Adult-onset Leukoencephalopathy with axonal Spheroids and Pigmented glia (ALSP) is a rare neurological disorder characterized by demyelination of white matter, spheroidal axons, and pigmented glia. The majority of ALSP cases have been linked to mutations in the colony stimulating factor 1 receptor (CSF1R) gene, a transmembrane tyrosine kinase receptor that expresses in brain microglia. CSF1R function is necessary for the development and maintenance of microglia. Similar to CSF1R, TREM2 is a receptor expressed in brain microglia, sharing a common signaling pathway with CSF1R to activate microglia. Thus, PR009-induced increase in cellular TREM2 is expected to compensate for CSF1R loss-of-function in patients and ameliorate ALSP-CSF1R-associated pathophysiology.

To mimic CSF1R loss observed in patients, we developed in vitro and in vivo CSF1R-inhibition models. PR009, designed to deliver a functional hTREM2 gene packaged in a microglia-tropic capsid, was delivered in a CSF1R-inhibition mouse model to test efficacy in addition to NHPs to evaluate safety and biodistribution.

Currently, there is no disease-modifying therapy for ALSP-CSF1R and the use of available drugs is limited to managing disease associated symptoms. Our findings suggest that PR009 has the potential to treat the underlying cause of ALSP-CSF1R by expressing hTREM2 in the microglia of patients, resulting in restoration of microglial function and survival.