Use of induced pluripotent stem cell models to probe the pathogenesis of Choroideremia and to develop a potential...

Area of Science:

• Ophthalmology
• Genetics
• Stem Cell Biology

Background:

• Choroideremia (CHM) is an X-linked inherited retinal disease caused by mutations in the REP1 gene.
• The specific retinal cells affected in CHM pathogenesis remain unclear.
• Induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) models offer a platform to study CHM.

Purpose of the Study:

• To investigate CHM pathogenesis using iPSC-RPE models.
• To evaluate a potential gene therapy for CHM using adeno-associated virus (AAV) delivery.
• To identify optimal AAV serotypes for targeting retinal cells.

Main Methods:

• Generated iPSC-RPE models from four distinct CHM patient forms.
• Identified AAV7m8 as an efficient vector for retinal gene delivery.
• Constructed AAV7m8.hCHM for delivering the human CHM gene.
• Assessed functional restoration in CHM iPSC-RPEs post-gene therapy.

Main Results:

• CHM iPSC-RPEs exhibited abnormal cellular, biochemical, and physiological functions.
• AAV7m8 demonstrated efficient transduction of iPSC-RPEs and primate retinal cells.
• Gene therapy with AAV7m8.hCHM restored protein prenylation, trafficking, and phagocytosis in CHM iPSC-RPEs.
• Therapeutic effects were observed irrespective of the specific CHM mutation.

Conclusions:

• iPSC-RPE models are valuable for studying CHM disease mechanisms.
• AAV7m8-mediated gene delivery is a promising strategy for CHM therapy.
• Successful gene therapy rescues key cellular defects in CHM, offering hope for vision restoration.