LAMA1

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:

It is generally believed that the adaptability of the adult brain mainly takes place in the cortex. However, a new study shows that the thalamus, a relay station for incoming motor and sensory information, plays an unexpectedly important role in this process. It is generally believed that the adaptability of the adult brain mainly takes place in the cortex. However, a new study from the Netherlands Institute for Neuroscience shows that the thalamus, a relay station for incoming motor and sensory information, plays an unexpectedly important role in this process. "This could be an interesting starting point for various therapies," says Christiaan Levelt. Learning new things requires a tremendous capacity of our brains. The adaptation of our brain as a result of new experiences is called plasticity. There are periods during our development when neural networks show a lot of plasticity, known as critical periods. But also the adult brain is capable of adapting. Where this plasticity takes place in adult brain is not well understood. To gain more insight into this question, Yi Qin and his colleagues, under the supervision of Christiaan Levelt, examined the visual system of mice. This is a popular model for studying plasticity due to its ease of manipulation. Visual information reaches the thalamus through the retina. This brain nucleus then transmits processed information to the visual cortex and vice versa. An experiment in mice can clearly demonstrate how well the adult brain is able to adapt. When one eye of the mouse is occluded for several days, the visual cortex starts to respond less effectively to the closed eye and better to the open eye. How this is precisely regulated has been unclear for a long time. But these new results bring an important player to the forefront: the thalamus. New Perspective Christiaan Levelt: "Five years ago, we discovered that the thalamus plays a crucial role in the plasticity of the visual cortex during critical periods of development. This has changed our perspective on how this whole system works. We all thought that this process was regulated by the visual cortex, but it turned out not to be the whole story. We found out by removing a very specific component, the GABA-alpha 1 subunit, in the thalamus of mice during their critical period for vision. This component is responsible for inhibiting the thalamus, so its removal resulted in reduced inhibition. When we closed one eye in these mice, the shift in responses no longer occurred. Because the adult brain uses different plasticity mechanisms than the developing brain, an important question was whether adaptation in the adult visual system also involved the thalamus." Yi Qin: "In the current study, we performed the same experiment in adult mice and observed similar results. We observed that plasticity also took place in the adult thalamus, but disappeared when we removed the alpha-1 subunit. Consequently, there was no longer a shift in the cortex either. Since we know that the visual cortex also sends information back to the thalamus through a feedback mechanism, we were curious if the visual cortex also plays a role in plasticity of the thalamus. We investigated this by reversing the experiment and shutting down the visual cortex. What happens to the shift in responses in the thalamus then? In adult animals, we did not see any difference: the shift persisted. However, in animals during their critical period, we observed that when we shut down the visual cortex, the shift reverted back in the thalamus. So, at a young age, plasticity in the thalamus and cortex influence each other much more, while in the adult brain, the thalamus is particularly important for plasticity in the cortex but not the other way around." Involved in many processes Levelt continues: "Plasticity is important in many processes. We are currently focusing on sensory plasticity (vision), but plasticity is also fundamental for memory and other functions. These new insights could be relevant, for example, in understanding learning disabilities. It is possible that the origin of these problems lies in the thalamus rather than the cortex. Therefore, a different approach is needed. Instead of solely looking at the cortex, we should also consider the thalamus when it comes to therapies and the pathogenesis of these issues. This is an important new interpretation." Qin: "Even in the case of lazy eye, it is assumed to be a problem of the cortex, but it could also involve the thalamus. In Europe, we test for the presence of lazy eye from a young age. This condition can be corrected during the critical period by temporarily patching the 'good eye,' which strengthens the connections to the weaker eye. In the US, for example, this is not routinely checked at a young age, resulting in more people carrying a lazy eye into adulthood. Since the critical period has already passed for them, it becomes more challenging to treat these individuals. Our study provides a hint that we need to look beyond the cortex, which can provide guidance for a new treatment strategy."