🕒 4 min
Friedrich’a ataxia (FA) is a progressive neurodegenerative disease that affects 1 in every 50 000 people worldwide. Therefore, it falls under the umbrella of rare diseases. The thing with rare diseases is that it’s hard to get funding for researching their pathophysiology and possible therapies (ergo the name “orphan drugs”). However, with the recent rise of gene therapy, more and more private investors put their money towards finding a cure for 1 in 50 000 people. So don’t be misled by the title of this article – FA is still a rare disease, but its popularity among research groups and institutes has been growing for the past few years. The main reason for such blooming is the emerging field of gene therapy.
One aspect of gene therapy is using genetically modified viruses to deliver genes, proteins or drugs inside tissues and cells that are affected by a certain disease. Since each virus targets different tissues with different efficiencies, the first step is determining which virus to use and how to genetically modify it. The real magic of gene therapy lies in the fact that it is opening doors to treatments for, up until now, untreatable diseases. Not only does gene therapy enable us to potentially treat the untreatable, but it also gives us a chance for better, smarter and more efficient treatment of already curable diseases.
However, since our general understanding of rare diseases is poor, I decided to dedicate this article to Friedrich’s ataxia, while leaving gene therapy and its principles for another time. So, buckle up and let’s dig into FA!
The who, the when and the why
FA is, as previously mentioned, a genetic, progressive, neurodegenerative disease which is inherited through so-called autosomal recessive inheritance. This means that, to get FA, a child would have to inherit mutated genes for a protein called frataxin from both parents, who might not be clinically affected by the disease in case they have one healthy gene (or allele) for frataxin. Typically, the first symptoms are seen at the age of 10 to15 years, although there are cases of first onset of symptoms at the age of 5 or 60. The prognosis is better in women, but overall prognosis is not exactly optimistic. Most patients become wheelchair bound within 11 to 15 years and, once that happens, it often leads to death in the next 8 years.
So, what exactly happens? There are two types of mutations that can happen in the FXN gene (a gene for frataxin protein). The first one consists of excessive repeats of 3 nucleotides: GAA (guanine and two adenines) which are seen in every patient, while the second one is the deletion of a part of a gene, which is seen more rarely. Note that a “healthy” FXN gene has around 30 repeats of GAA at the end of the gene, while individuals with FA usually have between 100 and 1300 repeats of GAA.
Consequently, the gene is being silenced because such long repetitions of the same nucleotides are very often seen in so called “junk DNA” and are therefore “ignored” during the transcription process. This results in a dysfunctional frataxin protein that’s usually either too short or folds in a weird and useless way. Interestingly, the longer the GAA repetitions, the sooner the onset of symptoms.
So, what exactly is frataxin and how can it cause so much damage? Frataxin is a mitochondrial protein and when it’s not functioning properly or if there’s not enough of it, that leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species in mitochondria. That’s why iron chelators, antioxidants and energy metabolism enhancers are a part of supportive therapy, with hope that they would slow the damage progression due to frataxin deficit.
The good, the bad and the ugly
Let’s start with the ugly. The primary symptom of FA after which the disease partly got a name is ataxia of the limbs and during walking. Ataxia is essentially inadequate muscle coordination which results in an unsteady gait, poor control of fine limb movements and scoliosis (sideways curvature of the spine). Because mouth and throat muscles are also affected, impaired swallowing and slurred speech are also commonly seen. Individuals can also develop sensory loss, visual dysfunction and hearing loss.
All the above-mentioned symptoms are neural, but the real problem, and most often the cause of death in the long term, are accompanying extraneural symptoms and diseases. Those include progressive cardiomyopathy, elevated risk of diabetes type 1 and type 2, urinary dysfunction and depression. Because of so many comorbidities that develop in FA, multiple specialists are needed for optimal clinical care.
The bad is current treatment, as it’s only supportive and symptomatic. Each comorbidity is targeted separately, while prostheses, walking aids, wheelchairs and physical therapy are used for movement disabilities. You are probably wondering: how is that bad? Well, none of this slows the progression of the disease or, better yet, cures it. That’s where the good comes in – gene therapy.
There are a few molecules currently in clinical trials and many more in preclinical trials, but the most recent ones are GeneTacs – small molecules designed to target the result of gene expansion, by promoting or preventing the generation of full-length mRNA. That way, a “healthy” frataxin protein is being formed and the symptoms are ideally gone, but realistically milder and the disease slower in progression. Hopefully, we are close to achieving that.
Bürk K. Friedreich Ataxia: current status and future prospects. DOI: 10.1186/s40673-017-0062-x
Figueriedo M. First Clinical Trial of GeneTAC Therapy for FA Expected in 2022. https://friedreichsataxianews.com/, accessed January 14 2022.
Friedreich’s Ataxia. https://rarediseases.org/, accessed January 13 2022.
Gatt G. Funding boost for research to treat Friedreich’s ataxia. https://www.uow.edu.au/, accessed January 13 2022.
Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich Ataxia: Multidisciplinary Clinical Care. DOI: 10.2147/JMDH.S292945.