Gene Editing Breakthrough Could Offer Hope for Muscle Disorder Patients; Berlin Spin-Off

A January 2 study published in Nature Communications details a significant advancement in treating Limb-Girdle Muscular Dystrophy Type 2B (LGMD2B), a debilitating muscle-wasting disorder caused by mutations in the DYSF gene. Researchers successfully used CRISPR-Cas9 technology to restore the production of a key protein, dysferlin, which is critical for muscle repair. This breakthrough was achieved by reframing genetic sequences at the RNA and protein levels, offering a new path forward for treating this previously untreatable disease.

The study was led by Helena Escobar, Post Doctoral Researcher and Dr. Simone Spuler, both at Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charité Campus Buch, both in Berlin and colleagues.

Fixing the genetic code

The team focused on a common DYSF mutation that disrupts the reading frame of the gene, preventing the proper production of dysferlin. Using CRISPR-Cas9, they introduced a single nucleotide insertion—called a "+1A indel"—that corrected the genetic error. Remarkably, this small edit restored the gene’s ability to produce functional dysferlin at levels comparable to healthy individuals. The edited cells were tested in lab-grown human muscle cells, humanized mouse models, and stem cells derived from patients. Across these systems, the correction consistently rescued protein function and enabled proper muscle repair.

Promising long-term results

Beyond immediate protein restoration, the study demonstrated the long-term potential of this therapy. Gene-edited muscle stem cells transplanted into mice not only repaired damaged muscle but also repopulated the muscle stem cell pool. This finding suggests the edits could have lasting effects, supporting ongoing muscle regeneration and health. Importantly, these results were achieved without immune-suppressing drugs, making the approach safer and more feasible for real-world applications.

Why CRISPR works so well here

One key reason for the therapy's success is the predictable nature of the gene edits. The specific "+1A" insertion proved highly consistent across different cell types, donors, and even species, underscoring the reliability of the editing mechanism. This predictability could simplify the path toward regulatory approval and clinical adoption. The authors also highlighted how this approach is particularly suited to DYSF mutations compared to alternative strategies like exon skipping, which often fall short of restoring full-length, functional proteins.

Clinical implications

This breakthrough could pave the way for personalized treatments for LGMD2B patients, many of whom have no viable therapeutic options. By using a patient’s own stem cells, repairing the genetic mutation ex vivo, and transplanting the corrected cells back into the body, this method avoids the risks associated with immune rejection. Moreover, restoring even 10% of normal dysferlin levels is believed to be sufficient to improve symptoms. In this study, editing efficiencies exceeded 60%, suggesting the potential for curative outcomes.

Challenges and future directions

While promising, the research also raised questions that need further exploration. For instance, it remains unclear whether gene-edited cells might trigger immune responses, especially in patients who completely lack dysferlin. Additionally, scaling up the therapy for systemic treatment, rather than localized cell transplantation, will require significant advancements in gene delivery technologies, such as lipid nanoparticles or non-viral carriers. Other techniques, like prime editing, are on the horizon and could offer even more precise genetic repairs. However, these methods are still in early development and face challenges like large delivery components and potential safety risks.

Significant step forward

For patients with LGMD2B, this research represents a significant step forward. The ability to restore dysferlin production through a minimally invasive, highly precise method could transform the outlook for this rare but devastating condition. With further development and clinical trials, CRISPR-based therapies might soon offer a lifeline to patients and families affected by LGMD2B.

Disclosures

One of the lead authors, Prof. Simone Spuler, is an inventor of a technology for primary human muscle stem cell isolation and manufacturing (IP: (DE10 2014 216872), 2015 PCT (WO 2016/030371), granted in EU and US). Spuler and Helena Escobar are co-inventors on a pending patent application on gene editing of human muscle stem cells (European Patent Office 21 160 696.7). Spuler is co-founder of MyoPax GmbH and MyoPax Denmark ApS. The remaining authors declare no competing interests.

The Spin-Off

MyoPax is a spin-off from the Muscle Research Unit of the Charité Universitätsmedizin and the Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association in Berlin. Upon its launch in 2022, MyoPax joined the BioInnovation Institute in Copenhagen. They have a subsidiary in Denmark. The startup seeks to become the international leader in biological muscle therapy.

The company brings talent with over 30 years of relevant experience in human skeletal muscle research and development. They cite their passion for the mission and determination to succeed, empowered by strong science, state-of-the-art technology and preeminent clinical expertise. 

For pipeline and strategy follow the company link.

Lead Research/Investigator

Helena Escobar, Post Doctoral Researcher, Charité Universitätsmedizin Berlin

Simone Spuler, Professor at Charité Universitätsmedizin Berlin, Co-Founder MyoPax

Other authors can be viewed at the source.

Source: Nature