FORCE platform delivers ERT directly to muscles, nervous system

FORCE-GAA shows promise for treating Pompe in mouse model of disease

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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A trio of mice are pictured among oral prescription medicine bottles, with one of the rodents holding a capsule in its paws.

Dyne Therapeutics has unveiled promising preclinical data for its enzyme replacement therapy (ERT) FORCE-GAA — part of the company’s propriety FORCE platform — designed to treat Pompe disease.

The novel therapy has demonstrated the potential to deliver the treatment directly to skeletal and heart muscles, as well as the central nervous system (CNS), comprising the brain and spinal cord, according to a study conducted in a mouse model of the disease.

Specifically, FORCE-GAA significantly reduced glycogen accumulation in muscle and CNS cells, as well as blood levels of a marker of nerve cell damage — demonstrating a higher efficacy and the potential for less frequent dosing than is needed for currently approved ERTs, the study found.

The results of this early testing were presented at the New Directions in Biology and Disease of Skeletal Muscle Conference, held June 23-26, in Fort Lauderdale, Florida. The conference was hosted by the Myology Institute of the University of Florida.

“These preclinical data show for the first time the ability of FORCE to deliver enzymes to skeletal and cardiac muscle as well as the CNS,” Oxana Beskrovnaya, PhD, chief scientific officer of Dyne, said in a company press release, said of the platform testing. “The data support the potential of FORCE to enable effective enzyme replacement therapy with the opportunity to substantially improve upon available treatments for Pompe disease.”

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Pompe disease is caused by mutations in the GAA gene, which provides instructions for producing the acid alpha-glucosidase (GAA) enzyme, required to break down glycogen, a complex sugar molecule. These mutations result in no production of the GAA enzyme or an enzyme that doesn’t work properly.

Consequently, glycogen builds up to toxic levels within lysosomes, the cell structures where glycogen is broken down, which become enlarged and cause muscle damage. This leads to Pompe symptoms such as progressive muscle weakness and enlargement of the heart muscle, impairing the heart’s function. Pompe also is characterized by central nervous system manifestations, including behavioral and cognitive issues.

Enzyme replacement therapy, the only approved treatment approach for Pompe disease to date, involves the administration of a working version of the GAA enzyme. However, despite its benefits, ERT has proven inadequate in addressing the various symptoms associated with the disease, particularly those affecting skeletal muscles — those attached to bones and responsible for facilitating body movements — and the CNS.

FORCE-GAA is an ERT that uses a proprietary antibody to target the transferrin receptor 1 (Trf1) on muscle and CNS cells. By linking this antibody to a functional version of the GAA enzyme, FORCE-GAA enables the targeted delivery of the enzyme to the affected cells. Trf1 is expressed at high levels on the surface of muscle cells, where it is required for iron transport into these cells.

In a mouse model of Pompe disease expressing human Trf1, FORCE-GAA was administered by intravenous (into-the-vein) infusion, at 5 or 20 mg/kg doses every two weeks, mimicking the standard of care regimen of ERT in Pompe patients.

After eight weeks, FORCE-GAA led to glycogen clearance and normalized lysosome size in heart and skeletal muscle cells, and in the brain and spinal cord.  Moreover, it reduced the blood levels of neurofilament light chain (NfL), a marker of nerve fiber damage, and neuroinflammation, evidencing the potential treatment benefit in the CNS.

We look forward to continuing to explore this application of our platform as part of our mission to deliver life-transforming therapies for people with serious muscle diseases.

Additionally, FORCE-GAA displayed a superior efficacy and dose potency compared with GAA alone and also was effective when given monthly at 20 mg/kg doses. Specifically, the monthly regimen led to glycogen clearance, reduced lysosome pathology in muscle and CNS, and normalized NfL blood levels.

According to the company, these data support the applicability of FORCE-GAA for the treatment of Pompe disease and suggest the potential for monthly dosing, which is less frequent than with currently approved ERTs.

“We look forward to continuing to explore this application of our platform as part of our mission to deliver life-transforming therapies for people with serious muscle diseases,” Beskrovnaya said.