Alternative approaches targeting Duchenne Muscular Dystrophy treatment

• Grant number: 16/22318-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2017
• End date: March 31, 2022
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Mayana Zatz
• Grantee: Felipe de Souza Leite
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 19/20208-1 - Investigation of NOTCH rare SNV as protective modifiers in Duchenne muscular dystrophy, BE.EP.PD

Abstract

The main goal of this project is to advance for an efficient therapy for Duchenne Muscular Dystrophy (DMD) based on a novel therapeutic approach. DMD is the most common and severe muscular dystrophy, affecting 1 in 3.500 to 5000 newborn male children. DMD is caused by the absence of dystrophin, an intracellular membrane-associated protein responsible for damping the mechanical stress from myofibril work. The lack of dystrophin increases the chances of membrane rupture, leading to homeostasis unbalance, atrophy and apoptosis of muscle fibers. Since there is no effective treatment for DMD affected boys have a progressive muscular weakness and a short lifespan. Without special care, most patients do not live beyond age 20. The current therapeutic trials, which aim to increase dystrophin expression, are not showing any significant clinical improvement. This shows the need for alternative treatments, not focused on dystrophin, which is the aim of the current project. Recently, a study led by Dr. Zatz in collaboration with researchers from Harvard University have associated the over-expression of Jagged1 with a mild phenotype of two outstanding Golden Retriever Muscular Dystrophy (GRMD) dogs. GRMD dogs are severely affected and represent the best animal model for DMD. The high levels of Jagged1 allowed a normal muscle function and a long lifespan in these two exceptional GRMD dogs. This groundbreaking study outlined a novel way for therapy aiming to investigate the clinical effect of Jagged1 increased expression in different DMD animal models. Data obtained from the proposed study may, in the future, guide a safe and effective treatment for humans. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

HAEGER, RICARDA; DE SOUZA LEITE, FELIPE; RASSIER, DILSON E.. Sarcomere length non-uniformities dictate force production along the descending limb of the force-length relation. PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, v. 287, n. 1937, OCT 28 2020. (16/22318-0, 19/20208-1)

MELO, UIRA SOUTO; LEITE, FELIPE DE SOUZA; COSTA, SILVIA; ROSENBERG, CARLA; ZATZ, MAYANA. A fast method to reprogram and CRISPR/Cas9 gene editing from erythroblasts. STEM CELL RESEARCH, v. 31, p. 52-54, AUG 2018. (16/22318-0, 13/08028-1, 16/14517-3)