The Friedreich’s Ataxia Research Alliance (FARA), the CureFA Foundation, and fara Australia are supporting four research projects that aim to better understand the biology underlying Friedreich’s ataxia (FA) and pave the way for future treatment approaches, FARA announced in a press release.
The Award for Innovative Mindset (AIM) is designed to encourage high-risk, high-reward research in FA, with the aim of fostering creativity and innovation. Seventeen applications were received this year, and four were selected to be funded. Award amounts were not disclosed.
FA is caused by a lack of working frataxin due to mutations in the gene that codes for this protein. Specifically, FA is thought to develop when cells express frataxin protein levels that are about 10‐20% of normal levels. This makes FA somewhat unusual — in many other disorders caused by a protein loss-of-function, disease develops when protein levels are 5% or lower than normal.
Led by Sanjay Bidichandani, PhD, at the University of Oklahoma, one funded project aims to characterize the expression of frataxin at the single-cell level. The idea behind this project is that the “10-20%” figure may actually be an inaccuracy caused by averaging — that is, some cells may have extremely low frataxin levels (causing disease), while levels in others are near normal.
By measuring frataxin expression cell-by-cell, researchers will be able to test this idea which, if true, could have important implications for the understanding of how FA develops, and how it might be treated.
Gene therapies aim to deliver a healthy copy of a mutated gene to cells — in the case of FA, a working version of the FXN gene. Typically, the gene is delivered using an engineered virus as a transport agent, but there are drawbacks to such viruses, from difficulties in targeting exact types of cells to risks of an immune reaction against the virus.
This project aims to make an FA gene therapy using nanoparticles instead of viruses. Nanoparticles are small aggregates made of fats and other molecules that can deliver a specific payload, such as a gene, to cells. The nanoparticles used will be designed to target only cells affected in FA by coating them with targeting molecules such as antibodies.
While some patients die of cardiomyopathy (heart disease) in the third or fourth decade of life, many show normal cardiac health until shortly before their death. This suggests that, to some degree, the hearts of FA patients are often able to adapt to stresses caused by the loss of frataxin.
This project postulates that such adaptation may involve the mitochondrial integrated stress response, a metabolic pathway that, as the name implies, is used by cells to offset the effects of stressors. The work will determine whether this pathway is active in a mouse model of FA.
Increased inflammation has been linked to FA, but its causes are not clear. This work aims to determine whether damage to mitochondria — which produce energy for cells — due to frataxin loss leads to the activation of an innate immune pathway that can sense that damage, triggering inflammation.
These research awards are partly supported by funds raised in Lend Us Some Muscle, a global awareness and fundraising campaign organized by FARA and fara Australia.
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