Tackling fibrosis and inflammation in LAMA2-RD by in vivo modulation of a novel modifier gene

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.