Blocking TRPC6 Calcium Channel May Help to Treat Duchenne MD
Study in mice finds survival and muscle gains, with related therapy now in trials
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Blocking a calcium channel called TRPC6 prolonged survival in a mouse model of Duchenne muscular dystrophy (DMD) by improving skeletal and heart muscle function and reducing bone deformities, a study showed.
Its results support clinical trials of TRPC6 inhibitors in Duchenne patients as “a novel DMD therapy,” the researchers wrote, noting that one called BI 764198 is under testing in people with a type of kidney disease.
The study, “Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy,” was published in JCI Insight.
TRPC regulates calcium levels in muscle cells, aiding their function
Transient receptor potential canonical (TRPC) is a group of calcium channels present at the surface of muscle cells that regulate calcium levels, usually in response to mechanical actions. This is a critical mechanism for the normal function of muscle cells.
In addition to the lack of working dystrophin — a protein that helps to protect muscles from wear-and-tear over time — increased calcium levels inside muscle cells are among the cellular mechanisms contributing to DMD.
These changes might involve the TRPC6 calcium channel, whose levels are known to be elevated in heart and skeletal muscle in DMD patients and mouse models. Skeletal muscles are those connecting to the bones and involved in voluntary movement.
To clarify the role of TRPC6 in DMD, a U.S. research team suppressed the calcium channel in two mouse models of DMD: one presenting milder symptoms and another displaying more severe disease better resembling its severity in people.
TRPC6 suppression was achieved either through treatment with a selective TRPC6 small-molecule inhibitor called BI 749327 or by deleting Trpc6, the gene coding for the calcium channel.
Researchers found that Trpc6 deletion in the severe DMD mouse model was associated with greater total body, heart, and skeletal muscle mass, aiding motor function and bone structure, and lengthening the animals’ survival. Similar survival benefits were observed in the milder model in the absence of TRPC6.
TRPC6 suppression with BI 749327 was also found to improve heart muscle function, reduce heart and skeletal muscle scarring, and improve bone structure and mobility, almost doubling the lifespan of mice in both models.
Of note, heart and skeletal muscle scarring is a prominent characteristic of DMD.
Further analyses in the animals’ heart tissue indicated that TRPC6 suppression with either approach reduced the activity of genes that control fatty molecule metabolism, blood sugar uptake and signaling, and scarring.
“Whether similar patterns are found in skeletal muscle remains to be determined,” the study noted.
These findings point to TRPC6 “as a major component of the [underlying mechanisms] of DMD,” the researchers wrote.
TRPC6 “chronic suppression genetically and, most importantly, using a small-molecule inhibitor improves … muscle function, improves bone remodeling, lessens muscle [scarring], and improves survival in one of the most severe DMD mouse models yet generated,” they added.
“To our knowledge, the current study is the first to demonstrate survival efficacy from a small molecule therapy,” the researchers wrote.
Benefits observed with TRPC6 inhibition, not involving dystrophin replacement, indicates that it plays an important role in DMD.
Notably BI 764198, a similar TRPC6 inhibitor, has already been tested in Phase 1 and 2 clinical trials, including in healthy men (NCT04665700 and NCT03854552), and in people with kidney disease (NCT04176536) and COVID-19 (NCT04604184). A global Phase 2 study (NCT05213624) in up to 60 adults with a kidney disease known as primary focal segmental glomerulosclerosis is underway.
“Ongoing development and clinical testing of BI 764198 … may pave the way for studies in individuals with DMD,” the researchers wrote.
They emphasized that this approach would likely need to tested in combination with standard immunosuppressive therapies or those aiming to restore dystrophin function.
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