combination of stem cell and gene therapy ameliorates symptoms in Huntington’s disease mice. NPJ Regen Med 2019;4:7.

[36] Choi DE, Shin JW, Zeng S et al. Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington’s disease. eLife 2023;12.

[37] Chuang TJ, Lin KC, Chio CC et al. Effects of secretome obtained from normoxia-preconditioned human mesenchymal stem cells in traumatic brain injury rats. J Trauma Acute Care Surg 2012;73:1161–1167.

[38] Ciosi M, Maxwell A, Cumming SA et al. TRACK-HD team. A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 2019;48:568–580.

[39] Cisbani G, Saint-Pierre M, Cicchetti F. Single-cell suspension methodology favors survival and vascularization of fetal striatal grafts in the YAC128 mouse model of Huntington’s disease. Cell Transplant 2014;23:1267–1278.

[40] Colin E, Zala D, Liot G et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J 2008;27:2124–2134.

[41] Cong W, Bai R, Li YF et al. Selenium nanoparticles as an efficient nanomedicine for the therapy of Huntington’s disease. ACS Appl Mater Interfaces 2019;11:34725–34735.

[42] Connor B. Concise review: the use of stem cells for understanding and treating Huntington’s disease. Stem Cells 2018;36:146–160.

[43] Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 2015;162:516–526.

[44] Cooke JN, Ellis JA, Hossain S et al. Computational pharmacokinetic rationale for intra-arterial delivery to the brain. Drug Deliv Transl Res 2016;6:622–629.

[45] Coppen EM, Roos RA. Current pharmacological approaches to reduce chorea in Huntington’s disease. Drugs 2017;77:29–46.

[46] D’egidio F, Castelli V, Lombardozzi G et al. Therapeutic advances in neural regeneration for Huntington’s disease. Neural Regen Res 2024;19:1991–1997.

[47] Dabrowska M, Juzwa W, Krzyzosiak WJ et al. Precise excision of the CAG tract from the Huntingtin gene by CaS9 Nickases. Front Neurosci 2018;12:75.

[48] Datson NA, González-Barriga A, Kourkouta E et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One 2017;12:e0171127.

[49] Debnath K, Pradhan N, Singh BK et al. Poly(trehalose) nanoparticles prevent amyloid aggregation and suppress polyglutamine aggregation in a Huntington’s Disease Model Mouse. ACS Appl Mater Interfaces 2017;9:24126–24139.

[50] Dey ND, Bombard MC, Roland BP et al. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behav Brain Res 2010;214:193–200.

[51] Dhankhar J, Shrivastava A, Agrawal N. Amendment of altered immune response by curcumin in Drosophila model of Huntington’s disease. J Huntingtons Dis 2023;12:335–354.

[52] Didiot MC, Hall LM, Coles AH et al. Exosome-mediated delivery of hydrophobically modified siRNA for huntingtin mRNA silencing. Mol Ther 2016;24:1836–1847.

[53] Ding DC, Lin CH, Shyu WC et al. Neural stem cells and stroke. Cell Transplant 2013;22:619–630.

[54] Di Pardo A, Maglione V, Alpaugh M et al. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci U S A 2012;109:3528–3533.

[55] Dominici M, Le Blanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006;8:315–317.

[56] Douaud G, Gaura V, Ribeiro MJ et al. Distribution of grey matter atrophy in Huntington’s disease patients: a combined ROI-based and voxel-based morphometric study. Neuroimage 2006;32:1562–1575.

[57] Driscoll R, Hampton L, Abraham NA et al. Dose-dependent reduction of somatic expansions but not Htt aggregates by di-valent siRNA-mediated silencing of MSH3 in HdhQ111 mice. Sci Rep 2024;14:2061.

[58] Duan L, Xu L, Xu X et al. Exosome-mediated delivery of gene vectors for gene therapy. Nanoscale 2021;13:1387–1397.

[59] Duan L, Li X, Ji R et al. Nanoparticle-based drug delivery systems: an inspiring therapeutic strategy for neurodegenerative diseases. Polymers (Basel) 2023a;15:2196.

[60] Duan W, Urani E, Mattson MP. The potential of gene editing for Huntington’s disease. Trends Neurosci 2023b;46:365–376.

[61] Dunah AW, Jeong H, Griffin A et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’s disease. Science 2002;296:2238–2243.

[62] Duyao M, Ambrose C, Myers R et al. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet 1993;4:387–392.

[63] Ebert AD, Barber AE, Heins BM et al. Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington’s disease. Exp Neurol 2010;224:155–162.

[64] Ekman FK, Ojala DS, Adil MM et al. CRISPR-CaS9-mediated genome editing increases lifespan and improves motor deficits in a Huntington’s Disease Mouse Model. Mol Ther Nucleic Acids 2019;17:829–839.

[65] Elias S, Thion MS, Yu H et al. Huntingtin regulates mammary stem cell division and differentiation. Stem Cell Rep 2014;2:491–506.

[66] Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington’s disease clinical trials corner: August 2023. J Huntingtons Dis 2023;12:169–185.

[67] Estevez-Fraga C, Tabrizi SJ, Wild EJ. Huntington’s disease clinical trials corner: March 2024. J Huntingtons Dis 2024;13:1–14.

[68] Evans SJ, Douglas I, Rawlins MD et al. Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J Neurol Neurosurg Psychiatry 2013;84:1156–1160.

[69] Evers MM, Konstantinova P. AAV5-miHTT gene therapy for Huntington disease: lowering both huntingtins. Expert Opin Biol Ther 2020;20:1121–1124.

[70] Eygeris Y, Gupta M, Kim J et al. Chemistry of lipid nanoparticles for RNA delivery. Acc Chem Res 2022;55:2–12.

[71] Falkner S, Grade S, Dimou L et al. Transplanted embryonic neurons integrate into adult neocortical circuits. Nature 2016;539:248–253.

[72] Ferguson MW, Kennedy CJ, Palpagama TH et al. Current and possible future therapeutic options for Huntington’s disease. J Cent Nerv Syst Dis 2022;14:11795735221092517.

[73] Ferreira NN, De Oliveira Junior E, Granja S et al. Nose-to-brain co-delivery of drugs for glioblastoma treatment using nanostructured system. Int J Pharm 2021;603:120714.

[74] Fink KD, Deng P, Gutierrez J et al. Allele-specific reduction of the mutant Huntingtin allele using transcription activator-like effectors in human Huntington’s disease fibroblasts. Cell Transplant 2016;25:677–686.

[75] Finkbeiner S. Huntington’s disease. Cold Spring Harb Perspect Biol 2011;3:a007476.

[76] Fisher ER, Hayden MR. Multisource ascertainment of Huntington disease in Canada: prevalence and population at risk. Mov Disord 2014;29:105–114.

[77] Flower M, Lomeikaite V, Ciosi M et al; TRACK-HD Investigators . MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 2019;142:1876–1886.

[78] Food and Drug Administration HHS. Eligibility determination for donors of human cells, tissues, and cellular and tissue-based products. Final rule. Fed Regist 2004;69:29785–29834.

[79] Food and Drug Administration HHS. Revisions to exceptions applicable to certain human cells, tissues, and cellular and tissue-based products. final rule. Fed Regist 2016;81:40512–40518.

[80] Francelle L, Lotz C, Outeiro T et al. Contribution of neuroepigenetics to Huntington’s disease. Front Hum Neurosci 2017;11:17.

[81] Frank S. Treatment of Huntington’s disease. Neurotherapeutics 2014;11:153–160.

[82] Furr Stimming E, Claassen DO, Kayson E et al. Huntington Study Group KINECT-HD Collaborators. Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington’s disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2023;22:494–504.

[83] Futter M, Diekmann H, Schoenmakers E et al. Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. J Med Genet 2009;46:438–446.

[84] Garriga-Canut M, Agustín-Pavón C, Herrmann F et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A 2012;109:E3136–E3145.

[85] Gaura V, Bachoud-Lévi AC, Ribeiro MJ et al. Striatal neural grafting improves cortical metabolism in Huntington’s disease patients. Brain 2004;127:65–72.

[86] Gauthier LR, Charrin BC, Borrell-Pagès M et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004;118:127–138.

[87] Ghasemi M, Roshandel E, Mohammadian M et al. Mesenchymal stromal cell-derived secretome-based therapy for neurodegenerative diseases: overview of clinical trials. Stem Cell Res Ther 2023;14:122.

[88] Ghilan M, Bostrom CA, Hryciw BN et al. YAC128 Huntington’s disease transgenic mice show enhanced short-term hippocampal synaptic plasticity early in the course of the disease. Brain Res 2014;1581:117–128.

[89] Giampà C, Alvino A, Magatti M et al. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington’s disease. J Cell Mol Med 2019;23:1581–1592.

[90] Godin JD, Colombo K, Molina-Calavita M et al. Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis. Neuron 2010;67:392–406.

[91] Gorabi AM, Kiaie N, Barreto GE et al. The therapeutic potential of mesenchymal stem cell-derived exosomes in treatment of neurodegenerative diseases. Mol Neurobiol 2019;56:8157–8167.

[92] Guo Z, Zhang L, Wu Z et al. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell 2014;14:188–202.

[93] Guo Q, Bin H, Cheng J et al. The cryo-electron microscopy structure of Huntingtin. Nature 2018;555:117–120.

[94] Guo C, Ma X, Gao F et al. Off-target effects in CRISPR/CaS9 gene editing. Front Bioeng Biotechnol 2023;11:1143157.

[95] Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. CAG repeat not Polyglutamine length determines timing of Huntington’s disease onset. Cell 2019;178:887–900.e14.

[96] Harrower TP, Tyers P, Hooks Y et al. Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson’s disease. Exp Neurol 2006;197:56–69.

[97] Hersch SM, Claassen DO, Edmondson MC et al. Multicenter, randomized, double-blind, placebo-controlled phase 1b/2a studies of WVE-120101 and WVE-120102 in patients with Huntington’s Disease 2017.

[98] Hickman S, Izzy S, Sen P et al. Microglia in neurodegeneration. Nat Neurosci 2018;21:1359–1369.

[99] Holbert S, Denghien I, Kiechle T et al. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 2001;98:1811–1816.

[100] Hong EP, Macdonald ME, Wheeler VC et al. Huntington’s disease pathogenesis: two sequential components. J Huntingtons Dis 2021;10:35–51.

[101] Huang TP, Newby GA, Liu DR. Precision genome editing using cytosine and adenine base editors in mammalian cells. Nat Protoc 2021;16:1089–1128.

[102] Huntington disease. Nature Reviews Disease Primers 2015;1.

[103] Jain KK. Cell therapy for CNS trauma. Mol Biotechnol 2009;42:367–376.

[104] Jeon I, Lee N, Li JY et al. Neuronal properties, in vivo effects, and pathology of a Huntington’s disease patient-derived induced pluripotent stem cells. Stem Cells 2012;30:2054–2062.

[105] Jgamadze D, Bergen J, Stone D et al. Colloids as mobile substrates for the implantation and integration of differentiated neurons into the mammalian brain. PLoS One 2012;7:e30293.

[106] Joao M, Pagani E, Wenceslau CV et al. A Phase I clinical trial on intravenous administration of immature human dental pulp stem cells (Nestacell Hdtm) to Huntington’s disease patients. Cytotherapy 2021;23:1.

[107] Jones L, Hughes A. Pathogenic mechanisms in Huntington’s disease. Int Rev Neurobiol 2011;98:373–418.

[108] Kaemmerer WF, Grondin RC. The effects of huntingtin-lowering: what do we know so far? Degener Neurol Neuromuscul Dis 2019;9:3–17.

[109] Kay C, Skotte NH, Southwell AL et al. Personalized gene silencing therapeutics for Huntington disease. Clin Genet 2014;86:29–36.

[110] Kay C, Collins JA, Skotte NH et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European Ancestry. Mol Ther 2015;23:1759–1771.

[111] Keller CG, Shin Y, Monteys AM et al. An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion. Nat Commun 2022;13:1150.

[112] Keryer G, Pineda JR, Liot G et al. Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway and is altered in Huntington disease. J Clin Invest 2011;121:4372–4382.

[113] Keskin S, Brouwers CC, Sogorb-Gonzalez M et al. AAV5-miHTT lowers Huntingtin mRNA and protein without off-target effects in patient-derived neuronal cultures and astrocytes. Mol Ther Methods Clin Dev 2019;15:275–284.

[114] Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A 1996;93:1156–1160.

[115] Kim A, Lalonde K, Truesdell A et al. New avenues for the treatment of Huntington’s disease. Int J Mol Sci 2021;22:8363.

[116] Kondziolka D, Gobbel GT, Fellows-Mayle W et al. Injection parameters affect cell viability and implant volumes in automated cell delivery for the brain. Cell Transplant 2011;20:1901–1906.

[117] Krauze MT, Saito R, Noble C et al. Reflux-free cannula for convection-enhanced high-speed delivery of therapeutic agents. J Neurosurg 2005;103:923–929.

[118] Lee ST, Im W, Ban JJ et al. Exosome-based delivery of miR-124 in a Huntington’s Disease Model. J Mov Disord 2017;10:45–52.

[119] Li M, Izpisua Belmonte JC. Organoids -Preclinical models of human disease. Reply. N Engl J Med 2019;380:1982.

[120] Li Z, Wang C, Wang Z et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 2019;575:203–209.

[121] Liang XS, Sun ZW, Thomas AM et al. Mesenchymal stem cell therapy for Huntington disease: a meta-analysis. Stem Cells Int 2023;2023:1109967.

[122] Lin YT, Chern Y, Shen CK et al. Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington’s disease mouse models. PLoS One 2011;6:e22924.

[123] Linares GR, Chiu CT, Scheuing L et al. Preconditioning mesenchymal stem cells with the mood stabilizers lithium and valproic acid enhances therapeutic efficacy in a mouse model of Huntington’s disease. Exp Neurol 2016;281:81–92.

[124] Liot G, Zala D, Pla P et al. Mutant Huntingtin alters retrograde transport of TrkB receptors in striatal dendrites. J Neurosci 2013;33:6298–6309.

[125] Liu G, Lin Q, Jin S et al. The CRISPR-Cas toolbox and gene editing technologies. Mol Cell 2022;82:333–347.

[126] Liu L, Malagu K, Haughan AF et al. Identification and optimization of RNA-splicing modulators as Huntingtin protein-lowering agents for the treatment of Huntington’s disease. J Med Chem 2023;66:13205–13246.

[127] Lopes C, Tang Y, Anjo SI et al. Mitochondrial and redox modifications in Huntington disease induced pluripotent stem cells rescued by CRISPR/CaS9 CAGs targeting. Front Cell Dev Biol 2020;8:576592.

[128] Lunney JK, Van Goor A, Walker KE et al. Importance of the pig as a human biomedical model. Sci Transl Med 2021;13:eabd5758.

[129] Ma CY, Zhai Y, Li CT et al. Translating mesenchymal stem cell and their exosome research into GMP compliant advanced therapy products: promises, problems and prospects. Med Res Rev 2023;44:919.

[130] Malloy KE, Li J, Choudhury GR et al. Magnetic resonance imaging-guided delivery of neural stem cells into the Basal Ganglia of nonhuman primates reveals a pulsatile mode of cell dispersion. Stem Cells Transl. Med 2017;6:877–885.

[131] Marcora E, Gowan K, Lee JE. Stimulation of NeuroD activity by huntingtin and huntingtin-associated proteins HAP1 and MLK2. Proc Natl Acad Sci U S A 2003;100:9578–9583.

[132] Martin JB, Gusella JF. Huntington’s disease. Pathogenesis and management. N Engl J Med 1986;315:1267–1276.

[133] Mathot F, Rbia N, Bishop AT et al. Adhesion, distribution, and migration of differentiated and undifferentiated mesenchymal stem cells (MSCs) seeded on nerve allografts. J Plast Reconstr Aesthet Surg 2020;73:81–89.

[134] Maxan A, Mason S, Saint-Pierre M et al. Outcome of cell suspension allografts in a patient with Huntington’s disease. Ann Neurol 2018;84:950–956.

[135] Medina Escobar A, Bruno V, Sarna JR. Second-generation antisense nucleotide targeting Huntingtin expression found to be safe in patients with Huntington’s disease. Mov Disord Clin Pract 2019;6:434–435.

[136] Miniarikova J, Zanella I, Huseinovic A et al. Design, characterization, and lead selection of therapeutic miRNAs targeting Huntingtin for development of gene therapy for Huntington’s disease. Mol Ther Nucleic Acids 2016;5:e297.

[137] Miniarikova J, Zimmer V, Martier R et al. AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther 2017;24:630–639.

[138] Miura Y, Li MY, Birey F et al. Generation of human striatal organoids and cortico-striatal assembloids from human pluripotent stem cells. Nat Biotechnol 2020;38:1421–1430.

[139] Monteys AM, Ebanks SA, Keiser MS et al. CRISPR/Cas9 editing of the mutant Huntingtin allele in vitro and in vivo. Mol Ther 2017;25:12–23.

[140] Morelli KH, Wu Q, Gosztyla ML et al. An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington’s disease models. Nat Neurosci 2023;26:27–38.

[141] Morizane A, Kikuchi T, Hayashi T et al. MHC matching improves engraftment of iPSC-derived neurons in non-human primates. Nat Commun 2017;8:385.

[142] Mouro Pinto R, Arning L, Giordano JV et al. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1. Hum Mol Genet 2020;29:2551–2567.

[143] Nakamura M, Gao Y, Dominguez AA et al. CRISPR technologies for precise epigenome editing. Nat Cell Biol 2021;23:11–22.

[144] O’connell MR. Molecular mechanisms of RNA targeting by Cas13-containing Type VI CRISPR-Cas systems. J Mol Biol 2019;431:66–87.

[145] O’reilly D, Belgrad J, Ferguson C et al. Di-valent siRNA-mediated silencing of MSH3 blocks somatic repeat expansion in mouse models of Huntington’s disease. Mol Ther 2023;31:3355–3356.

[146] Obtulowicz P, Lech W, Strojek L et al. Induction of endothelial phenotype from Wharton’s Jelly-Derived MSCs and comparison of their vasoprotective and neuroprotective potential with primary WJ-MSCs in CA1 Hippocampal Region Ex Vivo. Cell Transplant 2016;25:715–727.

[147] Oikemus SR, Pfister EL, Sapp E et al. Allele-specific knock-down of mutant Huntingtin protein via editing at coding region single nucleotide polymorphism heterozygosities. Hum Gene Ther 2022;33:25–36.

[148] Palacino J, Swalley SE, Song C et al. SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice. Nat Chem Biol 2015;11:511–517.

[149] Paolicelli RC, Bolasco G, Pagani F et al. Synaptic pruning by microglia is necessary for normal brain development. Science 2011;333:1456–1458.

[150] Park HJ, Han A, Kim JY et al. SUPT4H1-edited stem cell therapy rescues neuronal dysfunction in a mouse model for Huntington’s disease. NPJ Regen Med 2022;7:8.

[151] Park TY, Jeon J, Lee N et al. Co-transplantation of autologous T. Nature 2023;619:606–615.

[152] Parkhurst CN, Yang G, Ninan I et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013;155:1596–1609.

[153] Pischiutta F, Caruso E, Cavaleiro H et al. Mesenchymal stromal cell secretome for traumatic brain injury: focus on immunomodulatory action. Exp Neurol 2022;357:114199.

[154] Precious SV, Zietlow R, Dunnett SB et al. Is there a place for human fetal-derived stem cells for cell replacement therapy in Huntington’s disease? Neurochem Int 2017;106:114–121.

[155] Pringsheim T, Wiltshire K, Day L et al. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Mov Disord 2012;27:1083–1091.

[156] Qian H, Kang X, Hu J et al. Reversing a model of Parkinson’s disease with in situ converted nigral neurons. Nature 2020;582:550–556.

[157] Ran FA, Hsu PD, Lin CY et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell 2013;154:1380–1389.

[158] Robitaille Y, Lopes-Cendes I, Becher M et al. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features. Brain Pathol 1997;7:901–926.

[159] Rong Z, Wang M, Hu Z et al. An effective approach to prevent immune rejection of human ESC-derived allografts. Cell Stem Cell 2014;14:121–130.

[160] Rook ME, Southwell AL. Antisense oligonucleotide therapy: from design to the Huntington disease clinic. BioDrugs 2022;36:105–119.

[161] Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol 2011;10:83–98.

[162] Rosser AE, Barker RA, Harrower T et al; NEST-UK. Unilateral transplantation of human primary fetal tissue in four patients with Huntington’s disease: NEST-UK safety report ISRCTN no 36485475. J Neurol Neurosurg Psychiatry 2002;73:678–685.

[163] Rosser AE, Busse ME, Gray WP et al. Translating cell therapies for neurodegenerative diseases: Huntington’s disease as a model disorder. Brain 2022;145:1584–1597.

[164] Sadan O, Melamed E, Offen D. Intrastriatal transplantation of neurotrophic factor-secreting human mesenchymal stem cells improves motor function and extends survival in R6/2 transgenic mouse model for Huntington’s disease. PLoS Curr 2012a;4:e4f7f6dC013d4e.

[165] Saade J, Mestre TA. Huntington’s disease: Latest frontiers in therapeutics. Curr Neurol Neurosci Rep 2024;24:255–264.

[166] Sadan O, Shemesh N, Barzilay R et al. Mesenchymal stem cells induced to secrete neurotrophic factors attenuate quinolinic acid toxicity: a potential therapy for Huntington’s disease. Exp Neurol 2012b;234:417-427.

[167] Sakthiswary R, Raymond AA. Stem cell therapy in neurodegenerative diseases: from principles to practice. Neural Regen Res 2012;7:1822–1831.

[168] Saudou F, Humbert S. The biology of Huntingtin. Neuron 2016;89:910–926.

[169] Schellino R, Besusso D, Parolisi R et al. hESC-derived striatal progenitors grafted into a Huntington’s disease rat model support long-term functional motor recovery by differentiating, self-organizing and connecting into the lesioned striatum. Stem Cell Res Ther 2023;14:189.

[170] Schobel SA. Preliminary results from GENERATION HD1, a phase III trial of tominersen in individuals with manifest HD. CHDI Foundation Annual Therapeutics Conference, 2021.

[171] Shin JW, Kim KH, Chao MJ et al. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Hum Mol Genet 2016;25:4566–4576.

[172] Shiwach RS, Norbury CGA. controlled psychiatric study of individuals at risk for Huntington’s disease. Br J Psychiatry 1994;165:500–505.

[173] Silvestrini MT, Yin D, Martin AJ et al. Interventional magnetic resonance imaging-guided cell transplantation into the brain with radially branched deployment. Mol Ther 2015;23:119–129.

[174] Sivandzade F, Cucullo L. Regenerative stem cell therapy for neurodegenerative diseases: an overview. Int J Mol Sci 2021;22:2153.

[175] Snyder BR, Chiu AM, Prockop DJ et al. Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington’s disease. PLoS One 2010;5:e9347.

[176] Spronck EA, Vallès A, Lampen MH et al. Intrastriatal administration of AAV5-miHTT in non-human primates and rats is well tolerated and results in miHTT transgene expression in key areas of Huntington disease pathology. Brain Sci 2021;11:129.

[177] Stanek LM, Sardi SP, Mastis B et al. Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum Gene Ther 2014;25:461–474.

[178] Steffan JS, Kazantsev A, Spasic-Boskovic O et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 2000;97:6763–6768.

[179] Stiles DK, Zhang Z, Ge P et al. Widespread suppression of huntingtin with convection-enhanced delivery of siRNA. Exp Neurol 2012;233:463–471.

[180] Stine OC, Pleasant N, Franz ML et al. Correlation between the onset age of Huntington’s disease and length of the trinucleotide repeat in IT-15. Hum Mol Genet 1993;2:1547–1549.

[181] Stoyas CA, La Spada AR. The CAG-polyglutamine repeat diseases: a clinical, molecular, genetic, and pathophysiologic nosology. Handb Clin Neurol 2018;147:143–170.

[182] Sung YK, Kim SW. Recent advances in the development of gene delivery systems. Biomater Res 2019;23:8.

[183] Tabrizi SJ, Reilmann R, Roos RA et al. TRACK-HD investigators. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol 2012;11:42–53.

[184] Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 2019a;102:899.

[185] Tabrizi SJ, Leavitt BR, Landwehrmeyer GB et al. Phase 1–2a IONIS-HTTRx Study Site Teams. Targeting Huntingtin expression in patients with Huntington’s disease. N Engl J Med 2019b;380:2307–2316.

[186] Tabrizi SJ, Flower MD, Ross CA et al. Huntington disease: New insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol 2020;16:529–546.

[187] Tabrizi SJ, Estevez-Fraga C, Van Roon-Mom WMC et al. Potential disease-modifying therapies for Huntington’s disease: lessons learned and future opportunities. Lancet Neurol 2022;21:645–658.

[188] Tai W, Xu XM, Zhang CL. Regeneration through. Front Cell Neurosci 2020;14:107.

[189] Talifu Z, Liu JY, Pan YZ et al. astrocyte-to-neuron reprogramming for central nervous system regeneration: a narrative review. Neural Regen Res 2023;18:750–755.

[190] Tan D, Wei C, Chen Z et al. CAG repeat expansion in THAP11 is associated with a novel Spinocerebellar Ataxia. Mov Disord 2023;38:1282–1293.

[191] Tang Q. Regulatory T cells aid stem-cell therapy for Parkinson’s disease. Nature 2023;619:470–472.

[192] Tomé S, Manley K, Simard JP et al. MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington’s disease mice. PLoS Genet 2013;9:e1003280.

[193] Torres EM, Trigano M, Dunnett SB. Translation of cell therapies to the clinic: characteristics of cell suspensions in large-diameter injection cannulae. Cell Transplant 2015;24:737–749.

[194] Van Der Burg JM, Björkqvist M, Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol 2009;8:765–774.

[195] Viglietta V. A PH1b/2a study of WVE-003, an investigational allele-selective, mHTT-lowering oligonucleotide for the treatment of early manifest Huntington’s disease, and review of PRECISION-HD results. CHDI Foundation Annual Therapeutics Conference, 2021.

[196] Wahyuningtyas D, Chen WH, He RY et al. Polyglutaminespecific gold nanoparticle complex alleviates mutant Huntingtin-induced toxicity. ACS Appl Mater Interfaces 2021;13:60894–60906.

[197] Wang Z, Zheng Y, Zheng M et al. Neurogenic Niche conversion strategy induces migration and functional neuronal differentiation of neural precursor cells following brain injury. Stem Cells Dev 2020;29:235–248.

[198] Wang LL, Serrano C, Zhong X et al. Revisiting astrocyte to neuron conversion with lineage tracing in vivo. Cell 2021;184:5465–5481.e16.

[199] Wang W, Li Y, Ma F et al. Microglial repopulation reverses cognitive and synaptic deficits in an Alzheimer’s disease model by restoring BDNF signaling. Brain Behav Immun 2023;113:275–288.

[200] Wei JK, Wang WC, Zhai RW et al. Neurons differentiated from transplanted stem cells respond functionally to acoustic stimuli in the awake monkey brain. Cell Rep 2016;16:1016–1025.

[201] Wenceslau CV, De Souza DM, Mambelli-Lisboa NC et al. Restoration of BDNF, DARPP32, and D2R expression following intravenous infusion of human immature dental pulp stem cells in Huntington’s Disease 3-NP Rat Model. Cells 2022;11:1664.

[202] Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol 2017;16:837–847.

[203] Winkler C, Reis J, Hoffmann N et al. Anodal transcranial direct current stimulation enhances survival and integration of dopaminergic cell transplants in a Rat Parkinson Model. eNeuro 2017;4:ENEURO.0063–ENEU17.2017.

[204] Wong YC, Holzbaur EL. The regulation of autophagosome dynamics by huntingtin and HAP1 is disrupted by expression of mutant huntingtin, leading to defective cargo degradation. J Neurosci 2014;34:1293–1305.

[205] Wright GEB, Collins JA, Kay C et al. Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease. Am J Hum Genet 2019;104:1116–1126.

[206] Wu Z, Parry M, Hou XY et al. Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease. Nat Commun 2020;11:1105.

[207] Xu X, Tay Y, Sim B et al. Reversal of phenotypic abnormalities by CRISPR/CaS9-mediated gene correction in Huntington disease patient-derived induced pluripotent stem cells. Stem Cell Rep 2017;8:619–633.

[208] Yamanaka S. Pluripotent stem cell-based cell therapy-promise and challenges. Cell Stem Cell 2020;27:523–531.

[209] Yan S, Tu Z, Liu Z et al. A Huntingtin Knockin Pig Model recapitulates features of selective neurodegeneration in Huntington’s disease. Cell 2018;173:989–1002.e13.

[210] Yan S, Zheng X, Lin Y et al. Cas9-mediated replacement of expanded CAG repeats in a pig model of Huntington’s disease. Nat Biomed Eng 2023;7:629–646.

[211] Yang S, Chang R, Yang H et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington’s disease. J Clin Invest 2017;127:2719–2724.

[212] Yang W, Li S, Li XJ. A CRISPR monkey model unravels a unique function of PINK1 in primate brains. Mol Neurodegener 2019;14:17.

[213] Yohrling GJ, Farrell LA, Hollenberg AN et al. Mutant huntingtin increases nuclear corepressor function and enhances ligand-dependent nuclear hormone receptor activation. Mol Cell Neurosci 2003;23:28–38.

[214] Zala D, Hinckelmann MV, Saudou F. Huntingtin’s function in axonal transport is conserved in Drosophila melanogaster. PLoS One 2013;8:e60162.

[215] Zeitler B, Froelich S, Marlen K et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat Med 2019;25:1131–1142.

[216] Zhang M, Wang F, Li S et al. TALE: a tale of genome editing. Prog Biophys Mol Biol 2014;114:25–32.

[217] Zhang C, Konermann S, Brideau NJ et al. Structural basis for the RNA-guided ribonuclease activity of CRISPR-Cas13d. Cell 2018;175:212–223.e17.

[218] Zhou H, Su J, Hu X et al. Glia-to-neuron conversion by CRISPR-CasRx alleviates symptoms of neurological disease in mice. Cell 2020;181:590–603.e16.

[219] Zuccato C, Ciammola A, Rigamonti D et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001;293:493–498.

[220] Zuccato C, Tartari M, Crotti A et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat Genet 2003;35:76–83.

[221] Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev 2010;90:905–981.

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