Creating an In-Vivo Model of Pompe`s Disease

Glycogen storage disease type II (Pompe’s disease) is a genetic disease caused by a mutation in the gene encoding for acid α-glucosidase (GAA) enzyme. Disease progression is the manifestation of undigested glycogen-filled lysosome accumulation, and the extent of myofibril disturbance. Patient biopsies from skeletal muscle are readily available thus well characterized, whereas less is known about pathophysiological processes in cardiomyocytes. Recombinant human GAA (rhGAA) has dramatically improved patient outcome, yet patients still suffere from various arrhythmias, sensorineural or conductive hearing loss, and some degree of residual muscle weakness. Due to the need of upgraded therapy and some limited knowledge regarding disease pathophysiology there is an enduring demand for a researchable disease model.

We recruited the induced pluripotent stem cell (IPSC) technology to establish an in-vivo model for Pompe’s disease. Human IPSC derived cardiomyocytes (hIPSC-CMs) were injected to mouse hearts under echocardiography guidance intramyocardially. Treating study mice with rhGAA had a remarkable therapeutic effect clearing away lysosomal glycogen pools opposed to the untreated control group. To prove that Pompe hIPSC-CMs can restore their contractile function when supplied with a normal alpha-galactosidase, we created 3 study groups of rats in which MIs were induced. We then transplanted only two of them with Pompe hIPSC-CMs. One Pompe hIPSC-CMs group received an rhGAA treatment, and the other received a vehicle. The non-transplanted group also received rhGAA and served as a control. The control group left ventricular (LV) function deteriorated with time. The Pompe hIPSC-CMs group which did not receive a treatment had an LV function like the control group. However, rhGAA treated Pompe hIPSC-CMs engrafted mice showed a significant improvement reaching 20% rise in LV fractional shortening.

Such in-vivo models will pave the way to investigate patient specific mutations, their pathophysiology and drug responsiveness in a more biologically relevant setup.