Frontotemporal Dementia (FTD)

Frontotemporal dementia (FTD) is one of most common forms of dementia in individuals under the age of 65 (second after Alzheimer’s disease), affecting 50,000 to 60,000 patients in the U.S. and over 100,000 in the European Union. This disease is characterized by the progressive degeneration of the frontal and temporal lobes of the brain, causing a decline in behavior, language, and executive function. FTD progresses more rapidly than Alzheimer’s disease, and death typically occurs three to ten years after the onset of symptoms. There are currently no approved therapies for FTD.

Approximately 30-40% of FTD cases are familial and linked to autosomal dominant mutations, primarily in three genes: granulin (GRN), microtubule-associated protein tau, and chromosome 9 open reading frame 72. In up to 10% of patients with FTD, the disease is caused by mutations in the GRN gene, resulting in deficiency of progranulin (PGRN). PRGN is a highly conserved and secreted protein thought to play several critical roles in multiple functions, including but not limited to neuroprotection, wound healing, and inflammation. Patients with FTD caused by mutations in the GRN gene (FTD-GRN) produce about half as much PRGN as healthy people. This reduction in PRGN leads to age-dependent lysosomal dysfunction, inflammation of the brain, and neurodegeneration.

Approximately 30-40% of FTD cases are familial and linked to autosomal dominant mutations, primarily in three genes: granulin (GRN), microtubule-associated protein tau, and . In up to 10% of patients with FTD, the disease is caused by mutations in the GRN gene, resulting in deficiency of progranulin (PGRN). PRGN is a highly conserved and secreted protein thought to play several critical roles in multiple functions, including but not limited to neuroprotection, wound healing, and inflammation. Patients with FTD caused by mutations in the GRN gene (FTD-GRN) produce about half as much PRGN as healthy people. This reduction in PRGN leads to age-dependent lysosomal dysfunction, inflammation of the brain, and neurodegeneration.

AGTC is developing a gene therapy product (AGTC-601) using a recombinant adeno-associated viral (rAAV) vector designed to potentially treat . In order to restrict expression to the central nervous system and avoid the concerns over systemic expression, the vector expresses a human GRN gene under the control of a neuronal promoter and is packaged in an AAVrh.10 capsid. Facilitated by a route of direct delivery to cerebrospinal fluid by an intracisterna magna injection, the vector is tailored to specifically augment PRGN levels in the central nervous system and restore its physiological balance with a single dose. We believe our approach has the potential to make a significant impact on the lives of FTD-GRN patients.