06VP In vivo modulation of novel modifier genes for LAMA2-RD

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.204
• Main Authors: Pini, V., Bonaccorso, R., Porrello, E., Burris, T., Morgan, J., Muntoni, F., Previtali, S.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.213

Merosin-deficient congenital muscular dystrophy (LAMA2-RD) is a neuromuscular disorder caused by mutations in LAMA2 gene, coding for the α2 subunit of laminin-211 (merosin). Most LAMA2-RD patients carry LAMA2 loss-of-function mutations that prevent merosin production and follow an invariably severe clinical phenotype characterised by the inability to acquire ambulation. Missense mutations in LAMA2 gene allow instead the production of a partially functional protein, resulting in a wider (usually milder) severity spectrum. To date, only one LAMA2-RD patient was reported with a very mild phenotype despite the total merosin absence in muscle. This patient is still ambulant at the age of 33 with no respiratory insufficiency nor cardiomyopathy. Interestingly, this patient carries the same LAMA2 loss-of-function mutation as its severely affected sibling who also completely lacks merosin in muscle. We hypothesized that not yet characterized genetic modifier(s) are acting in the atypical patient to mitigate the consequences of complete merosin absence via a novel mechanism. Combining genomic data of both siblings and RNA-sequencing data from the atypical patient's and unrelated LAMA2-RD patients’ muscle, we identified a subset of genes uniquely altered in the atypical patient and acting on pathways affected in LAMA2-RD (i.e. metabolism, inflammation and muscle regeneration). We modulated the expression of two presumed modifiers in vivo, treating LAMA2-RD mice with agonist compounds, and performed a battery of functional tests to assess endurance and muscle strength upon treatment. The analysis of the histological/molecular changes occurring in muscles of treated mice is ongoing to complement functional data. We expect the lead modifier to improve muscle morphology and ameliorate the LAMA2-RD phenotype in treated animals. This project will shed light on novel mechanisms attenuating LAMA2-RD severity easing the development of new therapeutic approaches for this disorder.