Pre-clinical development of AAV9-NF1 gene therapy for neurofibromatosis type 1

In vivo delivery of adeno-associated virus (AAV) vectors is the leading approach to develop gene therapies for genetic diseases with AAV9 being the most utilized for neurological diseases because of its neuronal tropism and safety profile. The major challenge in developing an AAV gene therapy for NF1 is the 8.4 kb open reading frame, which exceeds the 4.7kb packaging capacity of AAV. To address this challenge, we developed two AAV-NF1 vectors that restore NF1 function. 1) The AAV-NF1dual strategy uses two AAV vectors that split the human NF1 cDNA, and full-length protein expression relies on splicing across ITRs of concatemerized AAV genomes. Systemic AAV-NF1dual delivery leads to full-length NF1 expression in all tissues analyzed to date. 2) The AAV-NF1mini vector encodes a truncated NF1 protein composed of the GAP-related domain (GRD) and a lipid-binding domain. Results of this project will generate the pre-clinical dataset needed to conduct a pre-IND meeting with the FDA that will lead to the first in human AAV9-NF1 gene therapy clinical trial in NF1 patients.

Investigators

Miguel Sena-Esteves, PhD

UMass Chan Medical School

Miguel Sena-Esteves, PhD

UMass Chan Medical School

Current Stage

In Vivo Proof Of Concept

Discovery
In Vivo Proof of Concept
IND Enabling
Clinical Trial Phase 1
Clinical Trial Phase 2
Clinical Trial Phase 3