Unlocking New Hope for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating genetic condition caused by mutations that result in the loss of dystrophin, a critical structural protein. The consequences of this loss are severe: progressive muscle weakness, spinal deformities, heart failure and early mortality. While genetic therapies are being explored, current treatments for DMD largely only alleviate symptoms, emphasizing the urgency for innovative solutions.

Brian Lin, PhD, assistant professor of Cell Biology, Neurobiology, and Anatomy at the Medical College of Wisconsin (MCW), is at the forefront of one such promising approach. His research focuses on Transient Receptor Potential Canonical 6 (TRPC6), a calcium channel that becomes hyperactive in DMD, contributing to muscle and heart dysfunction. Dr. Lin’s lab is investigating how inhibiting TRPC6 could counteract the detrimental effects of this hyperactivity, particularly in the context of dystrophic cardiomyopathy, an enlargement and weakening of the heart and the leading cause of death in DMD patients.

A Fortuitous Start to a Meaningful Mission

Dr. Lin’s interest in TRPC6 began serendipitously during his postdoctoral fellowship when he observed an anomaly in a mouse model of DMD. These mice, which typically succumb to DMD-like symptoms within 8 to 10 weeks, survived much longer – up to 25 weeks or more. He later discovered that these mice had TRPC6 genetically deleted. While working on other projects, he continued to follow up on the DMD mice with TRPC6 knocked out.

“About 30 mice later, we could clearly see that knocking out TRPC6 nearly triples the life expectancy of this DMD model,” Dr. Lin says.

The research demonstrated improvements in both heart and skeletal muscle function, solidifying TRPC6 as a critical target for intervention. These insights laid the foundation for Dr. Lin’s ongoing work. He says that the hyperactivity of TRPC6 channels in DMD leads to calcium overload, which disrupts muscle contraction and accelerates fibrosis. This dual impact on heart and skeletal muscles underscores the channel’s significance in disease progression and makes it a compelling therapeutic target.

Pioneering a New Therapeutic Pathway

To translate these findings into clinical practice, Dr. Lin is studying BI 749327, a selective TRPC6 inhibitor. A clinical version of this drug is currently undergoing phase 1 clinical trials for other disease conditions. Preliminary results from his lab show that the drug doubles the lifespan of DMD mouse models and reduces fibrosis and inflammation.

Using advanced tools such as spatial transcriptomics, Dr. Lin’s team is unraveling the molecular pathways affected by TRPC6 inhibition. This work not only sheds light on the mechanisms underlying muscle and heart damage in DMD but also highlights where TRPC6 inhibition is having an impact and the broader potential of targeting TRPC6 for related conditions.

One of Dr. Lin’s key breakthroughs is the discovery that TRPC6 can form structures with larger calcium-conducting pores, amplifying its pathological effects. This finding challenges traditional assumptions about the protein’s role and opens new avenues for investigating its impact in other diseases driven by calcium dysregulation.

From Mice to Humans

While the results in mouse models are promising, Dr. Lin emphasizes the complexities of translating these findings into human therapies. His lab is developing advanced stem cell-derived models that better study the clinical relevance of his work to human DMD pathology, providing a critical bridge between preclinical and clinical studies.

His collaborations with pharmaceutical companies aim to accelerate the development of treatments for DMD.

“We’re ensuring that our findings are relevant to real patients,” he says, highlighting the real-world impact of his work.

For Dr. Lin, this work represents more than just a career — it’s a chance to make a lasting impact. By targeting the molecular mechanisms underlying dystrophic cardiomyopathy, his work offers the potential to significantly improve patients’ quality of life and extend their lifespans, offering new hope to patients and families affected by DMD.

“This journey has been one of discovery, persistence, and serendipity,” Dr. Lin says. “I consider myself lucky to be here at MCW working with amazing people at a really exciting time in the field.”