FARA, the CureFA Foundation, and fara Australia are proud to announce the recipients of the Award for Innovative Mindset (AIM). AIM was designed to promote the exploration of high-risk, high-gain, and potentially groundbreaking concepts in FA research. The request for proposals was initiated in May, during Friedreich's Ataxia Awareness Month, and the research awards are supported in part by funds raised in the Lend Us Some Muscle campaign. The intent of the award was to inspire creativity, thoughtful reflection, innovation and to advance FA research, during a time when many investigators were away from their labs and daily routines due to the shutdown. Seventeen applications were received and four were awarded funding. A description of each project follows below.
Sanjay Bidichandani, PhD - University of Oklahoma
Single Cell Gene Expression Analysis in Friedreich Ataxia
This application proposes a new model to explain the (apparently) high residual level of frataxin seen in FA patients. The current understanding is that FA develops when cells express levels of frataxin protein that are 10‐20% of normal levels. Thus, when compared to other loss-of-function conditions, where disease is typically triggered at residual protein levels/activity of <5%, FA seems to manifest at relatively higher residual protein levels. The hypothesis put forward in this grant proposal is that most FA cells actually express very low levels of frataxin (<5%, as in other recessive disorders), and that a substantial minority of cells show “escape from gene silencing” and thus express near normal levels of transcript due to FXN genes that, despite containing an expanded GAA repeat, are not fully silenced. This group plans to test this hypothesis by analyzing FXN expression and silencing in individual cells. This model has important implications for the understanding of FA pathogenesis, and for the development of treatments.
Cosponsor: CureFA Foundation and fara Australia
Cosponsor: CureFA Foundation and fara Australia
Christina Cortez-Jugo, PhD - University of Melbourne, Australia
Targeted Delivery of Frataxin DNA to Proprioceptors of the Dorsal Root Ganglia
This application proposes to use nanoparticles instead of viruses to deliver the frataxin gene in gene therapy approaches. Nanoparticles are small aggregates made of polymers, lipids and other molecules that can deliver a specific cargo (in this case the frataxin gene) to cells. This investigator proposes to improve the delivery of the cargo to the specific cell types that are mostly affected in FA, by coating the nanoparticle surface with antibodies and ligands that will promote their binding and uptake by the target cells. The ability to target specific cells affected in FA could increase the concentration of the therapeutic where it is needed, and reduce dosage, cost of treatment and side effects.
Cosponsor: CureFA Foundation and fara Australia
This application proposes to use nanoparticles instead of viruses to deliver the frataxin gene in gene therapy approaches. Nanoparticles are small aggregates made of polymers, lipids and other molecules that can deliver a specific cargo (in this case the frataxin gene) to cells. This investigator proposes to improve the delivery of the cargo to the specific cell types that are mostly affected in FA, by coating the nanoparticle surface with antibodies and ligands that will promote their binding and uptake by the target cells. The ability to target specific cells affected in FA could increase the concentration of the therapeutic where it is needed, and reduce dosage, cost of treatment and side effects.
Cosponsor: CureFA Foundation and fara Australia
Giovanni Manfredi, MD, PhD - Weill Cornell Medicine & Helene Puccio, PhD - Institute NeuroMyoGène, Lyon, France
Mitochondrial integrated stress response in FA cardiomyopathy
The hypothesis of this proposal stems from the observation that death from cardiomyopathy in FA occurs in the third or fourth decade of life, but surprisingly the FA heart often maintains adequate function until shortly before death. This suggests that the FA heart is able to adapt, at least initially, to the defects caused by the loss of frataxin. This adaptation likely involves metabolic rewiring to allow the utilization of alternative energy sources and other events. The investigators propose that these events recapitulate the “mitochondrial integrated stress response” (well characterized in other mitochondrial diseases) which is an evolutionarily conserved response designed to help the organisms face periods of acute stress, but if chronic and unresolved, becomes “maladaptive”. This proposal aims to determine whether there is evidence of mitochondrial integrated stress response in the heart of an FA mouse model.
Cosponsor: CureFA Foundation and fara Australia
The hypothesis of this proposal stems from the observation that death from cardiomyopathy in FA occurs in the third or fourth decade of life, but surprisingly the FA heart often maintains adequate function until shortly before death. This suggests that the FA heart is able to adapt, at least initially, to the defects caused by the loss of frataxin. This adaptation likely involves metabolic rewiring to allow the utilization of alternative energy sources and other events. The investigators propose that these events recapitulate the “mitochondrial integrated stress response” (well characterized in other mitochondrial diseases) which is an evolutionarily conserved response designed to help the organisms face periods of acute stress, but if chronic and unresolved, becomes “maladaptive”. This proposal aims to determine whether there is evidence of mitochondrial integrated stress response in the heart of an FA mouse model.
Cosponsor: CureFA Foundation and fara Australia
Seth Masters, PhD - Walter and Eliza Hall Institute, Melbourne Australia
Targeting neuroinflammation in Friedreich's Ataxia
This grant proposal addresses the role of inflammation in FA. There is evidence of inflammation due to low levels of frataxin in cell lines, in mouse models, and in patients with FA, however mechanistic insights into the trigger for inflammation in FA are missing. This investigator hypothesizes that a specific innate immune pathway drives inflammation in FA. The cellular pathway normally detects virus/bacteria, but is also known to respond to damaged mitochondria. In FA, the damage to mitochondria due to frataxin loss would cause activation of this specific innate immune pathway. The aim of this proposal is to demonstrate mitochondrial damage leading to activation of this innate immune pathway with associated inflammatory biomarkers which may help stratify and direct therapy for FA.
Cosponsor: CureFA Foundation and fara Australia
This grant proposal addresses the role of inflammation in FA. There is evidence of inflammation due to low levels of frataxin in cell lines, in mouse models, and in patients with FA, however mechanistic insights into the trigger for inflammation in FA are missing. This investigator hypothesizes that a specific innate immune pathway drives inflammation in FA. The cellular pathway normally detects virus/bacteria, but is also known to respond to damaged mitochondria. In FA, the damage to mitochondria due to frataxin loss would cause activation of this specific innate immune pathway. The aim of this proposal is to demonstrate mitochondrial damage leading to activation of this innate immune pathway with associated inflammatory biomarkers which may help stratify and direct therapy for FA.
Cosponsor: CureFA Foundation and fara Australia
