CMT Association, Applied Team Up on Therapy for New Subtype

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by Patricia Inacio PhD |

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A new partnership is seeking to identify people with a mutation in the sorbitol dehydrogenase (SORD) gene — the cause of a newly identified type of Charcot-Marie-Tooth disease (CMT) — who may be eligible for clinical trials investigating potential treatments for this recessive subtype.

In this collaboration, the Charcot–Marie–Tooth Association (CMTA) and Applied Therapeutics, a clinical-stage biopharmaceutical company, will seek people with SORD mutations who may be interested in participating in future clinical trials through the CMTA’s Patients as Partners in Research initiative, according to a press release.

Patients will be able to get tested for free for SORD mutations at home or at a doctor’s office — and their perspectives will be taken into account during the design of new trials.

The partnership with Applied Therapeutics is part of the CMTA’s Strategy to Accelerate Research (STAR), established to foster the connection between leading CMT clinicians, researchers, and pharmaceutical partners. The goal is to develop treatments and a cure for CMT.

The SORD gene has the instructions for an enzyme, called sorbitol dehydrogenase, that converts sorbitol, a sugar alcohol found in fruits and plants, into fructose, a simple sugar. Mutations in SORD increase sorbitol levels and have been implicated in nerve damage (neuropathy) associated with diabetes.

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SORD and CMT

Research Ongoing Into Newly Identified Subtype Tied to SORD Gene

A team led by Stephan Züchner, MD, PhD, chair of the department of human genetics at the University of Miami, in Florida, discovered this new, recessive CMT subtype. As a recessive disorder, a person must inherit a faulty SORD copy from each parent to develop this form of CMT.

In a study with flies, the researchers found that the loss of SORD led to abnormally high levels of sorbitol and nerve degeneration that affected movement.

Treating the flies with two different aldose reductase inhibitors, epalrestat — which is approved in Japan to treat diabetic neuropathy — and ranirestat, reduced the accumulation of sorbitol and lessened motor symptoms, the data showed. Aldose reductase is an enzyme that mediates the conversion of glucose to sorbitol.

AT-007 is an oral aldose reductase inhibitor being developed by Applied Therapeutics as a treatment of several rare conditions. By blocking this specific enzyme, the therapy prevents the formation of sorbitol. Notably, AT-007 is able to cross the blood-brain barrier — a semipermeable membrane that protects the brain and spinal cord — to exert therapeutic effects in the central nervous system.

A recent pilot study examined AT-007 in eight patients diagnosed with SORD deficiency, a progressive hereditary neuropathy caused by deficiency in the sorbitol dehydrogenase enzyme. Treatment with AT-007 was found to lower sorbitol levels by 66% in the blood. The reduction across patients ranged from 54% to 75%, according to the press release.

Applied Therapeutics now is planning a registrational study involving people with SORD deficiency in the U.S. and Europe. That study is scheduled to start by year’s end.

The company hopes the results of the trial support the approval of AT-007 as the first therapy for people with SORD deficiency.

AT-007 also has been studied in healthy volunteers, as well as in adults and children with galactosemia, a rare disorder in which a genetic defect impairs the breakdown of another sugar, called galactose. The therapy also is under development for people with phosphomannomutase 2 deficiency, an inherited disorder characterized by imbalances in sugar metabolism pathways.