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A breakthrough approach and supporting data using epigenome editing technology to treat LAMA2 congenital muscular dystrophy (LAMA2-CMD), a genetic disease that is a type of muscular dystrophy, is presented.
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A single dose of MDL-101 using an AAV vector sustained upregulation of LAMA1 (gene of interest) in skeletal muscle tissue for up to 12 months, modified muscle pathophysiology, significantly extended lifespan, and dyW It was demonstrated that the mice gained weight. , LAMA2-CMD disease model.
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A modified AAV9 vector, MYOAAV, significantly increased muscle tropism, resulting in a 10-fold lower viral vector dose compared to conventional natural vectors.
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Systemic administration of MYOAAV version MDL-101 to adult and young NHPs demonstrated broad muscle-specific vector distribution and was successful in inducing LAMA1 to a level that restored overall skeletal muscle tissue function without adverse effects. This suggests the possibility of clinical efficacy as a therapeutic approach for serious genetic diseases. hindrance.
Tokyo and Waltham, Massachusetts, May 7, 2024–(BUSINESS WIRE)–Modalis Therapeutics, Inc. (Tokyo Stock Exchange: 4883) is leveraging its proprietary CRISPR-based epigenome editing technology, CRISPR-GNDM, to develop innovations for the treatment of rare genetic diseases. We are a pioneering company that develops innovative pharmaceuticals.®published a preprint paper titled “Efficient and sustained gene activation by Cas9-mediated epigenome editing” in vivoThe company reported data demonstrating exceptional durability, robust efficacy and safety in the dyW mouse disease model of LAMA2-CMD and in adult and juvenile NHP.
LAMA2-CMD is a severe early-onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Although gene therapy has made significant advances and approximately 12 treatments have been approved, the size of the disease-causing gene for LAMA2-CMD is over 3,000 amino acids, making it difficult to use AAV vectors to treat healthy patients. Traditional gene therapy approaches to deliver versions of the gene have been hampered. mutated gene. There are no approved treatments that address the root cause of this condition and are in clinical trials. Modalis proprietary CRISPR-GNDM®The expression of disease-related genes can be specifically regulated without introducing double-stranded DNA breaks. Our MDL-101 has the potential to be a first-in-class therapy that solves this challenge and provides a life-changing treatment for patients. LAMA2-CMD.
“We are excited to submit comprehensive preclinical data to bioRxiv that supports the development of MDL-101. , represents one of the first demonstrations of successful systemic epigenome editing in NHPs in a viable therapeutic format, “LAMA1 gene expression throughout muscle tissue,'' said Modalis CEO Haru Morita. “Furthermore, our study is one of the first to show that systemic Cas9 expression is safe and well-tolerated in NHPs. These findings raise the potential of CRISPR-GNDM. I'm emphasizing it.”® The technology as a next-generation gene therapy platform for a variety of neuromuscular and other genetic diseases. ”
About bioRxiv (bioRxiv – Biology Preprint Server)
bioRxiv is a preprint server for life science, medical, and biology journals. This allows for early publication without waiting for a long peer review period. Most major journals in the life sciences, medicine, and biology fields are affiliated with bioRxiv, so manuscript files and metadata submitted to bioRxiv can be sent directly to partner journals upon submission. Additionally, papers submitted to bioRxiv are assigned a DOI and are eligible for citation.
About MDL-101
MDL-101 is an experimental epigenetic editing therapy being investigated for the treatment of LAMA2 congenital muscular dystrophy (LAMA2-CMD). MDL-101 consists of an enzyme-deficient Cas9 (dCas9) fused to a guide nucleotide, a transactivation domain driven by a muscle-specific promoter, targeting the LAMA1 gene, a highly homologous sister gene of the disease-causing gene LAMA2. and muscle-specific AAV vectors. MDL-101 is a one-time, long-lasting drug that benefits people living with LAMA2-CMD because it upregulates the LAMA1 gene product in patients' muscle tissue to compensate for the loss of function caused by mutations in LAMA2. may provide effective treatment.
About Modalis:
Modalis Therapeutics uses epigenome editing technology to develop precision genetic medicines. Modalis is pursuing treatments for genetic diseases in orphans using his proprietary CRISPR-GNDM.® A technology that enables gene/locus-specific regulation of gene expression and epigenome editing without the need to cut DNA or change the DNA sequence. The company is headquartered in Tokyo, with all research and development operations located in Waltham, Massachusetts, and is listed on the Growth Market of the Tokyo Stock Exchange. For more information, please visit www.modalistx.com.
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