Since 2008, the medical field has designated February 28 as Rare Disease Day, a day to honor patients with all varieties of rare diseases. The international celebration has been practiced since 2009, when the National Organization for Rare Disorders offered its hand in spreading the day to others, helping to get advocacy groups in the United States—and eventually around the world—to observe the day.
NeurologyLive® proudly works in partnership with several rare disease advocacy organizations—including the ALS Association, Cure SMA, the Dravet Syndrome Foundation, the Lennox-Gastaut Syndrome Foundation, the TSC Alliance—aiming to increase awareness and inform clinicians of the latest advances for these rare and challenging-to-treat disorders. In observance of Rare Disease Day, our team spoke with experts on the current state of care and treatment for a few rare diseases implicated in neurological care, including Friedreich ataxia, myotonic muscular dystrophy, among others.
Switch between the slides below to learn more about the progress in Friedreich ataxia and myotonic muscular dystrophy. For more updates on progress in rare diseases, check out our updates on Pompe disease and Rett syndrome.
First described by German physician Nikolaus Friedreich in 1863, Friedreich Ataxia (FA) is a rare, inherited, degenerative disorder that damages the spinal cord, peripheral nerves, and cerebellum portion of the brain. About 1 in 50,000 people in the US has FA, with an estimated 15,000 affected individuals worldwide. Symptoms of FA typically begin to occur between the ages of 5 and 18 years, with late onset occurring in less than one-fourth of the population. FA progresses slow, and the sequence and severity of its progression is highly variable.1
There are a number of physical symptoms these patients face, including trouble walking, tiredness, loss of sensation and reflexes, slow or slurred speech, hearing and vision loss, chest pain, shortness of breath, and heart palpitations. Fatigue, an issue seen across all of neurology, remains among the most notable symptoms, says Giovanni Manfredi, MD.
"You measure the strength of these people and the muscle seems to be working pretty well, but they get tired quickly,” he said. "That’s probably a bioenergetic problem, right? Even though the instantaneous strength is not affected so much, the ability to perform aerobic exercise, for example, is quite affected. That is at every organ level." Manfredi currently serves as a professor of neurology at Weill Cornell Medical College and a professor of neuroscience at Weill’s Brain and Mind Research Institute.
The other major area of need for FA is cardiac dysfunction, which is widely accepted as the most common cause of mortality in these patients. Nearly all patients with FA develop cardiomyopathy at some point in their lives.2 The cardiac involvement seen in the disease is believed to be a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. Previous research has shown that dilated cardiomyopathy and arrhythmia are associated with mortality in FA, whereas hypertrophic cardiomyopathy is not.3
"There are some symptomatic treatments that limit the amount of neuropathic pain or the amount of stiffness that can treat the late phases of cardiomyopathy and end stage heart failure. But other than that, there’s truly nothing other than treating symptoms,” David Lynch, MD, PhD, a neurologist in the Division of Neurology at the Children’s Hospital of Philadelphia (CHOP) and director of the Friedreich’s Ataxia Program, told NeurologyLive®.
Both Lynch and Manfredi serve on the Friedreich’s Ataxia Research Alliance’s (FARA) Scientific Advisory Board, with Lynch as an advisor and Manfredi as a co-chair. Manfredi’s main focus of research in his laboratory is on the regulation of mitochondrial metabolism in diseases associated with mitochondrial dysfunction, such as FA. Lynch has been a part of research efforts in FA that include double-blind clinical trials, identifying biomarkers, and leading mechanistic studies in animal and cellular models.
Trials on omaveloxelone, a promising agent in development for FA, were led by Lynch and others. The phase 2 MOXIe extension study (NCT02255435) was the main trial that supported the new drug application of the therapy, which targets NrF2 pathways. In MOXIe, changes from baseline in the primary end point of modified Friedreich's Ataxia Rating Scale (mFARS) scores in the omaveloxolone group (–1.55 points; SD, 0.69) and placebo group (0.85 points; SD, 0.64) showed a significant between-group difference of –2.40 points (SD, 0.96; P = .014). Additionally, transient reversible increases in aminotransferase levels were observed in omaveloxolone without increases in total bilirubin or other signs of liver injury.4
The FDA extended the review period for omaveloxolone in August 2022 as a result of newly submitted supportive data.5 If approved, it would become the first therapy specific to treat patients with FA. "It’s a good drug, maybe even a very good drug. It’s not a cure,” Lynch stated. "One fortunate thing is it does not have many adverse events associated with it. It’s what we like to call a clean drug. It can be well managed, and I think everyone will probably give it a try once it’s available."
Giovanni suggested similar thoughts, but noted the agent’s approval could springboard future drug development. "I do not believe a drug like omaveloxolone will drastically change the disease course, but it may have an impact. Evidence so far suggests there is a slowdown, a delay in disease progression, at least for that time period." If approved, he noted "at that point, there are many drugs that could potentially be competing in the same space. Omaveloxolone is going to be the benchmark. Everything is going to be measured against that. For a new drug to be approved along the same disease mechanisms, it will have to be substantially better."
Omaveloxolone treats a downstream mechanism of FA, not the original root cause of the disease. FA, a progressive neurodegenerative disease, is caused by a genetic deficiency of frataxin, a small nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently, ATP production abnormalities.6
In recent years, significant advances in gene replacement therapy and ability to edit genes have garnered much interest as a treatment approach for FA. Considering almost all patients with the disease have the same single gene mutation, it’s an approach that could have promising results. While these patients only make 50% of normal frataxin, it’s believed that they are less likely to have an immune response to replacing this protein.
Most of the studies assessing gene therapy approaches have not made it out of preclinical stages, but this could change in the coming years, Lynch stated. "I would expect that this would come to fruition and we’ll move forward again. The issue will be that we cannot replace frataxin in every cell in the body. Pick the times you need, understand the adverse events, and then figure out where you can do it."
There are several approaches in the pipeline aiming to replace frataxin deficiency, including the use of stem cell therapies, specifically autologous stem cell therapy. A 2014 paper exploring the idea of autologous stem cell transplant for FA concluded that transfected bone marrow-derived mesenchymal stem cells could retain the ability to differentiate into neurons and cardiomyocytes.7
The paper, written by Naoki Tajiri, PhD, PT, et al, also noted that "More importantly, determination of genetic correction of GAA repeats, fraxatin mRNA levels, and frataxin protein expression will be key outcome measures of a robust stem cell donor for FRDA. The basic science, translational, and clinical significance of this envisioned gene-based stem cell therapy is the demonstration that bone marrow-derived mesenchymal stem cells from patients with FA subjected to genetic correction will display phenotypes of healthy neurons and cardiomyocytes and free of FA-associated disease hallmarks, thereby representing a novel source of transplantable autologous cells for FRDA patients."
Lynch believes the current progress of stem cell research is similar to where gene therapy is now, stating that both have issues with location. "Where can you get to? Can you get the right cells? And how broad can you get? These are not easily solved, but they will be solved," he said.
Other research effort outside of gene and cell therapy or replacement strategies include a better understanding of the mitochondrial defects associated with the disease, developing new animal models of FA that closely mimic the gene mutations found in the disease, and developing biomarkers for future clinical trials.
"When you think of Rare Disease Day, the FA field is a community of patients, caregivers, researchers, and clinicians, just like the whole rare disease community. It’s very much the same, all working forward and hopefully learning from each other. Through that sort of approach, we can make true progress," Lynch concluded.
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