Red blood cell-specific transgene expression for treating genetic enzyme deficiencies

Stanford researchers have developed a new gene editing approach that enables red blood cell-specific gene expression for the treatment of enzyme deficiencies.

Available protein-based enzyme replacement therapies are not curative, require frequent infusions, and often become less effective over time. Similarly, emerging strategies that use a viral vector to deliver a functional copy of the defective gene to the liver are limited by pre-existing neutralizing antibodies, potentially life-threatening immune responses, and a decline in enzyme production over time.

Researchers therefore developed a new strategy in which red blood cells are turned into enzyme-producing factories, taking advantage of the fact that red blood cells are produced in large numbers and circulate throughout the body. To achieve red blood cell specific gene expression, researchers use ex vivo CRISPR/Cas editing of hematopoietic stem cells to insert a functional copy of the enzyme behind a promoter (HBA1 or HBA2) that is only active in red blood cells. Scientists further optimized this strategy for the treatment of hemophilia B, caused by mutations in factor IX. They increased the amount of factor IX secreted into the bloodstream by over 3-fold and engineered the protein to be 3.3-fold more active.

Stage of development
Animal data: treatment of phenylalanine hydroxylase deficiency and hemophilia B in mice