Sortilin

Class

Anti-sortilin monoclonal antibody (progranulin-raising)

Sortilin is a transmembrane sorting receptor belonging to the VPS10P-domain family. One of its principal functions is to bind the secreted protein progranulin and route it into cells, where it is delivered to lysosomes and degraded. By controlling this clearance step, sortilin sets the steady-state amount of progranulin available in blood and tissue, including the central nervous system. Progranulin itself is a growth-factor-like protein with neurotrophic and anti-inflammatory properties, and it supports normal lysosomal function within neurons and immune cells. In certain neurodegenerative conditions, most notably a genetic form of frontotemporal dementia caused by mutations in the progranulin gene, one copy of the gene is nonfunctional, leaving roughly half the normal amount of protein. This shortfall is thought to impair neuronal and lysosomal health over time. An antibody that blocks the sortilin-progranulin interaction prevents progranulin from being taken up and destroyed, raising its circulating and tissue concentrations. The therapeutic rationale is to compensate for genetic deficiency by increasing the supply of a protein whose scarcity drives disease, rather than by correcting the underlying mutation. This mechanism is being explored broadly for progranulin-deficiency states and other conditions where lysosomal or neuroinflammatory dysfunction contributes to neurodegeneration.