Can we use fish to model FA?
A tractable vertebrate model that recapitulates key aspects of Friedreich ataxia
Animal models of Friedreich’s ataxia (FA) are important to study the disease and test potential therapies before they are assessed in humans. There are many mouse models of FA that have been created to study different aspects of the disease; however, these models are not perfect.
Dr. Robert Wilson at the Children’s Hospital of Philadelphia has used gene editing to delete the frataxin gene in zebrafish, effectively creating a zebrafish model of FA.
These FA zebrafish rapidly develop a more pronounced phenotype than FA mice, making the testing of potential therapies faster. They are also cheaper to work with and have some features that are more closely related to humans.
We are pleased to award a grant to Dr. Robert Wilson to further explore this FA zebrafish model. FARA is co-funding this grant in partnership with FARA Ireland (https://faraireland.eu/). In this grant, Dr. Wilson’s lab will validate additional characteristics of this model.
Dr. Wilson’s lab will also use this model to try to identify drug effects that may be predictive of efficacy in humans. They will do this by dosing the FA zebrafish with drugs that have not shown efficacy in clinical trials and drugs that have (such as omaveloxolone). The goal is to identify a predictor of drug efficacy that can be used to increase the likelihood that drugs in the clinical trial pipeline will show efficacy in humans.
Scientific News
FARA funds research progress
In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA's Grant Program and the Treatment Pipeline.
New Grant Awarded to Robert Wilson, MD, PhD – Can we use fish to model FA?
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New Grant Awarded to Esther Becker, PhD – Can we grow a brain in a dish to study FA?
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Can we grow a brain in a dish to study FA?
Modelling Friedreich Ataxia in human iPSC-derived cerebellar organoid
Nerve cells in the cerebellum are particularly susceptible to damage in Friedreich's ataxia (FA). Understanding why these specific cells are vulnerable may help to develop treatments for FA that target these vulnerabilities.
The #FARAGrantProgram is pleased to award a grant to Dr. Esther Becker at the University of Oxford. Dr. Becker's lab will create 3D models of the human cerebellum in a dish. These ‘cerebellar organoids' are generated by first reprogramming cells obtained from a skin biopsy into Induced Pluripotent Stem Cells (IPSCs). IPSCs, which are capable of turning into any cell type in the body, are then turned into the cells of the cerebellum and grown to create a 3D model.
This project aims to extensively characterize the damage that occurs in the FA cerebellum using these cerebellar organoids. Dr. Becker's lab will also use this new understanding of the damage to test potential therapeutic compounds.
Thank you to the FA community for contributing to research like this by volunteering for skin biopsies!
Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular Functions
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- Category: Funded Research
SynTEF1, a prototype synthetic genome reader/regulator (SynGR), was designed to target GAA triplet repeats and restore the expression of frataxin (FXN) in Friedreich's ataxia patients. It achieves this complex task by recruiting BRD4, via a pan-BET ligand (JQ1), to the GAA repeats by using a sequence-selective DNA-binding polyamide. When bound to specific genomic loci in this way, JQ1 functions as a chemical prosthetic for acetyl-lysine residues that are natural targets of the two tandem bromodomains (BD1 and BD2) in bromo- and extra-terminal domain (BET) proteins. As next-generation BET ligands were disclosed, the authors tested a select set with improved physicochemical, pharmacological, and bromodomain-selective properties as substitutes for JQ1 in the SynGR design. Here, two unexpected findings are reported: (1) SynGRs bearing pan-BET or BD2-selective ligands license transcription at the FXN locus, whereas those bearing BD1-selective ligands do not, and (2) rather than being neutral or inhibitory, an untethered BD1-selective ligand (GSK778) substantively enhances the activity of all active SynGRs. The failure of BD1-selective SynGRs to recruit BRD4/BET proteins suggests that rather than functioning as "epigenetic/chromatin mimics," active SynGRs mimic the functions of natural transcription factors in engaging BET proteins through BD2 binding. Moreover, the enhanced activity of SynGRs upon cotreatment with the BD1-selective ligand suggests that natural transcription factors compete for a limited pool of nonchromatin-bound BET proteins, and blocking BD1 directs pan-BET ligands to more effectively engage BD2. Taken together, SynGRs as chemical probes provide unique insights into the molecular recognition principles utilized by natural factors to precisely regulate gene expression, and they guide the design of more sophisticated synthetic gene regulators with greater therapeutic potential.
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Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models
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The objective of this study is to quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). Multi-shell diffusion magnetic resonance imaging (dMRI) was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ 2 > 0.46). Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA.
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Emerging small molecule inhibitors of Bach1 as therapeutic agents: Rationale, recent advances, and future perspectives
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The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA-approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non-specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, the authors discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy.
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- Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy
- Experimental drugs for Friedrich's ataxia: progress and setbacks in clinical trials
- Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis
- Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature
- End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases