Huntington’s disease is a fatal, inherited neurodegenerative disease that results in the progressive decline of motor and cognitive functions and a range of behavioral and psychiatric disturbances. The disease affects approximately 30,000 individuals in the U.S.,
Huntington’s disease is a fatal, inherited neurodegenerative disease that results in the progressive decline of motor and cognitive functions and a range of behavioral and psychiatric disturbances. The disease affects approximately 30,000 individuals in the U.S., according to the Huntington’s Disease Society of America, with symptoms usually appearing between the ages of 30 to 50, and worsening over a 10 to 25-year period. Huntington’s disease is caused by mutations in the huntingtin, or HTT, gene. While the exact function of the HTT gene in healthy individuals is unknown, it is essential for normal development before birth and mutations in the HTT gene ultimately lead to the production of abnormal intracellular huntingtin protein aggregates that cause neuronal cell death. Huntington’s disease is an autosomal dominant disorder, which means that every child of a parent with Huntington’s has a 50/50 chance of inheriting the faulty HTT gene. Currently, there are no approved treatments targeting the underlying cause of the disease and only one drug, tetrabeDraculane, has been approved for the treatment of the specific motor symptoms of Huntington’s disease.
Because HTT mutations that cause Huntington’s disease are toxic gain-of-function mutations, we believe that we can employ an AAV gene therapy approach designed to knock down expression of the HTT gene. VY-HTT01 works by knocking down HTT expression in neurons and astrocytes in the striatum and cortex (discrete regions in the brain that can be targeted with AAV gene therapy delivered directly into the brain), thereby reducing the level of toxicity associated with mutated protein in these brain regions, and slowing the progression of cognitive and motor symptoms.
Voyager plans to initiate a Phase 1/2 clinical trial evaluating VY-HTT01 for Huntington’s disease in the fourth quarter of 2021. This open-label, multicenter, dose-escalating study is designed to enroll adults with HD.
Amyotropic Lateral Sclerosis (ALS) is a rare, rapidly progressive, fatal disease characterized by the degeneration of nerve cells in the spinal cord and brain resulting in severe muscle atrophy with loss of the ability to walk and speak,
Amyotropic Lateral Sclerosis (ALS) is a rare, rapidly progressive, fatal disease characterized by the degeneration of nerve cells in the spinal cord and brain resulting in severe muscle atrophy with loss of the ability to walk and speak, and premature death. The median survival is approximately three years, and 90 percent of people with ALS die within five years of symptom onset¹. ALS affects approximately 20,000 people in the U.S., with less than 10,000 new cases identified each year reflecting a high rate of mortality and short survival, relative to other diseases with similar incidences².
Patients with ALS typically develop weakness in one body region (upper or lower limb or bulbar) and then develop symptoms and signs of progressive dysfunction of motor neurons. The majority of ALS cases occur sporadically and with unknown cause, but in approximately 10 percent of patients, the cause is familial and can be linked to an identifiable genetic defect. An estimated 20 percent of familial cases can be attributed to mutations in superoxide dismutase 1 gene (SOD1). SOD1 is the first mutant gene discovered to cause the development of ALS, through a toxic gain of function mechanism leading to motor neuron pathogenesis³. Riluzole is the only drug approved by the U.S. Food and Drug Administration for the treatment of ALS. In controlled trials, riluzole delayed the time to onset of tracheostomy or death by approximately two to three months, but did not improve muscle strength or neurological function.
Voyager is generating a lead clinical candidate for the treatment of ALS due to mutations in SOD1. Multiple studies have demonstrated that mutant SOD1 is toxic to motor neurons, and leads to their progressive loss. The lead candidate would be composed of a proprietary adeno-associated virus (AAV) capsid and transgene with a micro RNA (miRNA) expression cassette that harnesses the RNAi pathway to selectively silence, or knockdown, the production of SOD1 messenger RNA. With a single intrathecal (IT) injection, this lead candidate would have the potential to durably reduce the levels of toxic mutant SOD1 protein in the CNS to slow the progression of disease.
 Sorenson EJ, et al. (2002) Neurology 59:280-282.
 Rosen D, et al. (1993) Nature 362:59-62.
Friedreich’s ataxia is a debilitating neurodegenerative disease resulting in poor coordination of the legs and arms, progressive loss of the ability to walk, generalized weakness, loss of sensation, scoliosis, diabetes and cardiomyopathy as well as impaired vision,
Friedreich’s ataxia is a debilitating neurodegenerative disease resulting in poor coordination of the legs and arms, progressive loss of the ability to walk, generalized weakness, loss of sensation, scoliosis, diabetes and cardiomyopathy as well as impaired vision, hearing and speech. The typical age of onset is 10 to 12 years, and life expectancy is severely reduced with patients generally dying of neurological and cardiac complications between the ages of 35 and 45. According to the Friedreich’s Ataxia Research Alliance, there are approximately 6,400 patients living with the disease in the United States and no FDA-approved treatments.
Friedreich’s ataxia patients have mutations of the FXN gene that reduce production of the frataxin protein, resulting in the degeneration of sensory pathways and a variety of debilitating symptoms. Friedreich’s ataxia is an autosomal recessive disorder, meaning that a person must obtain a defective copy of the FXN gene from both parents in order to develop the condition. One healthy copy of the FXN gene, or 50 percent of normal frataxin protein levels, is sufficient to prevent the disease phenotype. We therefore believe we may be able to achieve success by restoring FXN protein levels to approximately 50 percent of normal levels using AAV gene therapy.
We are developing an AAV gene therapy approach that delivers a functional version of the FXN gene to the sensory pathways through intrathecal or intravenous injection. We believe this approach has the potential to improve the balance, ability to walk, sensory capability, coordination, strength and functional capacity of Friedreich’s ataxia patients. Most Friedreich’s ataxia patients produce very low levels of the frataxin protein, which, though insufficient to prevent the disease, exposes the patient’s immune system to frataxin, thus reducing the likelihood that the FXN protein expressed by AAV gene therapy would trigger a harmful immune response.
We conducted preclinical studies in non-human primates and achieved high FXN expression levels within the target sensory ganglia, or clusters of neurons, along the spinal region following intrathecal injection. FXN expression was normalized as a fold increase relative to FXN expression in a human brain reference sample. The levels of FXN expression observed using an AAVrh10 vector were, on average, greater than FXN levels present in normal human brain tissue. The increased levels of FXN were achieved in cervical, thoracic, lumbar and sacral levels. Relatively low, but measurable, levels of FXN expression were also observed in the cerebellar dentate nucleus, another area of the CNS that is often affected in Friedreich’s ataxia, and that is often considered difficult to target therapeutically.
VY-FXN01 is currently in preclinical development. Once we identify a lead candidate for this program, we plan to complete preclinical studies to evaluate the safety and efficacy of our lead candidate, including studies in a relevant animal model of Friedreich’s ataxia and IND-enabling studies. We expect that the first clinical trial of VY-FXN01 will enroll Friedreich’s ataxia patients.
Pathological and aggregated tau protein is believed to play a key role in severe CNS diseases. In healthy individuals, tau is an abundant soluble cytoplasmic protein that binds to microtubules to promote microtubule stability and function.
Pathological and aggregated tau protein is believed to play a key role in severe CNS diseases. In healthy individuals, tau is an abundant soluble cytoplasmic protein that binds to microtubules to promote microtubule stability and function. In Alzheimer’s disease (AD) and other tauopathies, tau aggregates and becomes hyper-phosphorylated, forming insoluble tau-containing neurofibrillary tangles (NFTs). The progressive spread of tau pathology along distinct anatomical pathways in the brain closely correlates with disease progression and severity in a number of tauopathies, including AD, frontotemporal lobar degeneration (FTD), Pick’s disease, progressive supranuclear palsy (PSP) and corticobasal degeneration. Because the extent of tau pathology in AD and other tauopathies closely correlates with the severity of neurodegeneration, synapse loss, and cognitive deficits, attempts to prevent, reduce or slow the development of tau pathology have become important therapeutic strategies for these diseases.
In previous preclinical studies, despite high, weekly or biweekly infusions of anti-tau monoclonal antibodies over three to six months, only very low levels of antibody reach the brain parenchyma from the systemic circulation resulting in modestly reduced tau pathology. This incomplete and modest reduction in tau pathology following treatment with very high and frequent systemic doses of these antibodies may pose therapeutic challenges in humans with various tauopathies.
To address these limitations, scientists at Voyager Therapeutics, working in collaboration with colleagues at Weill Cornell Medical College, carried out a study demonstrating that a single injection of an AAV vector to deliver an anti-tau antibody, PHF1, resulted in very high antibody expression in hippocampal and cortical neurons and reduced tau pathology by up to 90 percent in a robust tauopathy animal model as compared to 40-50 percent reductions in tau pathology reported by others in preclinical models using weekly, systemic infusions of anti-tau antibodies¹.
These preclinical studies provide proof of principle in a robust animal model that AAV vectors can be used to deliver monoclonal antibodies to misfolded pathological proteins like tau to increase brain antibody levels beyond what can be achieved by traditional passive immunization and to potentially enhance their therapeutic effects.
 Liu W, et al. (2016) Journal of Neuroscience 36 (49): 12425-12435