LAMA1

LAMA2-CMD is characterised by the absence of the LAMA2 protein, leading to severe, early-onset muscular dystrophy. Credit: Ines Nepo/Shutterstock. The US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to Modalis Therapeutics’ investigational therapy, MDL-101, aimed at treating congenital muscular dystrophy type 1A (LAMA2-CMD). An epigenetic editing therapy, MDL-101 includes a guide nucleotide targeting the LAMA1 gene — a close homolog of the disease-causing LAMA2 gene. It utilises an enzyme-null Cas9 (dCas9) fused with a trans-activating domain, driven by a muscle-specific promoter and delivered via a muscle-specific AAV [adeno-associated virus] vector. MDL-101 works by upregulating LAMA1 gene products in patients’ muscle tissue to compensate for loss of function resulting from LAMA2 mutations. This approach has the potential to offer a one-time, long-lasting treatment option for individuals with LAMA2-CMD. ODD status facilitates the development of treatments for conditions affecting fewer than 200,000 patients in the US. See Also: UAE’s clinical trials space matures with experience from Covid-19 FDA approves Iterum’s ORLYNVAH NDA for uUTI treatment Under the ODD status for MDL-101, Modalis will receive benefits including exemption from application fees on filing new drug applications, tax reductions for clinical development and preferential treatment for the development and promotion of the asset in the US. On receipt of regulatory approval, MDL-101 would also receive seven years of exclusive sales rights in the US market. The US regulator previously granted rare paediatric disease designation for gene therapy for patients with LAMA2-CMD. LAMA2-CMD is characterised by the absence of the LAMA2 protein, a critical component comprising more than 3,000 amino acids. This leads to severe, early-onset muscular dystrophy, and due to the protein’s size, conventional gene therapy approaches such as using an AAV vector are challenging. Modalis focuses on the development of precision genetic therapies leveraging its epigenome editing technology, CRISPR-GNDM. This technology enables modulation of gene expression without causing double-strand DNA breaks. Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva . Editorial content is independently produced and follows the highest standards of journalistic integrity. Topic sponsors are not involved in the creation of editorial content. Free Whitepaper Cell and gene therapies: Pipe dream to pipeline The cell and gene industry is gaining momentum, with a new wave of therapies promising to transform the way doctors treat, and even cure, disease. In this report, Cytiva and GlobalData have collaborated to explore the rise of the cell and gene therapy industries, the current state of the market, present and future opportunities for advancement, and the challenges that lie ahead. Thank you. You will receive an email shortly. Please check your inbox to download the Whitepaper. By Cytiva Thematic By downloading this Whitepaper, you acknowledge that GlobalData may share your information with Cytiva Thematic and that your personal data will be used as described in their Privacy Policy

LAMA2-CMD is an early onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Image credit: Shutterstock/ Dan76. Modalis Therapeutics has been awarded a rare paediatric disease designation by the US Food and Drug Administration (FDA) for its congenital muscular dystrophy type 1a (LAMA2-CMD) gene therapy. As per the designation, the Japan-based company will be eligible to receive a priority review voucher if the drug candidate, MDL-101, is approved by the FDA. Recipients can redeem priority review vouchers themselves for any chosen drug or instead sell them to other pharma companies. Having the ability to slash four months off FDA review time, vouchers can sell for about $100m. The designation comes after a period of uncertainty for the vouchers’ future, with the programme facing a tight deadline on sunset provisions. The US House of Representatives ultimately passed a bill last week to reauthorise the rare paediatric priority review voucher program through September 2029. Modalis said it also pursuing orphan drug status for its candidate, with the FDA currently reviewing the company’s application. Orphan drug status provides benefits such as tax credits for US-based clinical trials and market exclusivity. See Also: FDA approves PureTech’s KarXT to treat schizophrenia in adults FDA greenlights Regeneron’s Dupixent for the treatment of COPD LAMA2-CMD is an early-onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Affected infants can have severe muscle weakness, hypotonia, and joint deformities, amongst others. As those with the disease grow, spinal curvature and speech issues can also develop. There are no approved therapies to treat LAMA2-CMD. Gene therapies for LAMA2-CMD using an adeno-associated virus (AAV) vector are difficult to develop as LAMA2 is made up of 3,000 amino acids, meaning it cannot be loaded onto a vector, according to Modalis. The company is therefore using its clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing technology to develop the therapy. MDL-101 works by inducing the expression of the sister gene LAMA1 in muscle tissues, which compensates for the deficient function of LAMA2. Modalis’s CEO Haru Morita said: “We have received many requests for our efforts from children and families around the world suffering from this disease for which there is currently no treatment, and we feel a mission to respond to the expectations of patients who are eagerly awaiting the start of clinical trials as soon as possible.” Modalis expects to file an investigational new drug (IND) application in 2025, according to a Q2 2024 financial results press release.

A breakthrough approach and supporting data using epigenome editing technology for the treatment of a type of muscular dystrophy, LAMA2-congenital muscular dystrophy (LAMA2-CMD), a genetic disorder, is presented. A single dose of MDL-101, using an AAV vector, demonstrated sustained upregulation of LAMA1 (Gene of Interest) in skeletal muscle tissues for up to 12 months, corrected muscle pathophysiology, significantly extended the lifespan, and increased the body weight of dyW mouse, a disease model of LAMA2-CMD. MYOAAV, an engineered AAV9 vector, significantly increased muscle tropism and consequently lowered the dose of the viral vectors at ten-times compared to conventional naturally occurring vectors. Systemic administration of MYOAAV version MDL-101 in adult and juvenile NHPs successfully demonstrated widespread muscle-specific vector distribution and induced LAMA1 to levels that restore function across skeletal muscle tissues without adverse effect, suggesting the potential for clinical efficacy as a therapeutic approach for serious genetic disorders. TOKYO & WALTHAM, Mass.--(BUSINESS WIRE)-- Modalis Therapeutics Corporation (Tokyo Stock Exchange: 4883), a pioneering company developing innovative drugs for the treatment of rare genetic diseases, utilizing its proprietary CRISPR-based epigenome editing technology CRISPR-GNDM®, posted the preprint paper titled “Efficient and durable gene activation by Cas9-mediated epigenome editing in vivo” on bioRxiv. The company reported data demonstrating exceptional durability, robust efficacy and safety in dyW mouse disease model of LAMA2-CMD and in adult and juvenile NHPs. LAMA2-CMD is a severe, early onset congenital muscular dystrophy caused by the absence of the LAMA2 protein. Despite significant advances in gene therapy and the approval of about a dozen therapies, the size of the disease-causing gene of LAMA2-CMD, which exceeds 3,000 amino acids, hinders the conventional gene therapy approach using AAV vectors to deliver the healthy version of the mutated gene. No approved therapies to address the root cause of this condition exist or are in clinical trials. Modalis’ proprietary CRISPR-GNDM®, is capable of specific modulation of the expression of disease-relevant genes, without introducing double-strand DNA breaks, and our MDL-101 is potentially the first-in-class therapeutics to solve the challenge and provide life-changing therapeutics for the patients of LAMA2-CMD. "We are thrilled to post our comprehensive preclinical data supporting the development of MDL-101 on bioRxiv. This study represents one of the first demonstrations of successful systemic epigenome editing in NHPs in a viable therapeutic format, as evidenced by significant target engagement and induction of LAMA1 gene expression across muscle tissues,” said Haru Morita, CEO of Modalis. “Additionally, our study is among the first to show that systemic Cas9 expression can be safe and well-tolerated in NHPs. These findings underscore the potential of CRISPR-GNDM® technology as a next-generation gene therapy platform for a variety of neuromuscular and other genetic disorders”. About bioRxiv (bioRxiv - the preprint server for Biology) bioRxiv is a preprint server for life science, medical, and biological journals. It allows for early publication without waiting for long peer review periods. Most of the leading journals in life science, medical, and biology area are partnered with bioRxiv, so manuscript files and metadata submitted to bioRxiv can be directly transmitted to partnered journals when we submit. In addition, papers submitted to bioRxiv are assigned a DOI and are eligible for citation. About MDL-101 MDL-101 is an experimental, epigenetic editing therapy under investigation for the treatment of LAMA2-Congenital Muscular Dystrophy (LAMA2-CMD). MDL-101 is comprised of a guide nucleotide targeting LAMA1 gene, a highly homologous sister gene of the disease-causing gene LAMA2, enzyme-null Cas9 (dCas9) fused with trans-activating domain driven by a muscle-specific promoter and coded in a muscle-specific AAV vector. MDL-101 upregulates LAMA1 gene products in patients’ muscle tissue to compensate for loss-of-function caused by mutation of LAMA2, and therefore has the potential to provide a one-time, durable treatment to benefit people living with LAMA2-CMD. About Modalis: Modalis Therapeutics develops precision genetic medicines using epigenome editing technology. Modalis is pursuing therapies for orphan genetic diseases using its proprietary CRISPR-GNDM® technology which enables the gene/locus-specific modulation of gene expression or epigenome editing without the need for DNA cleavage or altering DNA sequence. Headquartered in Tokyo with all research and development operations in Waltham Massachusetts, the company is listed on the Tokyo Stock Exchange’s Growth market. For additional information, visit . View source version on businesswire.com: Contacts Modalis Therapeutics Sawako Nakamura media@modalistx.com Source: Modalis Therapeutics Corporation View this news release online at: