Rehabilitation Program on Genetic and Degenerative Ataxia (RAPP)

ClinicalTrials.gov ID NCT06089863. Sponsor Hospices Civils de Lyon.

The present protocol aimed at evaluating the Rehabilitation Program in collaboration with partner patient on the symptom intensity, activity and quality of life on genetic and degenerative ataxia. 

This PAMPERO program's effect will be assessed by comparing the difference of Intensity of symptom measured by to Scale for the Assessment and Rating of Ataxia (SARA) at inclusion and 3 months after the end of rehabilitation.

Detection of alternative DNA structures and its implications for human disease

Matos-Rodrigues G, Hisey JA, Nussenzweig A, Mirkin SM. Detection of alternative DNA structures and its implications for human disease. Molecular Cell. 2023 Oct;83(20):3622-3641. DOI: 10.1016/j.molcel.2023.08.018. PMID: 37863029. 

 The most well-known REDs include Huntington’s disease (HD), fragile X syndrome (FXS), and Friedreich’s ataxia (FRDA), which are caused by the expansion of (CAG)n, (CGG)n, and (GAA)n repeats, respectively. Thus, DNA sequences prone to formalternative DNA structures are highly frequent in the human genome and associated with several human diseases.

Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis

Gavriilaki M, Chatzikyriakou E, Moschou M, Arnaoutoglou M, Sakellari I, Kimiskidis VK. Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis. Cerebellum. 2023 Oct 27. doi: 10.1007/s12311-023-01621-6. Epub ahead of print. PMID: 37889470.

 Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified.

Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs

Sylvia Boesch & Elisabetta Indelicato (2023) Experimental drugs for Friedrich’s ataxia: progress and setbacks in clinical trials, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2023.2276758 

 Generally, therapeutic approaches in FA are divided in two categories. One group of therapeutics (including gene therapy) aims at increasing/restoring frataxin levels. The second group encompasses those approaches aiming at reversing the consequence of frataxin loss at a tissue level, for instance mitochondrial failure. The first class of therapeutics may appear the most appealing as they intervene very early in the pathogenic cascade and may be potentially curative. Currently, various gene therapy and genome editing strategies are explored in FA. The likelihood of toxicity issues when overexpressing frataxin and the need for a delivery system with widespread distribution and low immunogenicity are among the hurdles to be addressed. Beyond these biological hinders, it is however not clear when such treatments should be administered to guarantee a reversal or at least a substantial improvement of the clinical phenotype. The presence of a developmental aspect as well as of a neurodegenerative kind of progression after onset suggest that the benefit of gene therapy/genome editing would be limited if applied beyond an early clinical phase.

Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy

Teerapat Rojsajjakul, Juliette J. Hordeaux, Gourav R. Choudhury, Christian J. Hinderer, Clementina Mesaros, James M. Wilson & Ian A. Blair. Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy. Commun Biol 6, 1093 (2023). doi:10.1038/s42003-023-05472-z 

Increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. 

The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector.

PTC Therapeutics Provides Corporate Update and Reports Third Quarter Financial Results

NEWS PROVIDED BY PTC Therapeutics, Inc. , 26 Oct, 2023 

PTC had a type C written-response-only meeting with FDA for vatiquinone for Friedreich ataxia to determine whether the data from the MOVE-FA study would be sufficient to support an NDA for accelerated approval. In their written response, the FDA stated that while they see the value of upright stability as a clinically meaningful endpoint, they believed a confirmatory study would likely be needed to support NDA submission. PTC has requested a follow-up live meeting to address the issues raised by the FDA. PTC is participating in a scientific advice procedure with the EMA to determine if the MOVE-FA data could support a conditional marketing authorization application in the EEA. PTC expects to have the outcome of this procedure in the first quarter of 2024.

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure

Friedreich's Ataxia-Health Index Development and Validation of a Novel Disease-Specific Patient-Reported Outcome Measure, Jamison Seabury, Spencer Rosero, Anika Varma, Jennifer Weinstein, Charlotte Engebrecht, Nuran Dilek, John Heatwole, Danae Alexandrou, Brittany Cohen, Jane Larkindale, David R. Lynch, Courtney Park, Sub H. Subramony, Ellen Wagner, Susan Walther, McKenzie Wells, Christine Zizzi, Chad Heatwole Neurol Clin Pract Oct 2023, 13 (5) e200180; DOI: 10.1212/CPJ.0000000000200180 

 Participants with FA identified 18 symptomatic themes of importance to be included as subscales in the FA-HI. The FA-HI demonstrates high internal consistency and test-retest reliability, and it was identified by participants as highly relevant, comprehensive, and easy to complete. FA-HI total and subscale scores statistically differentiated between subgroups of participants with varying levels of disease burden.

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia

Frataxin Deficiency Drives a Shift from Mitochondrial Metabolism to Glucose Catabolism, Triggering an Inflammatory Phenotype in Microglia Francesca Sciarretta, Fabio Zaccaria, Andrea Ninni, Veronica Ceci, Riccardo Turchi, Savina Apolloni, Martina Milani, Ilaria Della Valle, Marta Tiberi, Valerio Chiurchiù, Nadia D’Ambrosi, Silvia Pedretti, Nico Mitro, Katia Aquilano, Daniele Lettieri-Barbato bioRxiv 2023.10.18.562916; doi:10.1101/2023.10.18.562916 

 The study also pinpointed Hcar2 (GPR109A) as a potential agent for butyrate anti-inflammatory impact on microglia. Tests on FRDA mice highlighted the neuroprotective attributes of butyrate intake, bolstering neuromotor performance. In essence, our findings shed light on how cerebellar microglia activation contributes to FRDA and highlight butyrate potential to alleviate neuroinflammation, rectify metabolic imbalances, and boost neuromotor capabilities in FRDA and similar conditions.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia

Gabriella Paparella, Cristina Stragà, Marinela Vavla, Nicola Pesenti, Vasco Merotto, Gian A. Martorel, Sara Zalunardo, Maria Armellin, Jimmy Comiotto, Andrea Martinuzzi; Effectiveness of rehabilitation intervention in persons with Friedreich ataxia. Front. Neurol. Sec. Neurorehabilitation Volume 14 - 2023 | doi: 10.3389/fneur.2023.1270296 

Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared. 

We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders.

Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature

Ashleigh N. Peterson, Leigh C. Hickerson, E. Rebecca Pschirrer, Lynsy B. Friend, Cynthia C. Taub, Management of Friedreich's Ataxia-Associated Cardiomyopathy in Pregnancy: A Review of the Literature, The American Journal of Cardiology, 2023, doi:10.1016/j.amjcard.2023.10.019. 

 Most patients with FRDA can deliver vaginally, and neuraxial analgesia is recommended during labor due to the risks associated with general anesthesia. Breastfeeding is encouraged, even for those taking cardiac medications.