Project description
Genetic modifiers for rare type of muscular dystrophy
Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is a rare, genetic neuromuscular disorder that causes severe muscle weakness from birth. It is caused by mutations in the LAMA2 gene that encodes a subunit of laminin 2 required for muscle fibre stability. With the support of the Marie Skłodowska-Curie Actions programme, the LAMA2-TFIMG project builds on a candidate modifier of fibrosis and inflammation, previously identified from a patient case with LAMA2-RD but with milder symptoms. Researchers will test whether reducing the modifier’s expression improves muscle strength and reduces inflammation and fibrosis. Investigation of the molecular and morphological changes in a mouse model of the disease will pave the way for novel therapeutic strategies for LAMA2-RD, which currently has no cure.
Objective
Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is caused by mutations in the LAMA2 gene, coding for the 2 subunit of laminin-211 (merosin). Typically, LAMA2-RD patients with absent merosin are clinically severe and unable to walk, while those producing a partially functional merosin are clinically milder. I identified a unique family in which the oldest of two affected siblings shows a novel and extremely mild phenotype despite the complete lack of merosin. This patient is still ambulant at 33 years with no respiratory insufficiency or cardiomyopathy. Notably, this patient carries the same LAMA2 loss-of-function mutation as the sibling who followed the typical severe disease course. Hypothesizing that genetic modifier(s) in the atypical patient mitigate the consequences of complete merosin deficiency via a novel mechanism, I isolated unique ultra-rare polymorphisms in genetic factors related to genes expressed in the atypical patient muscle but not in muscle of non-related LAMA2-RD patients, and I identified a novel candidate modifier controlling both fibrosis and inflammation (key drivers of LAMA2-RD pathogenesis). Given that this modifier is severely upregulated in the control LAMA2-RD patients but highly downregulated in the atypical patient, I will decrease its expression in the severely affected LAMA2-RD mouse model DyW/DyW by using the CRISPR-interference tool delivered by a single AAV9. I will then assess motor strength and endurance in treated mice. Finally, I will isolate highly affected muscles and sciatic nerve to characterize any molecular and morphological change occurring in these tissues upon modulating the modifier gene expression. I expect to observe functional improvement in LAMA2-RD animals, thus ameliorating their phenotype. The proposed project will elucidate novel mechanisms attenuating LAMA2-RD severity and will allow me to design new therapeutic approaches for this disorder for which, to date, there is no approved treatment.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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(opens in new window) HORIZON-MSCA-2023-PF-01
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20132 Milano
Italy
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