Crigler-Najjar Syndrome (CN) is a rare genetic disorder caused by a defect of the UGT1A1 gene, which encodes the protein responsible for metabolizing bilirubin. The resulting toxic accumulation of bilirubin can cause severe neurological impairment and death. Phototherapy can help manage bilirubin levels, but requires 10-12 hour treatments each day and becomes less effective with age, at which point a liver transplant is required. GTP and Audentes are collaborating to advance AAV8-UGT1A1 (AT342) for the treatment of CN. A phase 1/2, multinational, open-label, ascending-dose, delayed-treatment concurrent control clinical study is planned (VALENS; NCT03223194).
Spinal muscular atrophy (SMA) is a rare genetic disorder caused by mutations in the SMN1 gene. These mutations lead to a deficiency of the survival motor neuron (SMN) protein, which results in the loss of specialized nerve cells in the spinal cord and brainstem such that information cannot be passed from the brain to the muscle. This leads to severe muscle weakness and loss of muscle control, as well as impaired breathing and swallowing in severe cases. As part of a collaborative alliance with Biogen, GTP is developing an AAV gene therapy approach to elicit long-term expression of SMN1 in motor neurons for the treatment of SMA.
There are 500,000 influenza-related deaths annually worldwide. In addition to seasonal influenza, new strains of influenza have the potential to cause a global pandemic. Vaccines are not always effective at protecting humans from influenza, and may not be available during a pandemic. In collaboration with Janssen Pharmaceuticals, Inc., GTP is developing AAV-based prophylactics against influenza A and B as an alternative to the traditional influenza vaccine in the setting of seasonal and/or pandemic influenza infections.
Hemophilia A is a genetic disorder where blood does not clot normally due to low levels of clotting factor VIII (FVIII). More than half of hemophilia A patients have a severe form of the disease, characterized by heavy bleeding after minor injury and spontaneous internal bleeding that affects muscles, joints, and organs such as the kidneys, GI tract, and brain. Current treatment manages the disease with recombinant factor VIII infusions multiple times a week for life. GTP is supporting Dimension’s development of an AAV-mediated FVIII gene therapy (DTX201) to achieve sustained FVIII expression with the goal of reducing or discontinuing replacement therapy infusions for an extended period of time.
Ornithine transcarbamylase (OTC) deficiency is an inherited X-linked genetic disease that causes the ammonia formed when proteins are degraded to accumulate in the blood. A late-onset form of the disease affects both males and females, and can result in altered mental status, headaches, vomiting, and seizures. Treatment includes dietary protein restriction, amino acid supplementation, and nitrogen-scavenging drugs. GTP is supporting Dimension’s development of an AAV8-OTC gene therapy approach (DTX301) for the treatment of this disease, which has advanced to a Phase 1/2 clinical trial (NCT02991144).