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Abstract Details

Microglial-targeted Gene Therapy: Developing a Disease Modifying Treatment for ALSP Associated with CSF1R Mutations (ALSP-CSF1R)
General Neurology
P11 - Poster Session 11 (5:30 PM-6:30 PM)
4-012

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.

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.  

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.

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.

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.

Authors/Disclosures
Neda Masoudi (Prevail Therapeutics, a wholly-owned subsidiary of Eli Lilly and Company)
PRESENTER
No disclosure on file
Jessie Willen (Prevail Therapeutics) No disclosure on file
Carter Daniels (Prevail Therapeutics a wholly owned subsidiary of Eli Lilly & Co) No disclosure on file
Beverly Jenkins (Eli Lilly & Company) No disclosure on file
Ellen Furber (Eli Lilly) No disclosure on file
Milan Kothiya (Eli LIlly) No disclosure on file
Michael Banjoko (Prevail Therapeutics - Eli Liily) No disclosure on file
Raghavendra Gowda (Prevail Therapeutics, a wholly owned subsidiary of Eli Lilly and Company) No disclosure on file
Jeremiah Hendricks (Prevail Therapeutics) No disclosure on file
Yi-Ya Fang (Eli Lilly) No disclosure on file
Priyam Raut (Eli Lilly and Company) No disclosure on file
Adnan Arnaout (Eli Lilly and Company) No disclosure on file
FARES BASSIL (Eli Lilly) No disclosure on file
Li Chin Wong No disclosure on file
Garrett Daniels (Eli Lilly) No disclosure on file
Jorge Haller (Prevail Therapeutics) No disclosure on file
Sitharthan Kamalakaran (Prevail Therapeutics) No disclosure on file
Travis B. Lewis, MD, PhD (PREVAIL THERAPEUTICS) Dr. Lewis has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Lewis has stock in Eli Lilly and Company.
Theresa Day (Eli Lilly and Company) No disclosure on file
Ben Shykind No disclosure on file
Mansuo Shannon (Yes) No disclosure on file
Franz Hefti (Prevail Therapeutics) No disclosure on file
Anindya Sen No disclosure on file