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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.



Chemical synthesis of lipophilic methylene blue analogues which increase mitochondrial biogenesis and frataxin levels

As part of an ongoing program to develop potential therapeutic agents for the treatment of the neurodegenerative disease Friedreich׳s ataxia (FRDA), this group has prepared a number of lipophilic methylene blue analogues. Some of these compounds significantly increase mitochondrial biogenesis and frataxin levels in cultured Friedreich's ataxia cells . This data article describes the chemical synthesis and full physicochemical characterization of the new analogues.

Read the entire article HERE

Activating frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion

Friedreich's ataxia (FRDA) is an incurable neurodegenerative disorder caused by reduced expression of the mitochondrial protein frataxin (FXN). The genetic cause of the disease is an expanded GAA repeat within the FXN gene. Agents that increase expression of FXN protein are a potential approach to therapy. This group has previously described anti-trinucleotide GAA duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) that activate FXN protein expression in multiple patient derived cell lines. Here they test two distinct series of compounds for their ability to increase FXN expression. ASOs with butane linkers showed low potency, which is consistent with the low Tm values and suggesting that flexible conformation impairs activity. By contrast, single-stranded siRNAs (ss-siRNAs) that combine the strengths of dsRNA and ASO approaches had nanomolar potencies. ss-siRNAs provide an additional option for developing nucleic acid therapeutics to treat FRDA.

Read the entire article HERE

Novel Nrf2-Inducer Prevents Mitochondrial Defects and Oxidative Stress in Friedreich's Ataxia Models

In Friedreich's Ataxia, increased oxidative stress leads to a chronic depletion of endogenous antioxidants, which affects the survival of the cells and causes neurodegeneration. In particular, cerebellar granule neurons (CGNs) show a significant increase of reactive oxygen species (ROS), lipid peroxidation and lower level of reduced glutathione (GSH). In FRDA, one of the major pathways of oxidant scavengers, the Nrf2 antioxidant pathway, is defective. Previous studies on FRDA-like CGNs showed that the reduced level of frataxin and the oxidative stress induce mitochondrial impairments. By triggering the Nrf2 pathway pharmacologically we determined whether this could promote mitochondrial fitness and counteract oxidative stress. In this work, we sought to investigate the beneficial effect of a promising Nrf2-inducer, omaveloxolone (omav), in CGNs from two FRDA mouse models, KIKO and YG8R, and human fibroblasts from patients. We found that CGNs from both KIKO and YG8R presented Complex I deficiency and that omav was able to restore substrate availability and Complex I activity. This was also confirmed in human primary fibroblasts from FRDA patients. Although fibroblasts are not the major tissue affected, we found that they show significant differences recapitulating the disease; this is therefore an important tool to investigate patients' pathophysiology. Interestingly, we found that patient fibroblasts had an increased level of endogenous lipid peroxidation and mitochondrial ROS (mROS), and lower GSH at rest. Omav was able to reverse this phenotype, protecting the cells against oxidative stress. By stimulating the cells with hydrogen peroxide (H2O2) and looking for potential mitochondrial pathophysiology, we found that fibroblasts could not maintain their mitochondrial membrane potential (ΔΨm). Remarkably, omav was protective to mitochondrial depolarization, promoting mitochondrial respiration and preventing cell death. Our results show that omav promotes Complex I activity and protect cells from oxidative stress. Omav could, therefore, be used as a novel therapeutic drug to ameliorate the pathophysiology of FRDA.

Read the entire article HERE

Longitudinal analysis of contrast acuity in Friedreich ataxia

In the Friedreich Ataxia-Clinical Outcome Measures Study, participants (n = 764) underwent binocular high- and low-contrast visual acuity testing at annual study visits. Mixed-effects linear regression was used to model visual acuity as a function of time, with random intercepts and slopes to account for intraindividual correlation of repeated measurements. A time-varying covariate was used to adjust for diabetes, and interaction terms were used to assess for effect modification by GAA repeat length, disease duration, and other variables.

Across a median of 4.4 years of follow-up, visual acuity decreased significantly at 100% contrast (-0.37 letters/y, 95% confidence interval [CI]: -0.52 to -0.21), 2.5% contrast (-0.81 letters/year, 95% CI: -0.99 to -0.65), and 1.25% contrast (-1.12 letters/y, 95% CI: -1.29 to -0.96 letters/year). There was a significant interaction between time and GAA repeat length such that the rate of decrease in visual acuity was greater for patients with higher GAA repeat lengths at 2.5% contrast (p = 0.018) and 1.25% contrast (p = 0.043) but not 100% contrast. There was no effect modification by age at onset after adjusting for GAA repeat length.

Low-contrast visual acuity decreases linearly over time in Friedreich ataxia, and the rate of decrease is greater at higher GAA repeat lengths. Contrast sensitivity has the potential to serve as a biomarker and surrogate outcome in future studies of Friedreich ataxia.

Read the entire article HERE

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.

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