In Lesch-Nyhan Syndrome, the HPRT gene is affected which causes a myriad of symptoms including dopamine deficiency in the brain. To investigate a gene therapy intervention for LNS, an AAV (adeno-associated virus) vector carrying the HPRT gene was developed. It was initially thought that dopamine-producing neurons of the brain should be the target for delivery of the AAV, however, tests in a mouse model of LNS showed that targeting these neurons did not lead to an increase in dopamine levels. Other routes of administration were explored and delivery of vector directly to the cerebral spinal fluid (CSF) was identified as a potential route of administration. AAV carrying the HPRT gene could increase the level of dopamine expression in the brains of LNS mice when delivered intra-CSF to other types of cells in the brain.

With a lead gene therapy candidate and a route of administration identified, current mouse studies are focused on replicating the results, exploring dosing options, and understanding where HPRT expression in the brain is necessary for rescue. Once mouse studies are completed, a pilot non-human primate study using the same vector and route of administration will need to be conducted to assess the overall safety of this gene therapy vector. Once both mouse and non-human primate studies are completed, a pre-IND can be submitted to the FDA to ask for feedback regarding the development of this gene therapy for LNS patients.

• GENE THERAPY FOR LESCH-NYHAN SYNDROME PDF