Modalis Therapeutics Presents Data on MDL-101 for Treating LAMA2-CMD

A novel approach using epigenome editing technology has shown promise for treating LAMA2-congenital muscular dystrophy (LAMA2-CMD), a severe genetic disorder. This method employs a single dose of MDL-101 delivered through an AAV vector to significantly upregulate the LAMA1 gene in skeletal muscle tissues for up to a year. The treatment corrected muscle pathophysiology, extended lifespan, and increased body weight in dyW mice, which serve as a disease model for LAMA2-CMD.

A key innovation is MYOAAV, an engineered AAV9 vector that enhances muscle tropism, allowing for a tenfold reduction in viral vector dosage compared to traditional vectors. When MYOAAV-based MDL-101 was systemically administered to both adult and juvenile non-human primates (NHPs), it demonstrated broad muscle-specific distribution and induced LAMA1 expression to levels that restored muscle function without adverse effects. This suggests potential clinical efficacy for treating serious genetic disorders.

Modalis Therapeutics Corporation, listed on the Tokyo Stock Exchange, is at the forefront of developing innovative therapies for rare genetic diseases. Utilizing its proprietary CRISPR-based epigenome editing technology CRISPR-GNDM®, the company published a preprint paper on bioRxiv titled “Efficient and durable gene activation by Cas9-mediated epigenome editing in vivo.” The data from this study highlights remarkable durability, robust efficacy, and safety in both dyW mouse models and NHPs.

LAMA2-CMD is characterized by early onset and severe progression due to the absence of the LAMA2 protein. Traditional gene therapy approaches face challenges because the gene causing LAMA2-CMD is exceedingly large, exceeding 3,000 amino acids. Currently, no approved therapies directly tackle the root cause of LAMA2-CMD, nor are there any in clinical trials. Modalis’ CRISPR-GNDM® technology offers a targeted modulation of gene expression without causing DNA breaks, positioning MDL-101 as a potentially groundbreaking treatment for LAMA2-CMD patients.

"We are excited to share our comprehensive preclinical data supporting MDL-101 development on bioRxiv. This study marks one of the first successful demonstrations of systemic epigenome editing in NHPs, showing substantial engagement and induction of the LAMA1 gene across muscle tissues,” said Haru Morita, CEO of Modalis. “Our research is also among the first to indicate that systemic Cas9 expression can be safely tolerated in NHPs. These findings highlight the potential of CRISPR-GNDM® technology as a next-generation platform for treating various neuromuscular and genetic disorders.”

MDL-101 is an experimental therapy targeting LAMA2-CMD. It comprises a guide nucleotide aimed at the LAMA1 gene, an enzyme-null Cas9 fused with a trans-activating domain, all driven by a muscle-specific promoter and coded in a muscle-specific AAV vector. This configuration allows for the upregulation of LAMA1 gene products in muscle tissue to compensate for LAMA2 mutations, offering a durable, one-time treatment solution.

Modalis Therapeutics is dedicated to developing precision genetic medicines using its epigenome editing platform. The company focuses on therapies for orphan genetic diseases, leveraging its proprietary CRISPR-GNDM® technology to modulate gene expression without altering DNA sequences. Headquartered in Tokyo, with research and development operations in Waltham, Massachusetts, Modalis is a public company listed on the Tokyo Stock Exchange’s Growth market.