A University of Pittsburgh researcher is developing gene therapy for Prader-Willi syndrome (PWS). Developed using novel mini promoters to enhance gene expression and a PWS-minigene adeno-associated virus (AAV) vector, it may be possible to treat this neurodevelopmental disorder.
Description
PWS typically presents as behavioral abnormalities resulting in complications including overeating leading to obesity, self-injury, growth hormone deficiency, hypoglycemia and an increased risk of psychiatric conditions. The actual cause of PWS remains unknown, but a cluster of 10 genes are believed to be involved. Treatment of PWS is a clinical unmet need, and effective treatment could be life changing for patients, their families and society.
Applications
• Prader-Willi syndrome
• Developmental disorders involving multiple genes
Advantages
As a complex condition, PWS is not a consequence of just one gene but a cluster of 10 genes. The role of these 10 genes is poorly understood and difficult to target directly. Traditional management of PWS is through early diagnosis using DNA testing, modification of diet, and growth hormone treatment. However, many clinical issues remain untreated. Given the large number of genes involved in PWS, traditional gene therapy is not a feasible option due to limits in delivering more than one gene using AAV vectors.
This novel approach proposes a single AAV vector which can code up to 80% of PWS genes. Through miniaturization of genetic material and use of a novel minigene expression promoter, it should be possible to encode up to eight genes in a polycistronic AAV vector. This is the first of this type of multigenic AAV vector to be developed. Success will allow for the development of treatments that reactivate or replace silent or missing genes in PWS and other multigene conditions.
Invention Readiness
Currently at the concept stage, a PWS-minigene AAV vector has been designed to replace 80% of deficient functions in PWS. Genes involved in PWS are 2–3 Mb in length, far above the 4.75 kb packaging capacity of AAV-vectors. This PWS-minigene AAV vector will encode eight of the 10 major PWS genes including SNURF, SNRPN and five snoRNAs. In addition, using mini promoters based on the transcription factor NRF1 and synthetic introns the payload will remain below the 4.75 kb limit. Following synthesis and optimization of this AAV vector, in vitro and in vivo testing will be required.
IP Status
https://patents.google.com/patent/WO2024182378A1
