Why is Frataxin important in FA?

Frataxin is the protein that is missing in Friedreich’s ataxia. The gene encoding this protein is defective and thus, no frataxin is produced or else it is produced in such low amounts that it can’t do its job effectively. Studies have shown that if the cell ever has frataxin, it will handle this protein appropriately and has normal function. Frataxin is an iron binding protein that functions inside of mitochondria to bind and present iron to other protein complexes. In its absence, these other critical enzymes and proteins cannot function effectively. As a result, the mitochondria eventually stop producing energy and the cell no longer functions normally. Loss of mitochondrial function is critical for tissues, such as brain and heart, which use lots of energy.

Your early results have been promising.  What has your research into TAT-Frataxin shown so far?

We are excited about our findings. To date, we have been able to show that a TAT-Frataxin protein will move across the cell membrane into mitochondria. For cells in culture from patients with FA, we’ve been able to show that treating these cells with TAT-Frataxin restores their resistance to an oxidant stress from iron exposure. For the Friedreich’s ataxia mouse model from Helene Puccio, we’ve been able to partially rescue the animals with TAT-Frataxin and markedly extend their lifespan. They have better heart function. This is very important because these animals represent the most severe phenotype of FA in that they are completely lacking frataxin expression in certain tissues. These findings have encouraged us to pursue TAT-Frataxin to see if we can optimize its performance and function.

What is your goal with your TAT-Frataxin research?

There are two goals for this research: 1) Develop a therapy for Friedreich’s ataxia (FA). We are hopeful that we can develop TAT-Frataxin, or a variant of this protein, to function effectively as a new drug to treat patients with FA.  2) Take the lessons we learn from working with TAT-Frataxin and expand this technology to other mitochondrial diseases. This will help us develop new drugs and therapies for other diseases, and discover new knowledge about mitochondria.

Your research has been funded by Shire Human Genetics, Inc. Is this research a priority for the company?

Yes, they are deeply committed to this approach and this is a priority for this company. They have a mission to develop therapies and cures for rare and difficult diseases and have been successful in the past.

What is the timeline before TAT-Frataxin could be in patient clinical trials?

This is hard to guess at because there are so many variables and experiments that have yet to be done. If results from additional animal and laboratory studies progress as hoped, then it is quite possible that a TAT-Frataxin molecule could move into pre-clinical studies within two years. Phase I studies would follow after
these were completed and had been approved by the FDA. At the earliest, five years would be realistic for significant clinical trials.

You have taken a leading role in pulling together researchers to have a better understanding of various heart problems in FA patients. What specifically have researchers been doing recently?

Initially, clinicians logically focused on the neurologic impact of FA because this was the most prominent physical finding. However, the heart is affected as well and is frequently a cause of mortality in patients with FA. Researchers are now beginning to look at mechanisms for why and how the heart is affected in this disease, and how it can be helped. For example, the heart in patients with FA frequently becomes very thick and doesn’t function normally. This leads to problems later when surgeries are required, and can cause dangerous arrhythmias. Researchers are now looking at ways to decrease the thickness of the heart and improve its function. However, we still need more clinical studies of the heart in this disease because of the variability in how FA can affect the heart. More research on heart function using animal models of FA is also needed to determine the mechanisms of heart damage in this disease. In particular, better animal models are needed that more accurately mimic the genetics of the human FA patients.

At some recent scientific meetings, researchers have indicated that some earlier assumptions about how FA impacts the heart have been incorrect? What was wrong, and what is the current thinking?

In some patients with FA, the heart becomes very thick. Although the heart still ‘squeezes’ well and can pump the blood effectively, the increased thickness of the heart means it can’t fill with blood as easily. If this happens, it makes it much harder for the heart to adjust its output to match the demand for more blood to be pumped, i.e., if the blood can’t get into the heart, then there isn’t as much blood for the heart to pump out. It also means that the heart won’t tolerate large changes in blood volumes, such as during surgery for scoliosis, and can fail because of this stress. Greater education of physicians and families about the nature of this cardiac dysfunction in FA is needed, as are more clinical studies of the impact of FA on the heart.

How is the American Heart Association working with FARA and FA families on these issues?

The AHA has helped fund studies on heart function in animal models of FA and in patients. This is a significant recognition by a large and definitive scientific group that the heart is a key organ affected in FA and needs greater study.

What new insights do you expect from the current research into heart function in FA patients?

Hopefully, we will determine three things: 1) The mechanism for heart dysfunction in this disease. 2) How we can improve heart function in this disease to improve lifespan and decrease mortality. 3) Why some hearts are affected and others are not. This is a very puzzling aspect of FA and may offer clues about gene expression that can be taken advantage of to develop new therapies.

As you consider other potential FA therapies, what do you see as the most promising research underway?

At this time, two approaches would seem to offer the greatest possibility as a therapy for FA: 1) Those therapies designed to increase expression of native frataxin. These are primarily the HDAC inhibitors, which help increase expression of the normal frataxin protein from the defective FA gene. Significant work is well underway to develop small molecules that can increase gene expression without serious side effects. 2) Those therapies designed to increase the amount of frataxin protein in the cell. This is primarily by protein replacement (or enzyme replacement) strategies, such as TAT-Frataxin. Once again, work is well underway to develop cell penetrant fusion proteins, like TAT-Frataxin, that can deliver the missing frataxin protein to the mitochondria in all tissues. Both approaches, HDAC inhibitors and protein replacement therapy, come at the problem of FA from different directions and have unique strengths and weaknesses. Both approaches also have the strong appeal of potentially offering new technology to cure other diseases as well. Finally, it is quite probable that a combination of both approaches, which takes advantage of their combined strengths, will provide a cure for FA.

How long do you think it will be before there is a cure for FA?

Hard to guess on this but work is moving very, very fast. This is largely due to the high degree of focus and organization of groups such as FARA (Friedreich’s Ataxia Research Alliance). In particular, FARA has advanced our scientific understanding of FA while keeping attention focused on a cure based on this understanding. Again, I am hoping for clinical trials of both approaches above, and a therapy to advance to market within seven years.

The legacy of Marie Schlau: literature to help cure Friedreich's Ataxia

If you feel like reading an unputdownable novel while collaborating with a just and solidary cause, "The Legacy of Marie Schlau" is your book! 100% of all funds raised will be dedicated to medical research to find a cure for Friedreich's Ataxia, a neurodegenerative disease that affects mostly young people, shortening their life expectancy and confining them to a wheelchair.

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Research projects currently being financed by BabelFAmily

Currently, BabelFAmily is financing two promising research projects aimed at finding a cure for Friedreich's Ataxia. Whenever you make a donation to us or purchase a copy of "The legacy of Marie Schlau", this is where all funds raised will be devoted to:

1) Gene Therapy for Friedreich's Ataxia research project:


The project is the result of an initiative of Spanish people affected by this rare disease who are grouped in GENEFA in collaboration with the Spanish Federation of Ataxias and the BabelFAmily. The Friedreich’s Ataxia Research Alliance (FARA), one of the main patients’ associations in the United States now joins the endeavour.

2) Frataxin delivery research project:

The associations of patients and families Babel Family and the Asociación Granadina de la Ataxia de Friedreich (ASOGAF) channel 80,000 euros of their donations (50% from each organisation) into a new 18-month project at the Institute for Research in Biomedicine (IRB Barcelona). The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.



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