CMRI Claire Gordon Duncan Chair in Genetics and Professor of Pediatrics Sanjay Bidichandani, at University of Oklahoma Health Sciences Center in Oklahoma City, was awarded an MDA research grant totaling $300,000 over three years to address clinically and scientifically important questions regarding the use of existing and novel HDAC inhibitors to increase levels of the frataxin protein in Friedreich’s ataxia (FA). Bidichandani and colleagues recently found that the mechanism of gene silencing in FA involves shutting off the FXN gene promoter, a region of the gene that typically controls when and how much a gene should be turned on. They are now working to identify therapeutic molecules that will effectively reverse FXN promoter silencing in FA, and to determine the precise mechanism by which promoter inactivation and reactivation occurs.

Funding for this MDA research grant began Aug. 1, 2015.

Vijayendran Chandran, assistant professor in the department of pediatrics, University of Florida School of Medicine in Gainesville, was awarded an MDA research grant totaling $300,000 over three years to identify biomarkers in Friedreich’s ataxia (FA).

FA is caused by deficiency of the frataxin protein. With colleagues, Chandran has developed a mouse model for FA, that exhibits symptoms similar to those seen in people with the disease and in which he can control the onset and progression of disease.

Now the team will use the new model to identify biomarkers at different stages of disease that could predict disease onset and progression in humans.

If successful, Chandran’s work could help clinicians and researchers measure and predict disease progression, and aid in preclinical development and testing of potential FA treatments.

Funding for this MDA research grant began Feb. 1, 2017.

MDA has awarded a research grant totaling $398,541 to Giovanni Coppola, assistant professor and co-director at the University of California, Los Angeles, Informatics Center for Neurogenetics and Neurogenomics. The funds will help support Coppola's research into biological indicators, called "biomarkers," in Friedreich's ataxia (FA).

In a recent pilot study, Coppola and colleagues used microarray technology (a technique that allows researchers to check the gene "expression," or activity, level of thousands of genes at the same time) to identify a set of 77 genes that exhibited changes that correlated with disease status in 10 FA-affected individuals, 10 healthy volunteers and 10 FA "carriers," (people who carry only one defective copy of the gene responsible for FA).

In his new work, Coppola plans to validate the 77 previously identified genes by studying a 10-times larger group of subjects over a period of three years.

Coppola hopes to identify a "signature" of disease that can be used in clinical trials to monitor disease progression and the effects of experimental treatments.

"MDA funding will allow me to test an innovative approach to identifying biomarkers in Friedreich's ataxia, which can potentially be applied to a number of other neurogenetic diseases as well," Coppola said.

In parallel with its biomarker studies, Coppola's team plans to collect genetic information, including gene expression data, from study participants. The researchers will store the data in a large Web-based database, providing the scientific community with the first centralized repository of gene expression data in FA.

Funding for this MDA grant began February 1, 2011.

Manuela Corti, assistant professor in the department of pediatrics at the University of Florida in Gainesville, was awarded an MDA research grant totaling $298,954 over three years to study gene therapy in Friedreich’s ataxia (FA).

FA is caused by gene defects that result in insufficient levels of the frataxin protein in cells. With colleagues, Corti will work to establish a high-impact treatment for FA that involves delivering fully functioning frataxin genes to cells in the heart and nervous system.

The team will determine the best route of delivery for the frataxin gene, and test the safety of repeated delivery of the gene in combination with medications that will prevent immune-system reactions against the frataxin protein.

If successful, the work will help optimize gene therapy approaches to treat FA.

Funding for this MDA research grant began Feb. 1, 2017.

Michael Huang, the NHMRC Peter Doherty Postdoctoral Fellow in the department of pathology, Bosch Institute, at the University of Sydney, Australia, was awarded an MDA development grant totaling $177,100 over a period of three years to explore how deficiency of the frataxin protein in Friedreich’s ataxia (FA) may alter the function of cellular power supplies called mitochondria.

Because the heart and the nervous system rely heavily on mitochondria to fulfill their energy demands, they are most affected by mitochondrial dysfunction. Huang and colleagues will examine the extent to which frataxin protein deficiency disrupts mitochondrial function and the possibility of targeting this process as a therapy.

In cardiac- and neural-specific mouse models of FA, Huang’s team will explore alterations in the ability for mitochondria to fuse or divide in response to energy demands. They also will assess pathological changes in the synthesis and maintenance of mitochondria in FA, and will investigate whether vitamin B3 can boost mitochondrial health to prevent FA disease processes.

The work could lead to novel and accessible therapeutic strategies in FA.

Funding for this MDA development grant began Aug. 1, 2016.

“Several therapies in clinical trials have shown an unexpected immediate benefit — of days to a few weeks — especially improvement in fatigue and speech, very different from the slow disease progression based on neuronal loss,” David Lynch said. “These results imply that our understanding of Friedreich’s ataxia neuropathology is limited, in that some neurological deficits in FA are more readily modifiable at the early stage of disease.”

David Lynch, professor of neurology at the Children’s Hospital of Philadelphia, was awarded an MDA research grant totaling $300,000 over three years to improve understanding of neurological dysfunction in Friedreich’s ataxia (FA).

FA is caused by deficiency of the mitochondrial protein frataxin. To date, a number of clinical trials to test mitochondrial enhancers and frataxin restoration drugs in FA have shown an unexpected short-term response, particularly in speech dysfunction and fatigue. However, speech dysfunction in FA does not stem from brain regions in which cell loss occurs early in the disease. Instead, such deficits may be caused by early synaptic abnormalities. If this is the case, it may be possible to therapeutically target these abnormalities and ameliorate symptoms of speech deficit and fatigue.

In previous studies, Lynch and colleagues have identified early impaired cerebellar mitochondrial biogenesis and synaptic deficits in a mouse model with neurobehavioral deficits analogous to the clinical manifestations observed in people with FA. The team hypothesizes that deficiency of frataxin protein in the cerebellum leads to cerebellar mitochondrial and synaptic deficits that contribute to cerebellar dysfunction and ataxia in FA patients.

Now the team is working to determine if rescuing mitochondrial biogenesis or synaptic deficits can reverse cerebellar dysfunction and neurobehavioral deficits in the FA mouse models.

If successful, this work could improve the understanding of neurological dysfunction in FA, which could immediately translate to novel treatment strategies for FA patients.

MDA has awarded a research grant totaling $202,222 over two years to David Lynch, professor of neurology at Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine. The funds will help support Lynch's study of the relationship between diabetes and Friedreich's ataxia (FA).

Some individuals with FA develop severe cardiomyopathy (heart disease), while others also may develop diabetes and a resistance to the effects of the hormone insulin, Lynch said, noting "This phenomenon may have implications for the overall progression of FA and the mechanisms involved in causing the disease."

Lynch and colleagues plan to examine the relative likelihood of people with FA to develop diabetes. The team will use measurements of blood sugar and blood insulin levels to assess which features of FA make a particular individual more likely to have abnormal insulin resistance.

The team will work to identify specific genes that contribute to abnormal insulin resistance in FA and also determine whether frataxin, the protein that is deficient in FA, contributes to the development of insulin resistance and diabetes.

The MDA grant will “support development of the collaborative group of individuals who will contribute to this project, which leverages previous data also developed with MDA support," Lynch said.

Funding for this MDA grant began August 1, 2011.

Marek Napierala, assistant professor of molecular carcinogenesis at the MD Anderson Cancer Center of the University of Texas, Smithville, was awarded an MDA research grant totaling $320,451 over a period of three years to develop new models of Friedreich’s ataxia (FA) and explore new therapeutic approaches for the disease.

FA is caused by an increase in the number of short DNA sequences, termed GAA repeats, within a gene that encoded for the frataxin protein. This reduces the amount of frataxin that can be made in cells, a problem especially important in neurons (nerve cells) and heart muscle cells. These cells die during the course of the disease, leading to the symptoms of FA.

Napierala studies DNA-editing enzymes called zinc finger nucleases (ZFNs) that can target specific DNA sequences and, operating like a pair of molecular scissors, cut out disease-causing mutations. He will develop cell lines from patients with FA, and then use this technology to repair the gene within the cells.

“Editing the genome of FA cells via excision of the pathogenic expanded GAA repeats,” Napierala says, “will generate a perfect model system: ‘Patient neurons’ can be compared to ‘corrected patient neurons’ derived from the same individual, thus eliminating troublesome variability associated with analyses of patient/control pairs from separate, genetically different individuals.”

The technique will allow him to explore how cells respond when the defect is corrected, and to look for new targets for therapeutic intervention in the disease. In addition, it will establish methods that may be used for similar purposes in other repeat diseases, including myotonic muscular dystrophy (MMD or DM).

Funding for this MDA grant began Feb. 1, 2013.

Marek Napierala, an assistant professor in biochemistry and molecular genetics at the University of Alabama at Birmingham, was awarded an MDA grant totaling $279,518 over a period of three years to investigate a therapeutic strategy for Friedreich’s ataxia (FA).

FA is caused by abnormally high numbers of specific DNA sequences, called GAA repeats, in the frataxin gene. The extra DNA blocks the flow of information from DNA to RNA (an intermediate step between the genetic instructions in DNA and the manufacturing of proteins) and ultimately leads to a deficiency of frataxin protein, which is insufficient to maintain healthy cells.  

In collaboration with RaNA Therapeutics, Napierala and colleagues will study a new approach aimed at increasing the amount of frataxin in FA-affected cells. The team will use molecules called oligonucleotides (small specific DNA fragments that can enter diseased cells), to locate frataxin RNA and stabilize it in order to increase its “molecular lifespan” in patient cells. The strategy is not designed to increase production of frataxin RNA, which has proven to be difficult, but instead allows existing frataxin RNA to be available longer for the process of frataxin protein production.

Napierala’s team predicts that the result of oligonucleotide treatment will be an increased amount of frataxin protein in FA patient cells.

If the strategy is successful, Napierala’s work could lead to rapid development of treatments for FA.

Funding for this MDA research grant began Aug. 1, 2016.

Mark Payne, professor of pediatrics and medical and molecular genetics at the Indiana University School of Medicine in Indianapolis, was awarded an MDA research grant totaling $298,048 over a period of two years to study ways to overcome the vulnerability of heart muscle in Friedreich’s ataxia (FA).

Heart muscle is especially vulnerable in FA, leading to the possibility of severe heart failure and early death. The reason, Payne says, appears to relate to how mitochondria, the cell’s energy producers, obtain their own cellular fuel. “It appears that the mitochondria in the heart, which normally produce energy for the heart to beat, are not capable of using certain fuels (fats and sugars) to make energy. The result is that the heart does not have enough energy to withstand stressful situations.”

Payne will study this phenomenon further in a mouse model of FA, to understand altered mitochondrial function in the heart that may contribute to the development of heart failure. “In particular, we will determine if the mitochondria are capable of using fats and sugars from the diet in an appropriate manner to make energy,” he says, using a variety of advanced molecular biology and imaging techniques. He also will study whether supplying a good copy of the mutated gene responsible for the disease can reverse the faulty metabolism of the heart.

“The goal of this project is to understand the basic mechanisms of heart failure in this disease, and then develop approaches to improve heart function and save lives,” Payne says.

Funding for this MDA grant began Feb. 1, 2013.

MDA has awarded a research grant totaling $625,959 over a period of three years to Des Richardson, professor and senior principal research fellow at the University of Sydney (Australia) School of Medical Sciences. The funds will help support Richardson's continued research into iron metabolism in Friedreich's ataxia (FA).

The aim of Richardson's studies is to examine the role of altered iron metabolism in the cellular energy factories called mitochondria.

Using molecular and cellular models, as well as a research mouse model that closely mimics the neurodegeneration and heart problems observed in people with FA, Richardson and colleagues will test a variety of strategies designed to help elucidate the function of frataxin, the protein that’s deficient in this disease.

The team also will test a new experimental therapy designed to replace or bypass the function of frataxin by getting iron to the mitochondria in a form that can be easily utilized for the processes that are lacking when frataxin levels are inadequate.

"We gratefully acknowledge MDA funding," Richardson said. "The knowledge of these alterations is critical for developing new therapeutics that could replace the function of this molecule in patients."

Funding for this MDA grant began August 1, 2011.

MDA has awarded a research grant totaling $416,250 over three years to Joseph Sarsero, head of the Friedreich Ataxia Laboratory Research Program at the Murdoch Childrens Research Institute in Parkville, Victoria, Australia. The new funds will help support Sarsero’s development of a new mouse model of Friedreich’s ataxia (FA).

Prior to evaluating new therapies in people with FA, it is important that they be tested in appropriate biological models of the disease, Sarsero noted.

"Animal models that are generated by the 'knocking out' of specific genes often manifest the main symptoms of the corresponding human disorder; however, such models rarely recapitulate the precise molecular cause that underlies the human disease."

Accurate "humanized" mouse models of disease are designed to contain an entire human gene of interest and harbor the specific disease-causing mutations found in people with the disease. Such mice should not only manifest the main symptoms of a disorder, but also provide the correct underlying molecular cause of the disease.

Utilizing information and resources generated as part of the Human Genome Project, coupled with their expertise in handling the FA gene and their preliminary mouse models of the disease, Sarsero and colleagues plan to generate an improved humanized FA mouse model that will contain the entire human FA gene.

Funding for this MDA grant began February 1, 2011.

"The mouse model will more accurately reflect the underlying molecular cause of FA and exhibit the key molecular, biochemical, epigenetic and behavioral traits of the disorder," Sarsero said.

This new research tool is expected to enable scientists to better understand the molecular underpinnings of FA as well as provide a better subject in which to test potential FA therapeutics.

"MDA support has been pivotal in allowing us to pursue major projects aimed at identifying new pharmacological therapies for Friedreich's ataxia and the generation of accurate mouse models of the disorder," Sarsero said.