AL001 blocks the Sortilin/PGRN interaction and is a potential therapy for FTD-GRN

Frontotemporal dementia (FTD) is a rare, early-onset form of dementia that presents with marked changes in personality, speech, executive function, and movement.  Heterozygous loss-of-function GRN mutations in the progranulin gene (GRN) causes a more than 50% reduction in secreted functional progranulin protein (PGRN) and almost invariably lead to development of FTD, making GRN a causal gene for the disease.  Therefore, elevating functional PGRN levels in individuals carrying GRN mutations causative of FTD (FTD-GRN individuals) may be a viable therapeutic strategy.

In the brain, PGRN is expressed primarily by neurons and microglia and is involved in neuronal survival, neurite outgrowth, and synaptogenesis and is a key regulator of neuroinflammation and lysosomal function. The Sortilin receptor has been identified as the major regulator of PGRN levels. Sortilin binds extracellular PGRN and mediates its endocytosis and metabolism via lysosomes. Therefore, blocking Sortilin/PGRN interactions provides a therapeutic strategy for sustaining levels of functional secreted PGRN in the central nervous system (CNS) with the potential to minimize progression of FTD-associated dementias.

AL001 effectively binds Sortilin with a high affinity and blocks the interaction between PGRN and Sortilin receptor. Blocking Sortilin with the AL001 antibody increases PGRN levels in plasma and cerebrospinal fluid (CSF) in non-human primate models, healthy volunteers, and heterozygous carriers of GRN mutations.

AL001 is being developed for the treatment of carriers of GRN mutations causative of FTD to reduce the rate of neurodegeneration by increasing levels of PGRN in the periphery and the brain.