Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts

Area of Science:

• Genetics
• Molecular Biology
• Gene Therapy

Background:

• Lowe syndrome is a rare X-linked disorder affecting eyes, kidneys, and the central nervous system.
• It is caused by mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase.
• Currently, no effective targeted treatments exist for Lowe syndrome.

Purpose of the Study:

• To investigate the potential of adenine base editor (ABE) gene therapy for Lowe syndrome.
• To correct pathogenic point mutations in the OCRL gene using ABE technology in patient-derived cells.

Main Methods:

• Utilized an ABE8e-NG system to correct a specific disease-causing mutation (R844X) in the OCRL gene within Lowe patient fibroblasts.
• Assessed the restoration of OCRL gene expression at both mRNA and protein levels.
• Evaluated the correction of cellular abnormalities associated with OCRL dysfunction, including ciliogenesis, microtubule anchoring, and cytoskeletal organization.

Main Results:

• ABE-mediated gene therapy successfully corrected the R844X mutation in OCRL gene in patient fibroblasts.
• Restored OCRL expression at mRNA and protein levels.
• Reversed cellular hallmarks of OCRL dysfunction, such as defects in ciliogenesis and cytoskeletal organization.

Conclusions:

• ABE-mediated gene therapy is a feasible and promising treatment strategy for Lowe syndrome.
• This study lays the groundwork for applying ABE technology to treat this currently incurable genetic disorder.