Huntington Disease (HD)

Huntington disease (HD), an inherited disease of the brain, is characterized by the progressive loss of both mental faculties and physical control. The disease is due to expansion of the cytosine-adenine-guanine (CAG) trinucleotide sequence in the HTT gene; the resultant abnormal protein gradually causes neuronal destruction. Symptoms typically first appear in individuals between the ages of 30 and 50 years and worsen over 10 to 25 years. The weakened patient eventually dies of complications such as pneumonia, heart failure, and other diseases.1

At present, no effective treatment or cure for the illness is available; current medications mask symptoms temporarily but do not stop the underlying loss of neurons.1 Several experimental therapies are currently in development, not only to treat symptoms of disease but also to pursue underlying pathophysiology. 


Tominersen, also known as IONIS-HTTRx and RG6042, is an experimental antisense drug that targets the underlying cause of HD by reducing the production of huntingtin protein (HTT), including its mutant variant (mHTT).1 

GENERATION HD2 (NCT05686551), a phase 2 clinical trial, is currently enrolling participants. It will assess tominersen in patients with an early manifestation of HD and patients in the prodromal stage of the illness, when characteristic symptoms are not yet apparent.2 

Read more about HD clinical trials


SAGE-718, a derivative of the endogenous steroid 24(S)-hydroxycholesterol, is a positive allosteric modulator of the NMDA receptor. For this reason, it is crucial for learning and memory because it induces the long-term potentiation of synapses. 24(S)-hydroxycholesterol is the most abundant cholesterol metabolite in the brain. Its role in neurodegenerative diseases and brain function is complex. It has both beneficial and detrimental functions on neuronal survival, function, tau, and amyloid pathology. SAGE-718 is being developed to treat cognitive dysfunction in patients with neurodegenerative diseases.3 

The PERSPECTIVE Program, which includes 3 clinical research studies, is assessing the efficacy and safety of the investigational oral medication, SAGE-718, in adults with early HD. SAGE-718 is believed to address cognitive problems.4 

The first study in the PERSPECTIVE Program, DIMENSION (NCT05107128), is a randomized, placebo-controlled, double-blind phase 2 clinical research trial in which the efficacy and safety of SAGE-718 are being assessed in the management of cognitive symptoms in adults with premanifest or early-manifest HD. Cognitive symptoms may include poor judgment, forgetfulness, trouble focusing, and difficulty formulating solutions to complicated problems.5 

Read more about HD clinical features


INT41, an intrabody drug administered through gene therapy, inhibits gene dysregulation in HD by neutralizing a toxic fragment of huntingtin mutant protein (mHTT) in the cell nucleus.6 

Viral vectors are used to deliver antibodies that target mHtt as intrabodies; these attach to various epitopes of the target protein, inactivate the protein, stop intracellular protein misfolding, and improve protein clearance. The target in HD is the N-terminal exon 1 domain and polyP/proline-rich region. When coupled with a viral vector and injected into the striatum of R6/2 mice, rAAV6-INT41, an intrabody that targets the polyP/proline-rich area, has been shown to decrease small and large mHtt aggregates and alleviate cognitive impairments.7

INT41 has received an Orphan Drug Designation from the US Food and Drug Administration (FDA) for the treatment of HD.8 

Read more about HD genetics

Pepinemab (VX15/2503) 

Semaphorin 4D, a multifunctional membrane glycoprotein expressed by oligodendrocytes and astrocytes in the CNS, is the target of pepinemab, a humanized immunoglobulin G4 monoclonal antibody. Stressed or injured neurons generate soluble Sema4D, which binds to receptors on glia and triggers the release of inflammatory cytokines. Sema4D disrupts the blood-brain barrier and blocks axon extension and oligodendrocyte migration. Pepinemab neutralizes Sema4D to prevent these processes.9 

Pepinemab is being developed by Vaccinex as a potential therapy for HD. Pepinemab has the potential to become the first disease-modifying treatment for patients with HD because it targets Sema4D, which is thought to be a major contributor to neuroinflammation.13 

Pepinemab HD has received Orphan Drug and Fast Track designations from the FDA Division of Neurology Products for the treatment of HD.10 

Vaccinex recently completed SIGNAL-HD, a multicenter, randomized, double-blind, placebo-controlled, late-stage clinical study of pepinemab that examined the effect of pepinemab in patients with late prodromal or early-manifesting HD (NCT02481674). During 18 months of treatment, pepinemab was well tolerated, and the rates of discontinuation or study dropout were low. Pepinemab may aid cognition and prevent brain atrophy in patients with HD.10 

Read more about HD prognosis


  1. Tominersen. Ionis Pharmaceuticals. Accessed August 14, 2023.
  2. Shapiro L. New phase 2 trial of tominersen enrolling people at early stages. News release. Huntington’s Disease News; March 7, 2023.
  3. SAGE-718. AlzForum. Updated May 16, 2022. Accessed August 14, 2023.
  4. About the PERSPECTIVE program.  Sage Therapeutics. Accessed August 14, 2023.
  5. Sage Therapeutics provides important update on the clinical development program for Sage’s investigational drug, Sage-718. Huntington’s Disease Society of America. February 2022. Accessed August 14, 2023.
  6. Vybion’s Huntington drug neutralizes critical disease driver. News release. Vybion; September 3, 2013.
  7. Jurcau A, Jurcau MC. Therapeutic strategies in Huntington’s disease: from genetic defect to gene therapy. Biomedicines. 2022;10(8):1895. doi:10.3390/biomedicines10081895
  8. Vybion drug pipeline. Accessed August 14, 2023.
  9. Pepinemab. AlzForum. Updated February 14, 2023. Accessed August 14, 2023.
  10. Pepinemab neurology. Vaccinex. Accessed August 14, 2023.

Reviewed by Debjyoti Talukdar, MD, on 8/17/2023.