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FARA Funded Research

Your generous support has funded all the research listed below.

For more information on FARA-funded research & scientists, please visit FARA Supported Research, Active Clinical Trials and the Featured Scientist.



Understanding Recent Publication on the Effects of AAV Gene Therapy in a New Mouse Model

This month, Dr. Helene Puccio’s lab at INSERM in France published a new paper with some very exciting results showing the effects of an AAV (adeno-associated virus) gene therapy in a new mouse model of FA. This work gives a lot of hope for gene therapy for FA. Is this a treatment for FA? Unfortunately, not yet.

Promising Results:
The mouse model is designed such that the mouse frataxin can be switched off completed in specific cells in the nervous system, cells that are vulnerable in FA. Puccio’s lab demonstrated that once the frataxin is removed from these cells, the mice develop neurological symptoms similar to severe Friedreich’s Ataxia, although more severe since no frataxin is present. These effects could be prevented by inserting a human frataxin gene by AAV gene therapy. If the gene therapy was used after the mice had developed symptoms, the mice still showed great improvement, which suggests that at least some symptoms of FA may be reversible, in the mouse, if frataxin can be produced in the cells where it is needed. This is very exciting work, with a lot of learnings that will be critical to moving forward with gene therapies for FA.

Mice are not Patients:
These experiments were done on mice, which are not perfect models for human patients. The mice show symptoms similar to human patients, which can be reversed with the gene therapy. This is very encouraging for patient treatment! However, the mouse model differs from human patients in many ways, so while this is a very positive indication, the result will not necessarily directly translate to people, and there are many steps to go. We must first test animals whose size and physiology is closer to humans.

Finding an Effective and Safe Dose:
We need to work out what dose we need – how much therapy will be effective and safe in humans? You cannot scale this directly from mice by size, so you have to look in mice, rats, NHP, and possibly other animals. to figure out what dose might be effective. As (for now) gene therapies can only be administered once to a given patient, it is important to understand how much to give to have an effect before treating anyone.

At the same time, we have to do a large number of studies to look at safety, to make sure that we understand any safety concerns around the treatment – both the gene and the virus that delivers it, and how that changes with dose (almost any medication is toxic at some level, so we need to understand the “window” of doses where the treatment may be both effective and safe).

Then, we need to be able to deliver the treatment to the important organs in humans – mice are much smaller and gene therapies get in much more easily than in people and distribute to different tissues than in humans. So, we need to work out how to deliver the therapy to the places we need it in the cerebellum, spinal cord, heart etc. in humans.

Moving into Clinical Trials:
The worldwide regulatory agencies ensure that therapies that go into humans are manufactured to certain standards, to make sure that you get a pure version of the therapy in question that does not contain any harmful compounds, and does contain a known quantity of the agent which makes it effective (in this case, the AAV vector containing frataxin), so that you really know what dose you are giving people. This is essential both to make sure that the experimental treatment is likely to be safe and to make sure that the patient is getting the treatment they think at the dose they want.

These agencies (FDA, or Food and Drug Administration in the US, EMA or European Medicines Authority in Europe) review safety, dosing, manufacturing and efficacy data. If they think the proposed therapy is likely to be safe and may be effective, they will authorize the testing of the therapy in human patients in clinical trials. After significant testing in patients, if the therapy appears to have a benefit that is greater than the risks or side effects of treatment, the new therapy may be approved and prescribed by doctors.

Right to Try:
What about the new “Right to Try” mechanism in the US? Doesn’t that mean we can access such treatments now if we think the course of the disease is worth the risk of a not fully studied therapy? This law allows patients who are dying to request access to experimental treatments when they have been through Phase 1 safety trials in humans but have not completed later stages of clinical testing. This gene therapy needs a lot of work before it gets to a Phase I trial, so would not be covered by this law. Furthermore, the law does not guarantee that a company will give the patient access to the drug when asked, and there is no precedent yet as to what groups of patients are covered by the law. FARA joins the National Organization for Rare Disorders (NORD) and numerous rare disease advocacy groups in opposing the Right to Try Legislation. To read this statement from NORD, click here

In Conclusion:
Gene therapy in FA is a very exciting area right now, with several groups working on similar, but subtly different therapies. These all use different methods of delivery and vary in the precise gene therapy that is used. They all aim to introduce frataxin, but each has its own construct that may result in different levels of expression of frataxin in different tissues and therefore could affect different symptoms of FA to different degrees. None of these have yet reached human trials, but the first is expected to reach the clinic soon. At least three companies, as well as several academic groups, are working to move these therapies forward for FA. Many of these groups are working together – for example, Dr. Puccio acknowledges her role as an advisor to Voyager Therapeutics in this paper. Thus, lessons learned from papers like this one are shared with the wider community and help all of the projects move forward.

Work, like this work from the Puccio lab, is incredibly encouraging and teaches us a lot about what we need to be looking for in developing these therapies, how they may work, and how to optimize them to make them as effective and safe as possible. The new mouse model by itself is a very useful tool for exploring critical questions around the development of these genes therapies, as well as other therapies. This paper is a big step forward for the field and will help gene therapy research for FA move forward, but we still have work to do before a therapy is available.

Identification of cardioprotective drugs by medium-scale in vivo pharmacological screening on a Drosophila cardiac model of Friedreich's ataxia

Friedreich's ataxia (FA) is caused by reduced levels of frataxin, a highly conserved mitochondrial protein. There is currently no effective treatment for this disease, characterized by progressive neurodegeneration and cardiomyopathy, the latter being the most common cause of death in patients. We previously developed a Drosophila melanogaster cardiac model of FA, in which the fly frataxin is inactivated specifically in the heart, leading to heart dilatation and impaired systolic function. Methylene Blue (MB) was highly efficient to prevent these cardiac dysfunctions. Here, we used this model to screen in vivo the Prestwick Chemical library, comprising 1280 compounds. Eleven drugs significantly reduced the cardiac dilatation, some of which may possibly lead to therapeutic applications in the future. The one with the strongest protective effects was Paclitaxel, a microtubule-stabilizing drug. In parallel, we characterized the histological defects induced by frataxin deficiency in cardiomyocytes and observed strong sarcomere alterations with loss of striation of actin fibers, along with full disruption of the microtubule network. Paclitaxel and MB both improved these structural defects. Therefore, we propose that frataxin inactivation induces cardiac dysfunction through impaired sarcomere assembly or renewal due to microtubule destabilization, without excluding additional mechanisms. This study is the first drug screening of this extent performed in vivo on a Drosophila model of cardiac disease. Thus, it also brings the proof of concept that cardiac functional imaging in adult Drosophila flies is usable for medium-scale in vivo pharmacological screening, with potent identification of cardioprotective drugs in various contexts of cardiac diseases.

Read the entire article HERE

Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia

Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin-positive cells that recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, although fully dysfunctional, proprioceptive neurons can survive for many weeks without frataxin. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue of the sensory neuropathy associated with frataxin deficiency, thus establishing the pre-clinical proof of concept for the potential of gene therapy in treating FA neuropathy.

Read the entire article HERE

Drosophila melanogaster Models of Friedreich's Ataxia

Friedreich's ataxia (FRDA) is a rare inherited recessive disorder affecting the central and peripheral nervous systems and other extraneural organs such as the heart and pancreas. This incapacitating condition usually manifests in childhood or adolescence, exhibits an irreversible progression that confines the patient to a wheelchair, and leads to early death. FRDA is caused by a reduced level of the nuclear-encoded mitochondrial protein frataxin due to an abnormal GAA triplet repeat expansion in the first intron of the human FXN gene. FXN is evolutionarily conserved, with orthologs in essentially all eukaryotes and some prokaryotes, leading to the development of experimental models of this disease in different organisms. These FRDA models have contributed substantially to our current knowledge of frataxin function and the pathogenesis of the disease, as well as to explorations of suitable treatments. Drosophila melanogaster, an organism that is easy to manipulate genetically, has also become important in FRDA research. This review describes the substantial contribution of Drosophila to FRDA research since the characterization of the fly frataxin ortholog more than 15 years ago. Fly models have provided a comprehensive characterization of the defects associated with frataxin deficiency and have revealed genetic modifiers of disease phenotypes. In addition, these models are now being used in the search for potential therapeutic compounds for the treatment of this severe and still incurable disease.

Read the entire article HERE

Peripheral blood gene expression reveals an inflammatory transcriptomic signature in Friedreich's ataxia patients

Transcriptional changes in Friedreich's ataxia (FRDA), a rare and debilitating recessive Mendelian neurodegenerative disorder, have been studied in affected but inaccessible tissues - such as dorsal root ganglia, sensory neurons, and cerebellum - in animal models or small patient series. However, transcriptional changes induced by FRDA in peripheral blood, a readily accessible tissue, have not been characterized in a large sample. We used differential expression, association with disability stage, network analysis, and enrichment analysis to characterize the peripheral blood transcriptome and identify genes that were differentially expressed in FRDA patients (n = 418) compared to both heterozygous expansion carriers (n = 228) and controls (n = 93, 739 individuals in total), or were associated with disease progression, resulting in a disease signature for FRDA. We identified a transcriptional signature strongly enriched for an inflammatory innate immune response. Future studies should seek to further characterize the role of peripheral inflammation in FRDA pathology and determine its relevance to overall disease progression.

Read the entire article HERE

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