Utrophin upregulation is a therapeutic approach being explored for the potential treatment of Duchenne muscular dystrophy (DMD), a disease characterized by progressive muscle weakness and degeneration.
DMD is caused by mutations in the gene encoding a protein called dystrophin, a structural protein that protects muscle cells. The mutation causes no dystrophin protein to be made, resulting in muscle cells being easily damaged and gradually wasting away.
How utrophin upregulation works
Utrophin is a protein similar to dystrophin. It is produced naturally during embryonic development, but its production then stops. Researchers hypothesized that upregulating the production of utrophin into adulthood — making sure it is still produced past embryonic development — could compensate for the lack of dystrophin in DMD patients.
Research has shown that utrophin upregulation in mouse models of DMD prevents the development of symptoms similar to those seen in DMD patients. The approach could be beneficial for all DMD patients regardless of their genetic mutations, as well as for patients with Becker muscular dystrophy (BMD), who have faulty dystrophin protein instead of no dystrophin at all.
Currently, there are three therapies focused on resolving the lack of full-length dystrophin in patients with DMD and BMD by upregulating utrophin. These therapies are ezutromid, TVN-102, and rhLAM111. Each is at a different stage of preclinical and clinical investigation.
Potential treatments to upregulate utrophin production
Ezutromid (SMT C1100) is a small molecule that was developed by Summit Therapeutics for the potential treatment of DMD and BMD by upregulating utrophin.
A proof of principle study in mouse models of DMD demonstrated that daily oral administration of ezutromid increased utrophin levels and improved muscle physiology resulting in increased overall muscle strength and the ability to resist fatigue after forced exercise.
A Phase 1 placebo-controlled randomized clinical trial (NCT02383511 in 12 healthy male volunteers, and a Phase 1b placebo-controlled, randomized, double-blind study (NCT02056808) in 12 boys with DMD, demonstrated that ezutromid was safe and well-tolerated.
However, a Phase 2 clinical study (NCT02858362) in 40 patients with DMD to assess the effectiveness of ezutromid failed to achieve both the primary and secondary goals.
Based on these results, Summit Therapeutics terminated the development program of ezutromid.
Biglycan is a proteoglycan (protein bound to a sugar molecule called glycosaminoglycan) commonly present in the extracellular matrix in several tissues.
Research in mouse models of DMD has shown that systemically-administered recombinant human biglycan improves muscle structure and function with no signs of toxicity. The treated mice also had healthier and better-functioning skeletal muscles that degenerate less.
Tivorsan Pharmaceuticals is currently developing a potential treatment called TVN-102, a recombinant human biglycan for treating DMD and BMD. TVN-102 would be delivered systemically by injection into the bloodstream and is predicted to increase the production of utrophin in the muscles. It is hoped this will strengthen the muscle fibers and prevent or reverse muscle weakness and atrophy.
Tivorsan Pharmaceuticals reported it has completed pharmacological studies in rats and non-human primates to determine the safe dosage of TVN-102 to be used in clinical trials. It plans to scale up the production of the potential treatment to initiate Phase 1 and 2 studies in 2019.
The U.S. Food and Drug Administration (FDA) granted TVN-102 orphan drug status in 2016.
Another potential therapeutic candidate for upregulating utrophin in the muscles of DMD patients is another extracellular matrix protein called laminin 111. Research has shown that recombinant human laminin 111 (rhLAM111) can upregulate DMD modifier proteins such as utrophin and alpha7beta1 integrin, both of which can restore muscle cell adhesion, which is affected by the absence of dystrophin at the muscle membranes in DMD patients. rhLAM111 also can stimulate muscle regeneration.
Research in a mouse model of DMD has shown that rhLAM111 can strengthen muscles and improve muscle function. Prothelia is in the process of manufacturing sufficient quantities of rhLAM111 to use in clinical trials in DMD patients.
Last updated: 07/16/2019
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