Modalis Therapeutics Reports Data Supporting Development of a Transformative Epigenome Editing Therapeutic, MDL-101: a First-in-Class Epigenome Editing approach for the Treatment of LAMA2-deficient congenital muscular dystrophy (LAMA2-CMD)
07 Mayo 2024 - 1:05AM
Business Wire
- 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.
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 www.modalistx.com.
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Modalis Therapeutics Sawako Nakamura media@modalistx.com