Highlights of FA research from ICAR 2024

Knockdown of FDX2 has been identified as a novel therapeutic target for Friedreich’s ataxia (Meisel, D’Autreaux). Frataxin and FDX2 use overlapping binding sites on NFS1 and are competitive inhibitors of each other. When frataxin is deficient, FDX2 outcompetes FXN (Meisel).

Approximately 16% of FRDA patients have a new class of pathogenic allele that is a modifier of gene expression. These have been (and continue to be) missed by standard genetic diagnostic testing (Bidichandani). These have implications for carrier analysis, molecular mechanism of silencing, as well as therapeutic opportunities.

Role of inflammation in disease pathophysiology: Early glial activation – predominantly astrocytes and microglia – precedes neuronal degeneration in YG8-800 mouse models (Loria). FRDA microglia in the cerebellum are hyperinflammatory and reduce PC survival (Pernaci). Increased activity of satellite glial cell is observed in ex-vivo DRGs from the pVALB mouse model (Mokkachamy Chellapandi).

SynTEF1 a synthetic genome regulator that licenses transcription elongation past the repressive GAA repeats in FXN works synergistically with HDAC inhibitors. The selective HDACi-109 stabilizes active chromatin marks and enhances SynTEF1-mediated FXN expression by enabling SynTEF1 to override chromatin-based attenuation at FXN (Ansari).

Dysregulated cerebellar neuron firing may be a protective mechanism induced to allow function but which may lead to eventual degeneration. Synaptic instability and intrinsic cellular communication deficits are common features in FRDA mouse models and may be pathological biomarkers of neurological symptoms (Joseph).

The FXNI151F mouse model of Friedreich Ataxia has low FXN protein levels but, surprisingly, in this specific model there is no widespread deficiency of iron-sulfur clusters. It is only observed in specific proteins in certain tissues and at certain ages (Pazos-Gil). In dividing cells ISCU M141I substitution can bypass FXN lethality but shows a deficit in mitochondrial Fe-S clusters proteins, with normal cell cycle progression and less DNA damage compared to fibroblasts expressing the mutant protein FXN I154F. These results raise the question of how Fe-S clusters distribute among the different compartments of cells (Puccio).

The functional and cellular characteristics of induced FRDA mechanosensory neurons are consistent with the mechanosensory impairments that progressively deteriorate in FRDA individuals. Experiments are ongoing to investigate the hypothesis that decreased frataxin in FRDA sensory neurons induces to lipid dysregulation and altered membrane tension, which affects the ability of neurons to respond to mechanical stimuli (Hulme).

The unequal global distribution of FRDA, specifically the absence of FRDA in sub-Saharan Africa (where “long normal” alleles are present) has been explained by a study from Tackett et al that identifies FXN protomutation alleles in various populations. Expanded alleles evolved from “long normal” alleles via a key protomutation allele that has been present in Europe and Western Asia for thousands of years. Sub-Saharan African alleles are devoid of this haplotype, explaining the current population distribution of FRDA.

Transcription, tract length, and orientation of the repeats relative to transcription direction are the major factors affecting GAA repeat expansion (Napierala). Base editing strategies that efficiently introduce codon interruptions at repeat tracts significantly reduced somatic expansions and provide a tool to study repeat instability and FXN gene silencing (Matuszek).

In the gene therapy field, there have been breakthroughs in capsid engineering that achieve entry to the CNS via IV delivery of genetic medicines. At ICAR, Capsida announced that they have identified a systemically administered (IV) capsid that achieves NHP brain-wide biodistribution transducing large percentages of neurons in key FRDA-related brain areas in addition to delivering therapeutically significant levels of cardiac transduction (Stephany).

Retinal nerve fiber layer thickness may be a non-invasive biomarker for disease severity and progression in FRDA (Stovickova). RNFL provides a significant marker of both visual and neurologic progression, with R2 values generally higher than other published imaging approaches. GAA alone is not a reliable predictor of RNFL loss or eventual vision loss suggesting that other factors also contribute to optic neuropathy in FRDA (Balcer).

Preliminary 12-month longitudinal data from TRACK-FA reveals that, in children, the size of the spinal cord cross-sectional area and the cerebellum volume increased in controls over time (reflecting development) but decreased in FRDA. This provides neuroimaging evidence of impaired development and indicates the need to intervene early (Henry).

Several ongoing studies leveraging wearable devices and digital biomarkers aim at providing new functional and clinical assessments for many ataxias (Festenstein, Gupta, Ilg, Kulkarni, Manohar, Patel).

Exercise/physical activity can evoke gene expression of protective mechanisms (Seifert).

New FRDA-specific PRO Friedreich’s Ataxia-Health Index (FA-HI) and the Friedreich’s Ataxia Caregiver Reported-Health Index (FACR-HI) were able to distinguish between differing levels of disease burden (Engebrecht, Shupe).

Several updates on clinical programs   PTC Therapeutics reported results of their MOVE-FA trial to evaluate the safety and efficacy of vatiquinone in patients with FRDA. There were significant benefits recorded in the Upright Stability subscale of mFARS, a relevant metric of disease progression in younger, ambulatory FRDA patients, and the Modified Fatigue Impact Scale. Lexeo Therapeutics reported interim results of the SUNRISE-FA clinical trial to assess the safety and preliminary efficacy of AAVrh.10hFXN (LX-2006), a cardiotropic adeno-associated gene transfer vector coding for human frataxin, in treating FRDA cardiomyopathy. Administration of LX-2006 results in a dose-dependent increase of FXN in the heart. Larimar presented data from the dose exploration study of nomlabofusp, a frataxin protein replacement therapy. In patients with FRDA, daily administration of 25 mg and 50 mg nomlabofusp was well tolerated and resulted in increased frataxin concentrations in buccal and skin cells.