FARA Directed Research Projects

TRACK-FA is a natural history study to TRACK brain and spinal changes in individuals with Friedreich Ataxia.

The overall goal of this study is to understand how specific areas of the brain and spinal cord are affected in FA and how they change over time and with stage of disease, and which imaging measurements can be used in clinical trials to monitor response to treatment in the central nervous system. TRACK-FA is the first prospective, multi-site longitudinal magnetic resonance (MR) study in FA across six main sites in multiple countries. Based on a power analysis, the study has completed enrollment of 182 individuals with FA and 97 control participants assessed at baseline, 12 months, and 24 months. Participants with FA aged >5 years old were recruited and split into individuals in early stage (75%) and later stage (25%) of the disease to allow targeted sub-cohort analyses. A small group of younger children (≥5 and <10 yr) was scanned with a shorter protocol. Data processing and analyses have been allocated between the sites based on areas of expertise. A governance structure has been established including a steering committee comprising of site PIs, FARA, and industry representatives to monitor the overall progress of the study.

This study is enrolled and in active follow-up. for more information visit FARA’s active study post.

FARA Staff Project Manager: Jennifer Farmer

Academic Partners and Study Sites:

• Melbourne site – Monash University and Murdoch Children’s Research Institute, Melbourne, Australia
  • PIs – Nellie Georgiou-Karistianis, Ian Harding and Louise Corben
• Aachen site – Aachen University, Aachen, Germany
  • PIs – Kathrin Reetz, Imis Dogan and Sandro Romanzetti
• Minnesota site – University of Minnesota, Minnesota, USA
  • PIs – Christophe Lenglet, Pierre-Gilles Henry
• Sao Paulo site – University of Campinas, Sao Paulo, Brazil
  • PIs – Marcondes Franca Jr. and Thiago Rezende
• Philadelphia site – Children’s Hospital of Philadelphia, Pennsylvania, USA
  • PIs – Timothy Roberts, William Gaetz, David Lynch
• Gainesville site – University of Florida, Florida, USA
  • PIs – Manuela Corti, Sub Subramony, Thomas Mareci
• Montréal site ­ ­– McGill University, Montréal, Canada
  • PIs ­– Massimo Pandolfo, Alain Dagher, David Rudko

This research initiative supports the development of gene therapy drug products by establishing a potency assay for AAV-FXN viral lots for delivery in human subjects.

This type of assay will be required for all entities pursuing gene therapy for FA. Potency tests are used to measure product attributes associated with product quality and manufacturing controls, and are performed to assure identity, purity, strength (potency), and stability of products used during all phases of clinical study. Potency measurements are used to verify that only product lots that meet appropriate standards are used during drug clinical investigation and following market approval.

FARA Staff Project Manager: Elisabetta Soragni

Academic Partners:

• Jill Napierala, UT Southwestern
• Marek Napierala, UT Southwestern
• Robert Wilson, Children’s Hospital of Philadelphia
• Manuela Corti, University of Florida
• Barry Byrne, University of Florida

Lack of an appropriate animal model that recapitulates all or most aspects of the disease has been a major hurdle in pre-clinical studies of potential therapeutics for FA. To try to overcome this limitation, FARA is directing the development of a rat model of FA.

It is FARA’s hope that an FA rat model would better recapitulate more aspects of the human disease. Moreover, since rats are widely used for toxicology and pharmacology studies, FA rat models would be ideal to simultaneously evaluate safety as well as therapeutic benefits of potential drugs and perform pharmacokinetics and pharmacodynamics studies.

FARA Staff Project Manager: Elisabetta Soragni

The ultimate therapeutic goal in FA is to replenish frataxin levels to physiological levels in disease-relevant cells and tissues in vivo. Gene reactivation strategies are less encumbered by some of the complications that are involved in delivery of exogenous frataxin / FXN gene as a therapeutic strategy, and it is not unreasonable to surmise that the ultimate goal of widespread frataxin replenishment may be best achieved by a combination of exogenous delivery and reactivation of endogenous FXN genes.

Knowledge of the precise mechanism(s) of FXN gene silencing in FA is critical for the development of effective gene reactivation therapies. The current project aims at addressing gaps in knowledge about the spatial and temporal aspects of gene silencing and providing a systematic and comprehensive analysis of known silencing mechanisms with very controlled experiments. It also aims at validating cellular and mouse models for specific gene reactivation therapy.

FARA Staff Project Manager: Elisabetta Soragni

Academic Partners:

• Sanjay Bidichandani, University of Oklahoma
• Marek Napierala, UT Southwestern
• Jennifer Phillips-Cremins, University of Pennsylvania

Although cardiac disease is the major cause of early death in Friedreich’s ataxia (FA), there is insufficient understanding of how FA heart disease progresses over time. For example, it is not known if there are measurements of the heart that could be made at the time of diagnosis of FA that predict the course of the cardiac aspects of the disease or the impact of heart disease on lifespan. Several small studies have suggested that analyses of echocardiograms may undercover measurements that are useful in better understanding the FA heart, but a larger coordinated effort is needed to standardize these measurements. Once standard measures are available, drug developers will be able to assess treatment effects in the heart. This project will re-analyze existing echocardiograms to quickly assess the value of these data in understanding and predicting the progression of heart disease in FA.

FARA Staff Project Manager: Barbara Tate

 

Academic Partners:

Project Leads:

• Kimberly Lin, Children’s Hospital of Philadelphia
• Laura Mercer-Rosa, Children’s Hospital of Philadelphia
• Heather Griffis, Children’s Hospital of Philadelphia
• Steve Ampah, Children’s Hospital of Philadelphia

Collaborators:

• Mark Payne, Indiana University
• Aarti Patel, University of South Florida
• Anne Fournier, University of Montreal, CHU Sainte Justine
• Linda Cripe, Nationwide Children’s Hospital
• Talha Niaz, Mayo Clinic

FARA is constantly working to improve treatment and medical outcomes for individuals living with FA. One way to do this is by having educational materials available to physicians and people living with FA.

In 2014, >35 clinicians contributed to the first comprehensive Clinical Management Guidelines for FA. These guidelines are a giant step forward in documenting diagnosis, treatment and management of FA.

In 2020, FARA and the clinician community recognized the need to update these guidelines. This update employed a more the standard GRADE system, a universal approach, to grading and documenting evidence, that allows for more transparency and improves documentation and ability to update the recommendations going forward.

A steering committee was formed to provide recommendations and oversight. The steering committee identified a diverse (by specialty and geography) group of clinician experts to participate in the development of the Clinical Management Guidelines 2.0. The committee also recommended that individuals with FA be involved with the development and review of the updated guidelines.

The updated Clinical Management Guidelines for Friedreich Ataxia were published and made available to the FA community in November of 2022.

A significant component of these guidelines is the capacity to update the chapter information and/or the recommendations in line with emerging evidence. The recent approval in the US of SKYCLARYS (omaveloxolone) for use in individuals with Friedreich ataxia 16 years and over is a good example of when recommendations will require an update.

To this end, the steering committee has developed a framework for reviewing chapter content/recommendations and new evidence and anticipates annual reviews of each chapter unless new evidence comes to light in the intervening time, in which case the committee will update as needed.

FARA Staff Project Manager: Jennifer Farmer and Cait Monette

Lead Investigator:

• Louise Corben, Murdoch Children’s Research Institute

Steering Committee:

• Martin Delatycki, Murdoch Children’s Research Institute
• Kimberly Lin, Children’s Hospital of Philadelphia
• David Lynch, Children’s Hospital of Philadelphia
• Massimo Pandolfo, McGill University
• Jorg Schultz, Aachen University
• Sub Subramony, University of Florida

A repository of fibroblasts and iPSC lines derived from Friedreich's ataxia patients, carriers and healthy individuals can be accessed at the University of Texas Southwestern, in the laboratory of Dr. Marek Napierala.

The repository currently includes over 80 fibroblasts lines and 20 FRDA and control iPSC lines including three sets of patient and isogenic, CRISPR/Cas9-edited paired lines.

Cell lines in this repository are available to both academic and industry investigators for a fee (waived if the investigator currently holds a FARA grant) and by executing an MTA with UT Southwestern. This project was a collaboration between FARA and Dr. Marek Napierala at UT Southwestern and Dr. David Lynch at Children’s Hospital of Philadelphia.

Because many of the major targets of long-term therapy for FA are in the central nervous system (CNS), FARA worked with several FA investigators to write an in-depth review of the pathology present in the brain and spinal cords of patients with FA.

Patrick Ritschel, Director at FARA, assembled a diverse group of investigators to evaluate evidence gathered from human clinical observations, physiological, pathological and imaging approaches, as well as studies in animal models. Dr. Ian H. Harding (Monash University), Dr. David Lynch (Children’s Hospital of Philadelphia), Dr. Arnulf Koeppen (Albany Research Institute) and Dr. Massimo Pandolfo (McGill University) authored a review article that provides a detailed summary of the current understanding of what areas of the spinal cord and brain are impacted by the disease, including what specific cells are vulnerable to the loss of frataxin. Moreover, the review provides some insight into the temporal course of neuropathological changes in the CNS, which helps to offer information on areas that may respond to therapy and be successfully treated at different timepoints during the progression of the disease. This comprehensive review titled “Central Nervous System Therapeutic Targets in Friedreich Ataxia” is useful to patients, caregivers, physicians, as well as drug developers and is open access in Human Gene Therapy.