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OnlineSeminar - WWM Pim Pijnappel, PhD - "Cell and genetic therapies for lysosomal storage disorders"

Center for Lysosomal and Metabolic Diseases, Department of Pediatrics, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
When May 19, 2021
from 12:00 PM to 01:15 PM
Where TigemOnlineSeminar
Contact Name
Contact Phone 08119230659
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Abstract
Lysosomal storage diseases (LSDs) are a group of monogenic disorders caused by the deficiency of a particular lysosomal enzyme involved in the degradation and recycling of macromolecules. This results in accumulation of lysosomal substrate and a cascade of cellular pathology, ultimately resulting in cell death. Enzyme replacement therapy is available for a number of LSDs but has drawbacks such as variable efficacy and its inability to cross the blood brain barrier. The aim of our group is to develop improved therapies for LSDs based on stem cells and gene therapy. To this end, we have developed splice switching antisense oligonucleotides for late onset Pompe disease that normalized aberrant splicing caused by the common IVS1 GAA variant. For classic infantile Pompe disease we have developed hematopoietic stem cell-mediated lentiviral gene therapy. In a mouse model, this therapy fully normalized glycogen accumulation and cellular pathology in skeletal muscle, heart, and the central nervous system. A third therapeutic target is formed by muscle satellite cells, which are resident muscle stem cells involved in muscle regeneration upon injury or disease. We found that satellite cells fail to become activated in Pompe disease, but are fully capable of muscle regeneration when experimentally provoked, suggesting that promotion of satellite cell activation might be useful for the treatment of Pompe disease.

To test therapies in humanized in vitro systems, we have developed human induced pluripotent stem cell (hiPSC)-based model systems for skeletal muscle and cartilage. CRISPR/cas9 mediated gene editing is used to generate isogenic pairs of diseased and healthy cells to avoid influence from genetic backgrounds. To enable functional assessments such as contractile force in vitro, we have developed 3D-tissue engineered skeletal muscles, in which human muscle tissue is grown between two flexible pillars within versatile 3D printing-based platforms. Ongoing developments in the development of therapies and model systems will be discussed.


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