Huntington disease: Research & Drug Discovery Data

Drug discovery

drugs

With orphan designations

Overview

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, leading to progressive motor dysfunction (e.g., chorea, rigidity), cognitive decline, and psychiatric symptoms. Onset typically occurs in mid-adulthood (30–50 years), with juvenile forms (<20 years) presenting severe parkinsonism. Diagnosis is confirmed by genetic testing. While incurable, symptom management includes pharmacotherapy, multidisciplinary care, and emerging disease-modifying therapies targeting mutant huntingtin protein (mHTT) reduction [1][5][9][13].

Population

Global prevalence: ~4–12 per 100,000; higher in populations of European ancestry [2][6][18].
U.S.: ~41,000 symptomatic; >200,000 at-risk [17][20].

Burden

Life expectancy: 10–30 years post-onset; juvenile HD progresses faster [9][13].
High morbidity: Loss of independence, dysphagia, dementia, and suicide rates 4–8× higher than general population [9][13][16].
Economic/psychosocial strain: Full-time care required in advanced stages; significant caregiver burden [17][20].

Therapies

Symptomatic control: Chorea managed with VMAT2 inhibitors (tetrabenazine, deutetrabenazine), antipsychotics (olanzapine), and anti-glutamatergics (amantadine, riluzole) [3][9][19].
Supportive care: Physical/occupational therapy, psychiatric interventions, and caregiver support [1][17].
Emerging therapies: Antisense oligonucleotides (ASOs, e.g., RG6042 in Phase 3), RNA interference, and CRISPR-based gene editing to reduce mHTT [7][11][15].

Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders

Research Papers

4,753 drug discovery papers about Huntington disease, with 2 first-in-class and 50 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:

2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.

IntroductionReal-world evidence of deutetrabenazine (DTBZ) treatment for Huntington disease (HD)-associated chorea is limited.MethodsThis is a non-interventional, retrospective chart review study from a Huntington's Disease Society of America clinical practice at the University of Alabama at Birmingham (UAB). Patients had a diagnosis of HD-associated chorea, DTBZ initiation (4/2017-12/2021), ≥2 visits at UAB, and ≥3 months of chorea-related care records post DTBZ initiation. The last Unified HD Rating Scale-Total Maximal Chorea (TMC) score within 3 months prior to DTBZ initiation and first after reaching the last stable dose during follow-up were analyzed.ResultsAmong 80 eligible patient charts, mean (SD) age was 52.1 (12.6) years and 45 (56.3%) were female. Fifty patients had pre- and post-DTBZ TMC scores and reached a stable dose, including 30 with no prior tetrabenazine (TBZ) or DTBZ exposure, 8 with prior TBZ exposure with a switch to DTBZ after a gap, and 9 with prior TBZ exposure with a switch to DTBZ without a gap. Mean (SD) TMC score decreased (i.e., improved) by 3.7 (4.5), 7.8 (2.8), and 2.1 (4.2), respectively. Overall, 27 (33.8%) patients had ≥1 adverse event recorded between DTBZ initiation and the first visit with a TMC score after reaching their last stable DTBZ dose or DTBZ discontinuation for those without a stable dose.DiscussionThis real-world study describes improvements in TMC scores among patients with HD-associated chorea treated with DTBZ, regardless of prior treatment. The observed safety profile supports the known safety profile of DTBZ in this population.

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2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.

Huntington's disease (HD) is a progressive neurodegenerative disorder with no approved therapies. Despite multiple clinical trials, huntingtin (HTT)-lowering strategies have yet to show meaningful clinical benefit. Both somatic expansion and toxic HTT species are key molecular drivers of HD, yet therapeutic strategies targeting these pathways have never been directly compared or evaluated in combination. Using therapeutic divalent siRNAs, we assessed the long-term impact of silencing MutS homolog 3 (MSH3), a critical regulator of somatic expansion, HTT, or both in Q111 HD mice (>110 CAGs), which develop robust expansion, mutant HTT inclusions, and transcriptional dysregulation by 12 months. Long-term MSH3 silencing blocked somatic expansion, reduced inclusions, and normalized gene expression. HTT silencing alone had a limited effect, whereas combined MSH3/HTT targeting synergistically eliminated inclusions and restored transcriptomic profiles. Parallel treatment in wild-type mice showed no toxicity, supporting the safety of long-term intervention. These findings position somatic expansion as a promising therapeutic target and demonstrate the potential of RNAi-based cosilencing of MSH3 and HTT as a disease-modifying strategy for HD.

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2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.

Progressive neuronal loss is a hallmark of neurodegenerative diseases like Huntingtons disease (HD) and Amyotrophic lateral sclerosis (ALS) which are caused by convergent mechanisms such as oxidative stress, mitochondrial dysfunction, neuroinflammation, impaired autophagy and dysregulated cell death pathways. Both conditions share significant disruptions in metabolic and inflammatory signalling despite having different genetic origins and clinical manifestations; underscoring the necessity of pathway-oriented treatment approaches. In the central nervous system, peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear receptor has become an important regulator of inflammation, redox homeostasis, mitochondrial biogenesis and cellular stress responses. After giving a thorough overview of PPAR-γ structure activation and transcriptional regulation and the PGC-1α-mediated mitochondrial biogenesis axis, this chapter delves deeply into its interactions with major signalling pathways such as NF-κB, Wnt/β-catenin Nrf2/ARE and the autophagy-apoptosis networks. With a focus on experimental data showing PPAR-γ signaling's neuroprotective, anti-inflammatory, antioxidant and metabolic regulatory roles the pathophysiology of ALS and HD is critically investigated. Lastly the need for improved biomarkers, tailored multi-target strategies and selective modulators is highlighted in the discussion of current therapeutic limitations and translational difficulties.

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2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.

Huntington's disease (HD) is a genetically dominant neurodegenerative disorder characterized by several pathological mechanisms, including the disruption of brain cholesterol homeostasis. In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice. Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay. We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates. The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.

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2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

Huntington disease (HD) is a progressive neurodegenerative disease caused by an expanded CAG repeat in the HTT (huntingtin) gene, leading to the accumulation of mutant HTT (mHTT). IL17A (interleukin 17A), a proinflammatory cytokine primarily secreted by Th17 and γδ T cells, has been implicated in immune-mediated neurodegeneration. However, the role of IL17A in the pathogenesis of HD remains poorly understood. Here, we identify IL17A as a critical pathogenic factor in HD that promotes neuroinflammation, mHTT aggregation, and autophagy-lysosomal dysfunction. IL17A disrupts autophagic flux by downregulating CTSB and CTSD, inducing SQSTM1/p62 and MAP1LC3B-II/LC3-II accumulation, and impairing lysosomal reformation. Mechanistically, IL17A suppresses lysosomal biogenesis by inhibiting the nuclear translocation of TFE3. This regulation occurs via a novel GSK3B/GSK-3β-TFE3 signaling pathway. Therapeutic neutralization of IL17A with a monoclonal antibody (IL17A mAb) ameliorates disease phenotypes in R6/2 HD mice, improving motor performance, extending survival, and reducing gliosis. IL17A mAb also attenuates mHTT aggregation and enhances neuroprotective signaling, as evidenced by increased expression of DLG4/PSD-95, phosphorylated CREB1, and BDNF. Moreover, IL17A mAb restores autophagy-lysosomal function by facilitating the clearance of protein aggregates and upregulating lysosomal enzymes and biogenesis markers, including CTSB, CTSD, PIP5K1A, and LAMP2. These findings establish IL17A as a key modulator of HD pathophysiology and highlight IL17A inhibition as a promising therapeutic strategy for targeting autophagy-lysosomal dysfunction in HD.

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2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.

Open article ↗

2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.

Open article ↗

2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.

Open article ↗

2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.

Open article ↗

2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

Open article ↗

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Drug Discovery Landscape

78 orphan drug designations for Huntington disease, including 3 approved therapies.

Drug	Therapy type	Regulator	Orphan designation	Approval	Sponsor
21-amino acid peptide targeting expanded CAG repeat RNA	peptides	FDA	2026-08-03	—	Rare Power Limited
sulphamic acid, 6,7,8,9,10,11-hexahydro-6-oxobenzo[b]cyclohepta[d]pyran-3-yl ester	small molecules	FDA	2026-03-16	—	Olavide Neuron STX S.L.
a small molecule agonist of TrkB receptor	small molecules	FDA	2026-03-12	—	Shaanxi Micot Technology Co., Ltd.
tiapride	small molecules	FDA	2025-10-22	—	ArKri Therapeutics
Bevantolol hydrochloride	small molecules	EMA	2025-10-22	—	Som Innovation Biotech S.A.
monosialotetrahexosylganglioside sodium salt of porcine brain origin (pGM1)	other	FDA	2025-10-16	—	Zulia Biotech Inc.
Votoplam	small molecules	EMA	2024-12-13	—	Novartis Europharm Limited
2'-O-(2-methoxyethyl) and 2¿-O-methyl modified antisense oligonucleotide targeted to mutant huntingtin RNA	oligonucleotides	FDA	2024-11-07	—	Wave Life Sciences USA, Inc.
votoplam	small molecules	FDA	2024-10-25	—	Novartis Pharmaceuticals Corporation
(3beta,24S)-25,25,25-trifluoro-3-methyl-26,27-dinorergost-5-ene-3,24-diol	small molecules	FDA	2023-10-16	—	Sage Therapeutics
Virus-like particle containing Cas9/gRNA ribonucleoprotein targeting the human HTT gene	gene therapies	FDA	2023-10-05	—	Shanghai BDgene Co., Ltd.
Virus-like particle containing Cas9/gRNA ribonucleoprotein targeting the human HTT gene	gene editing enzymes	EMA	2023-08-16	—	Laura Nae
A plasmid encoding a rabies virus glycoprotein tag & lysosome-associated membrane glycoprotein 2 fusion protein gene and a mutant huntingtin small interfering RNA	combination	FDA	2023-04-10	—	ExoRNA Bioscience Nanjing Co. Ltd.
Dalzanemdor	small molecules	EMA	2023-02-15	—	Raremoon Consulting Esp S.L.
valbenazine [Ingrezza]	small molecules	FDA	2022-05-10	2023-08-18	Neurocrine Biosciences Inc.
synthetic 23 amino acid peptide AASSGVSTPGSAGHDIITEQPRS derived from the Huntingtin protein	peptides	FDA	2021-11-04	—	centre national de la recherche scientifique
humanized recombinant immunoglobulin G (IgG) 4 monoclonal antibody against C1q	antibodies	FDA	2021-10-25	—	Annexon, Inc.
an antisense oligonucleotide that has been developed to target expanded CAG repeats in messenger ribonucleic acid (mRNA)	oligonucleotides	FDA	2021-07-27	—	Vico Therapeutics B.V.
Bevantolol Hydrochloride (HCl)	small molecules	FDA	2021-06-24	—	SOM Innovation Biotech S.A.
Branaplam	small molecules	FDA	2020-10-19	—	Novartis Pharmaceuticals Corporation
fasudil HCL	small molecules	FDA	2020-08-25	—	Woolsey Pharmaceuticals, Inc.
Umbilical Cord Mesenchymal Stem Cells	cell therapies	FDA	2020-01-28	—	Acen Regenerative Medicine Sci-Tech Co., Ltd.
2-(3,7-dimethyl-octa-2, 6-dienyl)-6-ethylamino-3-hydroxy-5-pentyl-[1,4]benzoquinone	small molecules	EMA	2020-01-09	—	Emerald Health Pharmaceuticals España, S.L.
vasopressin 1a receptor antagonist	small molecules	FDA	2019-10-30	—	Azevan Pharmaceuticals, Inc.
glycerol tribenzoate	small molecules	FDA	2019-09-10	—	Forest Hills Partners Hong Kong Limited
(1E,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione OR [(1E,4Z,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one]	small molecules	FDA	2019-05-14	—	AnnJi Pharmaceutical Co. Ltd.
ADENO-ASSOCIATED VIRAL VECTOR SEROTYPE RH10 CONTAINING THE HUMAN CHOLESTEROL 24-HYDROXYLASE GENE	gene therapies	EMA	2019-04-01	—	AskBio France
recombinant adeno-associated virus, serotype 1, containing a transgene that encodes a microRNA targeting huntingtin messenger RNA	gene therapies	FDA	2019-03-15	—	Voyager Therapeutics
2,4-dinitrophenol	small molecules	FDA	2019-02-11	—	Mitochon Pharmaceuticals, Inc.
delta-9-tetrahydrocannabinol and cannabidiol	small molecules	FDA	2019-01-29	—	MMJ International Holdings
(+)-alpha-dihydrotetrabenazine	small molecules	FDA	2018-12-05	—	Adeptio Pharmaceuticals, Ltd
recombinant adeno-associated virus vector containing DNA encoding INT41 intrabody	gene therapies	FDA	2018-11-30	—	Vybion Inc.
monosialotetrahexosylganglioside	small molecules	FDA	2018-08-07	—	Qilu Pharmaceutical Co., Ltd.
2-(3,7-Dimethyl-octa-2, 6-dienyl)¿6-ethylamino-3-hydroxy-5-pentyl-[1,4]benzoquinone	small molecules	FDA	2018-02-01	—	Emerald Health Pharmaceuticals Inc.
Adeno-associated viral vector serotype 5 encoding a microRNA targeted to human huntingtin gene	gene therapies	EMA	2018-01-17	—	uniQure Biopharma B.V.
adeno-associated viral vector serotype 5 encoding a microRNA targeted to human huntingtin gene	gene therapies	FDA	2017-09-27	—	uniQure Biopharma B.V.
synthetic stereopure antisense oligonucleotide specific to the mutant huntingtin mRNA transcript at the U variant of single nucleotide polymorphism rs326331	oligonucleotides	FDA	2017-09-05	—	Wave Life Sciences Ltd.
laquinimod sodium	small molecules	FDA	2017-01-31	—	Active Biotech AB
Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Gly-Gly-Asp-Leu-Leu-Pro-Arg-Gly-Ser	peptides	EMA	2016-11-18	—	Granzer Regulatory Consulting & Services GmbH
humanized IgG4 monoclonal antibody that binds to the SEMA4D antigen	antibodies	FDA	2016-08-16	—	Vaccinex, Inc.
Mardepodect [PF-02545920]	small molecules	EMA	2016-07-14	—	Pfizer Limited
antisense oligonucleotide targeting the U isoform of SNP rs362307	oligonucleotides	FDA	2016-06-16	—	Wave LIfe Sciences
Tominersen	oligonucleotides	FDA	2015-12-29	—	Genentech, Inc.
5,7-dichloro-2-dimethylaminomethyl-8-hydroxyquinoline	small molecules	EMA	2015-05-21	—	[INACTIVE] Veristat Spain S.L.
AASSGVSTPGSAGHDIITEQPRS	peptides	EMA	2015-05-21	—	Centre National de la Recherche Scientifique (CNRS)
4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-ditert-butylphenol hydrochloride [BN82451B]	small molecules	EMA	2015-04-24	—	Ipsen Pharma
Chimeric 2'-O-(2-methoxyethyl) modified oligonucleotide targeted to huntingtin RNA	oligonucleotides	EMA	2015-03-19	—	Roche Registration GmbH
phenol, 4-[2-(aminomethyl)-4-thiazolyl]-2,6-bis (1,1-dimethyethyl) monohydrochloride	small molecules	FDA	2015-03-16	—	Ipsen Biopharmaceuticals, Inc.
2'-O-methyl phosphorothioate RNA oligonucleotide, 5'-m5CUGm5CUGm5CUGm5CUGm5CUGm5CUGm5CUG-3'	oligonucleotides	EMA	2015-02-18	—	Vico Therapeutics B.V.
5-bromo-N-(prop-2-yn-1-yl)-2-(1H-1,2,4-triazol-1-yl)pyrimidine-4,6-diamine	small molecules	EMA	2014-12-16	—	Palobiofarma S.L.
d6-tetrabenazine, deutetrabenazine [Austedo]	small molecules	FDA	2014-11-05	2017-04-03	Teva Branded Pharmaceutical Products R&D, Inc.
5,7-dichloro-2-dimethylaminomethyl-8-hydroxyquinoline hydrochloride	small molecules	FDA	2014-09-04	—	Prana Biotechnology Limited
Cysteamine bitartrate	small molecules	EMA	2014-07-29	—	Chiesi Farmaceutici S.p.A.
carbenoxolone	small molecules	FDA	2014-07-02	—	Oxalys Pharmaceuticals, Inc.
2-[4-(1-Methyl-4-pyridin-4-yl-lH-pyrazol-3-yl)-phenoxymethyl]-quinoline succinic acid	small molecules	FDA	2014-06-02	—	Pfizer Inc.
small molecule inhibitor of phosphodiesterase 10	small molecules	FDA	2013-09-26	—	Omeros Corporation
lithium citrate tetrahydrate (in reverse micelle formulation)	small molecules	FDA	2010-12-13	—	Medesis Pharma
Lithium citrate tetrahydrate (in reverse-micelle formulation)	small molecules	EMA	2010-01-28	—	Medesis Pharma
selisistat	small molecules	FDA	2009-12-07	—	AOP Orphan Pharmaceuticals AG
6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide	small molecules	EMA	2009-10-28	—	Aop Orphan Pharmaceuticals GmbH
recombinant adeno-associated virus encoded gene for X-linked mammalian inhibitor of apoptosis protein (XIAP)	gene therapies	FDA	2009-08-25	—	Neurologix, Inc.
dimebon	small molecules	FDA	2009-05-12	—	Medivation, Inc.
Latrepirdine dihydrochloride	small molecules	EMA	2009-01-20	—	IDEA Innovative Drug European Associates Limited
cysteamine	small molecules	FDA	2008-05-09	—	Horizon Therapeutics USA, Inc.
Clotrimazole	small molecules	FDA	2006-03-13	—	EnVivo Pharmaceuticals, Inc.
4-(3-Methanesulfonyl-phenyl)-1-propylpiperidine HCl	small molecules	FDA	2005-12-12	—	Prilenia Therapeutics
Creatine	small molecules	FDA	2005-10-11	—	Marathon Pharmaceuticals, LLC
4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine x HCl	small molecules	EMA	2005-06-20	—	Ferrer Internacional S.A.
ubiquinol	small molecules	FDA	2004-04-12	—	Gel-Tec, Division of Tishcon Corp.
Coenzyme Q10	small molecules	FDA	2001-03-05	—	Integrative Therapeutics, Inc.
Ethyl Eicosopentaenoate	small molecules	EMA	2000-12-29	—	Amarin Neuroscience Limited
Ethyl eicosapentaenoate	small molecules	FDA	2000-04-06	—	Laxdale Ltd.
Remacemide	small molecules	FDA	2000-03-06	—	AstraZeneca LP
Tiapride	—	FDA	1998-04-21	—	Sanofi-Synthelabo, Inc.
Tetrabenazine [Xenazine]	small molecules	FDA	1997-12-11	2008-08-15	Prestwick Pharmaceuticals, Inc
Porcine fetal neural gabaergic cells and/or precursors aseptically prepared for intracerebral implantation for Huntington's disease.	cell therapies	FDA	1996-12-10	—	Diacrin/Genzyme LLC
Porcine fetal neural gabaergic cells and/or precursors aseptically prepared and coated with anti-MHC-1 Ab for intracerebral implantation	cell therapies	FDA	1996-12-10	—	Diacrin/Genzyme LLC
Riluzole	small molecules	FDA	1996-10-15	—	Rhone-Poulenc Rorer Pharmaceuticals, Inc.

Huntington disease

Huntington disease

Huntington disease

Overview

Population

Burden

Therapies

Categories: rare genetic diseases, rare neurological diseases, rare ophthalmic disorders

Research Papers

2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.

2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.

2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.

2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.

2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

2026-08-14 | Real-world treatment patterns and outcomes of deutetrabenazine in patients with chorea associated with Huntington disease: A retrospective chart review study.

2026-08-12 | Blocking somatic repeat expansion and lowering huntingtin by RNAi synergize to attenuate Huntington's disease pathogenesis in mice.

2026-08-09 | Molecular insights of peroxisome proliferator-activated receptor-γ signalling in amyotrophic lateral sclerosis and Huntington's disease.

2026-08-05 | Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.

2026-07-24 | IL17A disrupts autophagy-lysosomal function and lysosome reformation through the GSK3B-TFE3 signaling pathway in Huntington disease.

Drug Discovery Landscape

Updated: Sep 6, 2026