Microglial-targeted Gene Therapy: Developing a Disease Modifying Treatment for ALSP Associated with CSF1R Mutations (ALSP-CSF1R)
Neda Masoudi1, Jessie Willen1, Carter Daniels2, Beverly Ann Jenkins8, Ellen Conceicao Furber8, Milankumar Kothiya3, Michael B. Banjoko3, Raghu Gowda7, Jeremiah Hendricks3, Yi-Ya Fang3, Priyam Raut2, Adnan Arnaout4, Fares Bassil8, LiChin Wong3, Garrett Daniels5, Jorge Francisco Haller5, Sid Kamalakaran2, Travis Lewis6, Theresa Ann Day9, Benjamin Shykind1, Mansuo Shannon7, Franz Hefti7, Anindya Sen1
1Preclinical R&D, 2Genomic Engineering and Modeling, 3Bioanalytical, 4Analytical development, 5Process and Analytical development, 6Clinical, Prevail Therapeutics, a wholly-owned subsidiary of Eli Lilly and Company, 7Prevail Therapeutics, a wholly-owned subsidiary of Eli Lilly and Company, 8Eli Lilly and Company, 9Neurobiological, Eli Lilly and Company
Objective:
We are developing PR009 (LY3884965), a rAAV gene therapy, as a disease-modifying, one-time treatment for ALSP-CSF1R. PR009 is designed to enhance microglial function in patients’ brains by increasing TREM2 (Triggering receptor expressed on myeloid cells-2) levels.
Background:
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.
Design/Methods:
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.
Results:
In the in-vivo CSF1R-inhibition model, PR009 ICV injection resulted in broad biodistribution throughout the CNS and dose-dependent increase in hTREM2 expression. In a CSF1R-inhibition mouse model, treatment of PLX3397, a non-selective CSF1R inhibitor, resulted in depletion of the microglial pool, while pre-treatment with PR009 effectively attenuated this microglial depletion and maintained microglial health.
Conclusions:
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.