Novel Cell Therapy for CTLA4 Haploinsufficiency

Invention Novelty

Scientists have developed a CRISPR-Cas9 based genome editing method for universal correction of disease-causing mutations in the CTLA4 gene, which most commonly manifest as a Primary Immunodeficiency. Current treatment involves monthly IV injections or weekly subcutaneous injections of a recombinant CTLA4-Ig fusion protein abatacept. This invention includes one-time infusion of a CTLA4-corrected autologous T cell therapy. The corrected patient cells are generated by ex vivo electroporation of a specific gRNA:Cas9 ribonucleoprotien (RNP) complex and cognate homology-directed-repair template (HDRT) targeting a functional copy of the CTLA4 gene within an intronic region of the endogenous CTLA4 gene. This combination allows for (1) highly efficient knockin (up to 70% in patient cells), (2) cell-type and context specific regulation of CTLA4 expression under natural promoter and regulatory elements, and (3) preservation of endogenous CTLA4 expression in uncorrected cells.

Value Proposition

• Universal open reading frame replacement strategy can be applied to the vast majority of known CTLA4 mutations.
• Intronic targeting approach prevents loss of CTLA4 in targeted cells to enhance product safety and activity.
• Fully non-viral engineering methods reduce manufacturing cost and complexity.
• Strategies can be applied to a wide variety of alternative inherited immune disorders.  

Related Materials

• High-yield genome engineering in primary cells using a hybrid ssDNA repair template and small-molecule cocktails - 08/25/2022

Patent Status

Patent Pending