Gene Therapy for SLC6A8 Creatine Transporter Disorder
Grant Award Details
Grant Type:
Grant Number:
DISC2-14090
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$2,296,920
Status:
Active
Grant Application Details
Application Title:
Gene Therapy for SLC6A8 Creatine Transporter Disorder
Public Abstract:
Research Objective
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).
Impact
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
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).
Impact
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.
Statement of Benefit to California:
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.
Publications
- Sci Rep (2025): [(18)F]FDG-PET and [(18)F]MPPF-PET are brain biomarkers for the creatine transporter Slc6a8 loss of function mutation. (PubMed: 40025148)
- Mol Ther (2024): Recent developments in translational imaging of in vivo gene therapy outcomes. (PubMed: 39741403)
