The innovative gene therapy approach (called SEAL technology), developed by Prof. Markus Rüegg and Prof. Peter Yurchenco and their teams over the past 20 years, overcomes the lack of laminin-α2 in muscle tissue by providing molecular connections with other laminins and with the plasma membrane of the muscle fibers. Available data demonstrate that the simultaneous expression of two specifically designed linker proteins functionally corrects the primary pathology of laminin-α2 deficiency, leads to sustained improvement in muscle histology, increased muscle mass and strength, improved body weight, and results in a remarkable increase in life span compared to untreated animals (see literature). The SEAL Technology is amenable as gene therapy approach as the relevant gene sequences can be delivered to muscle tissue via adeno-associated viral (AAV) vectors.
Schematic of the molecular principles of SEAL technology. In healthy controls (left), laminin-α2 (purple) forms a heterotrimer with other laminins and creates a stable extracellular matrix (ECM) that binds to receptors in the muscle fiber plasma membrane (PM). In LAMA2 MD patients, laminin-α2 is replaced by laminin-α4 (pink), which neither forms a stable ECM nor binds to PM receptors (middle). Simultaneous expression of two linker proteins allows laminin-α4 to bind the PM (linker 1) and form a stable ECM (linker 2), replacing the function of laminin-α2 in LAMA2 MD patients (right).
SEAL Therapeutics holds exclusive licenses to technology developed at the Biozentrum, University of Basel and Rutgers, the State University of New Jersey (USA).