CONGENITAL MUSCULAR DISTROPHY ASSOCIATED TO LMA

Congenital muscular distropy associated to LMNA (L-CMD) is a rare genetic disease that appear in infants and young patients, and is characterized by slow progressive muscle weakness and wasting, atrio-ventricular conduction block, and respiratory distress. It is caused by mutations in LMNA gene which encodes for A-type lamins (lamin A/C), proteins that are part of the nuclear lamina in eucariotic cells. L-CMD is a severe disease with no cure currently available. 

The aim of this project is to advance in the knowledge of the mechanisms underlying the development and progression of L-CMD and to test new therapeutic approaches based on advanced therapies. 

So far, we have:

• Generated a collection of mouse myoblasts (C2C12) with different mutations at Lmna exon 4 that have allowed us to study new features of the disease (Cells 2020, 9(5), 1286).
• Generated a conditional mouse model for the expression of the lmna-R249W mutation, which is causally associated with L-CMD in humans. 

• Explored, in vitro, the potential of two CRISPR based strategies, HITI and the use of mutation-specific sgRNAs. In both cases, we have decided to go further and validate our hypothesis in vivo using the lmna-R249W model.

• Carried out preliminary experiments to test the therapeutic potential of Remodelin and ARRY-797. Our initial results, in human myoblasts, were good enough to design and perform an in vivo study for both molecules.