NEW YORK – The Hereditary Neuropathy Foundation and Genome Medical recently introduced a program aimed at providing faster diagnoses for people with the rare Charcot-Marie-Tooth disorder.
The CMT Genie Project aims to get people with CMT diagnosed faster so that they can benefit from early interventions. Although CMT lacks a cure or any approved therapy, interventions such as exercise may delay the progression of symptoms.
The project comprises outreach, testing, and genetic counseling, with testing done via Invitae's Comprehensive Neuropathies Panel and genetic counseling conducted by Genome Medical.
Estela Lugo, program development manager for HNF, views the project as potentially being a "one-stop hub for everything genetic testing-related for CMT."
Physicians are often unfamiliar with the signs and symptoms of CMT and people living with it often find themselves on diagnostic odysseys involving multiple wrong diagnoses. Unfamiliarity with the disorder also sometimes leads physicians to prescribe medications that have neurotoxic effects on those with CMT. These drugs include vinca alkaloids such as vincristine, and taxols such as paclitaxel, docetaxel, and cabazitaxel.
The disorder is estimated to affect some 150,000 people in the US, although the difficulty in diagnosing it means that the actual number may be much higher.
"We still feel there's a significant amount of people that go their whole lives undiagnosed," said Lugo.
To that end, the CMT Genie Project also serves as somewhat of a public service announcement to educate the public on some of CMT's common as well as rare signs, since neither set is well known outside the rare disease community.
Commonly seen signs and symptoms of CMT, for instance, include high arched feet, hammer toes, and numbness or a burning sensation in the hands and feet. Some of CMT's rarer symptoms include breathing difficulties, hearing loss, and vocal cord paralysis.
Getting people tested and onto HNF's CMT registry also helps advance research into CMT.
"This is where it's so powerful because there are a lot of rare, rare types of CMT," Lugo said.
The disorder's rarity means that the full breadth of its genetic origins remains incompletely understood, and new CMT-related variants continue to be discovered.
For this reason, Invitae shares variants uncovered through testing with ClinVar, a public database archiving relationships between genetic variations and phenotypes, to help improve understanding of genetics and rare disease.
"Invitae also performs certain research and commercial activities for which patients may set their preferences in the Invitae patient portal," Swaroop Aradhya, head of global medical affairs at Invitae, said via email. "These activities aim to accelerate diagnosis, improve our understanding of rare diseases, and make patients and their clinicians aware of clinical trials and other opportunities."
Conducting clinical trials for rare diseases is notoriously difficult, owing largely to the small pool of eligible patients.
Last year, for instance, the US Food and Drug Administration caused controversy within the Friedreich's ataxia (FA) community when it decided that the results of a clinical trial of omaveloxolone failed to support approval, despite the trial having reached its primary endpoint and there being no other approved treatment for that rare neurodegenerative disease.
Although the agency has since allowed the drug's maker, Reata Pharmaceuticals, to submit an NDA, it had first suggested repeating the trial, which Reata and the wider FA community had argued would be unduly burdensome given the rarity of the disorder.
Several trials of potential CMT therapies are currently underway.
Drug developers such as Pharnext and Tasly GeneNet Pharmaceuticals, for instance, are testing PXT3003, a synergistic combination of baclofen, naltrexone, and sorbitol, meant to lower PMP22 protein levels. PMP22 protein is a component of myelin sheath that insulates neurons, and PMP22 gene variations such as duplications and point mutations underlie most cases of CMT. The exact function of this protein remains unknown.
Researchers are also investigating potential gene therapies, such as the feasibility of gene editing and gene replacement, although these studies are currently at earlier stages of development.
To drive participation in the CMT Genie program, the HNF is holding webinars, engaging in social media campaigns, offering continuing medical education courses, sending targeted ads, and directly contacting CMT-related healthcare providers such as neurologists and podiatrists.
Program participants receive a pre-test telehealth session with one of Genome Medical's genetic counselors before ordering Invitae's comprehensive neuropathy panel. This next-generation sequencing panel, performed at the firm's CLIA-certified, CAP-accredited laboratory, contains 102 genes, including all 57 genes on the company's Charcot-Marie-Tooth Disease Comprehensive Panel and others associated with similar disorders that are often considered in the differential diagnosis for CMT.
"We require a pre-test session in order to get all the history to decide if they qualify," said Steve Bleyl, chief medical officer at Genome Medical.
In addition to patient history, counselors discuss the risks and benefits of testing, information that can and can't be obtained in a genetic test, variants of unknown significance (VUS), and protections surrounding genetic information, such as those afforded by the Genetic Information Nondiscrimination Act.
While the company can't mandate post-test counseling, he added, it is strongly encouraged, as Genome Medical can use an individual's results to customize a clinical action plan.
Bleyl commented that while Genome Medical's services are largely covered by insurance, the Centers for Medicare and Medicaid Services does not currently cover genetic counseling, which can be a hindrance for some people. The firm, he said, works with patients on self-pay options and offers a "low-as-you-can-go" rate to be able to see any patients seeking their services.
For the test itself, Invitae has a maximum out-of-pocket price of $250, although it is also covered by a number of insurance plans. Qualifying patients may also be eligible for a no-charge option for the test, sponsored by Alnylam Pharmaceuticals.
"Most patients have an out-of-pocket under $100 through their insurance carrier," Aradhya commented, adding that the company's tests are extensively covered and that it also offers a discounted patient-pay price to those who wish to pay out of pocket.
The CMT Genie Project will be an ongoing program with no defined end date. As it is run by the HNF, it relies upon the donations made to that organization to continue running.
The HNF also partnered last year with Palo Alto, California-based biotech RareBase to search for approved compounds that can be repurposed to treat CMT. RareBase is currently screening a small molecule library of several thousand compounds for those that show promise in targeting 10 CMT subtypes.
"Since they are already FDA-approved drugs," Lugo said, "it would be a very smooth and accelerated track to approval. And actual patient need is great."
The HNF also uses the money it raises to fund the development of induced pluripotent stem cell lines that can assist in CMT research.