Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1)
Company: Eli Lilly & Co., Prevail Therapeutics
PR006 is a gene-replacement therapy that uses adeno-associated virus 9 (AAV9) to deliver a functional copy of the progranulin gene GRN to the brain. Progranulin mutations are a frequent cause of familial frontotemporal dementia. Mutations result in 30 to 50 percent reductions in cerebrospinal fluid progranulin levels compared to the normal range. The loss of progranulin interferes with proper lysosomal function, leading to build-up of toxic proteins, neuroinflammation, and neurodegeneration (e.g., Sept 2017 news).
GRN is also implicated in Alzheimer’s disease. Variants that reduce progranulin levels increase risk of AD, and progranulin reduction exacerbates AD pathology in animal models (reviewed in Elia et al., 2020).
PR006 is delivered as a one-time injection into the cerebrospinal fluid in the cisterna magna at the base of the brain. No preclinical work on PR006 is published. At conferences, company scientists reported that PR006 increased progranulin release and improved lysosomal function of neurons derived from FTD-GRN patients, that PR006 restored brain GRN expression and progranulin secretion into the CSF in progranulin knockout mice, and that PR006 appeared safe and resulted in broad progranulin expression in the brain and periphery in nonhuman primates (see Nov 2019 news, webcast).
In July 2020, Prevail began a Phase 1/2 trial of PR006 in 15 people with FTD due to a progranulin mutation. Participants must be living independently and have symptoms. The five-year study will test three doses, administered as a single injection concomitantly with an immunosuppressive regimen of steroids and sirolimus. There is no placebo group. The primary endpoints are number of adverse events over the five years, plus immunogenicity of the virus and progranulin, and progranulin levels in blood and CSF in the first year. Secondary outcomes are one-year changes in measures of clinical decline, as well as neurofilament light chain concentrations in CSF and blood. The first patient was treated in December 2020 (press release). The trial will run at four sites in the U.S. through 2027.
PR006 has orphan drug designation for FTD from U.S. and European regulators, and fast-track designation for FTD-GRN in the U.S.
In January 2021, Prevail was acquired by Eli Lilly & Company (press release).
For details on PR006 trials, see clinicaltrials.gov.
Last Updated: 22 Jan 2021
- Lysosomes Take Center Stage in Parkinson’s and Frontotemporal Dementia
- Time to Try Again: Gene-Based Therapy for Neurodegeneration
- Elia LP, Reisine T, Alijagic A, Finkbeiner S. Approaches to develop therapeutics to treat frontotemporal dementia. Neuropharmacology. 2020 Apr;166:107948. Epub 2020 Jan 8 PubMed.
No Available Further Reading