Experimental Treatments for Huntington's Disease
Antisense oligonucleotides are a type of gene-silencing treatment being developed for Huntington’s disease. A few of these experimental therapies are currently in various stages of the clinical development process. Antisense oligonucleotides are artificially created nucleotides that bind to the HTT messenger RNA and prevents it from being translated into protein. In this way, the gene is “silenced,” or blocked, from creating toxic proteins.
CRISPR/Cas9 is an experimental gene-editing technique that could permit the “silencing” of the mutated HTT gene and prevent the formation of faulty protein in Huntington’s disease. This potential therapeutic approach is aimed at cutting out the mutated region of the HTT gene, thus permanently removing the mutation from the genome of every cell that is edited. The approach is currently in preclinical testing for Huntington’s.
Deep Brain Stimulation
Deep brain stimulation is a treatment for certain neurological conditions that is also being investigated for Huntington’s. It involves the surgical implantation of an electrode in the brain Wires passing through the neck connect the electrode to a stimulator in the chest. The stimulator is a small device that delivers a controlled electronic pulse to the brain. The approach is being tested in a trial for the treatment of chorea in Huntington’s patients.
Pridopidine is an investigational small molecule being developed to potentially treat Huntington’s symptoms. At low doses, it binds to the sigma 1 receptor (S1R), which plays a role in neuroprotection. By binding to S1R in the brain, pridopidine may work to activate the receptor and possibly increase the production of brain-derived neurotrophic factor. It is currently being tested in an ongoing Phase 3 trial.
Resveratrol is a natural substance found in small quantities in grapes, blueberries, and cranberries, and is also available as a dietary supplement. Resveratrol directly or indirectly stimulates the activity of an enzyme called sirtuin type 1, which is known to upregulate key metabolic and anti-inflammatory pathways that protect cells from injury. Animal models of Huntington’s have shown the neuroprotective effects of resveratrol, and a Phase 3 trial in patients has been completed.
Gene silencing by RNA interference (RNAi) is a potential therapeutic approach for the treatment of Huntington’s disease. The goal of this strategy is to reduce the amount of abnormal huntingtin protein being produced in cells. RNAi therapy is intended to deliver, with the help of adeno-associated viral vectors, micro RNAs that degrade HTT messenger RNA so that the amount of HTT protein decreases.
SOM3355 is being developed to treat movement disorders in Huntington’s disease. The investigational therapy is thought to reduce chorea by inhibiting VMAT2. It is a repurposed treatment, based on the same formulation as Xenazine (tetrabenazine), another VMAT2 inhibitor approved for Huntington’s. It has successfully finished Phase 2a trials, and Phase 2b is currently underway.
SRX246 is being developed to treat neuropsychiatric conditions such as irritability and aggression. The investigational therapy interferes with the action of vasopressin, a signaling molecule in the brain that is associated with aggressive and irritable behavior. It recently completed a Phase 2 trial.
Triheptanoin (also known as C7 oil) is an artificially produced triglyceride, a kind of fat, being developed to treat brain energy deficits by improving brain metabolism. Triheptanoin is thought to have an anaplerotic role, meaning that it can replenish substances involved in the tricarbolic acid cycle, a pathway used by cells to produce energy, providing an alternative source of energy to the brain. It is currently being studied in Huntington’s patients in a a Phase 2 trial.
VX15/2503 (pepinemab) is a monoclonal antibody that targets the protein semaphorin 4D (SEMA4D) developed to slow down and prevent neurodegeneration in patients with Huntington’s disease. VX15/2503 blocks the activity of SEMA4D, thereby preventing the activation of microglia and astrocytes, which are the main inflammatory cells in the brain. A completed Phase 2 trial showed good tolerability.