Grant Award Details
- Develop and test a brain-delievered AAV-SLC6A8 gene therapy approach to treat disorders of the creatine transporter SLC6A8; efficacy will be explored in ethnically diverse human SLC6A8-mutated cell lines and B) a mutated Slc6a8 murine model of the disorder
Grant Application Details
- Gene Therapy for SLC6A8 Creatine Transporter Disorder
The objective is to define a final therapeutic candidate for an effective gene therapy for mutations of the creatine transporter SLC6A8, a major cause of X-linked intellectual disability (ID).
This disorder results in severe ID, autistic-like behavior, seizures, & lack or delay of speech with no treatment. Improving brain transduction is essential and widely applicable to other conditions.
Major Proposed Activities
- Develop multiple adeno-associated viral (AAV) vectors expressing human SLC6A8, package, determine titers and expression in human induced pluripotent stem cell (hiPSC)-derived neurons in vitro.
- Assess resolution of any deficits and improvement in creatine transport in SLC6A8-mutated hiPSC-derived neurons by vector-mediated expression.
- Assess transduction efficiency of AAV-SLC6A8 in vivo with brain cell expression and distribution of vector copies and tissue creatine levels in non-brain organs and tissues in Slc6a8-mutated mice.
- Assess disease modifying activity of AAV-SLC6A8 in the a murine Slc6a8-mutated model.
- Determine final therapeutic candidate, complete draft target product profile, and develop assays of purity, activity and identity.
- Request INTERACT meeting.
Genetic-based intellectual disability of all causes is a more common occurrence than is appreciated. Effective therapies for these intellectual disabilities, where often there are none, could improve the lives of thousands of afflicted Californians & their families along with many hundreds of thousands of afflicted people worldwide. Brain gene therapy may result in novel, effective treatments for these disorders & improvement in their quality of life, with applicability to other conditions.