Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients

Calcitriol treatment is safe and increases frataxin levels in Friedreich Ataxia patients. Berta Alemany-Perna, Jordi Tamarit, Daniel Lopez Dominguez, Anna Quiroga-Varela, Miguel Merchan-Ruiz, Lluis Ramio Torrenta, David Genis Batlle, Joaquim Ros; medRxiv 2023.10.28.23297713; doi:10.1101/2023.10.28.23297713 

The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. Conclusion: Calcitriol dosage used (0.25mcg/24h) is safe for FRDA patients and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits.

The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure

Cantrell AC, Zeng H, Chen JX. The therapeutic potential of targeting ferroptosis in the treatment of mitochondrial cardiomyopathies and heart failure. J Cardiovasc Pharmacol. 2023 Oct 10. doi: 10.1097/FJC.0000000000001496. Epub ahead of print. PMID: 37816193. 

We provide a brief overview of the potential roles of SIRT3 in mitochondrial iron homeostasis, as well as its contribution to the mitochondrial cardiomyopathy of Friedreich's ataxia (FRDA) and diabetic cardiomyopathy (DCM).

End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases

Anne-Claire D, Coarelli G, Heinzmann A, Verdon B, Manuella L, Petit E, Pierron L, Levy-Soussan M, Durr A, Gargiulo M, Ewenczyk C. End-of-Life Discussions With Patients and Caregivers Affected By Neurogenetic Diseases. Neurol Clin Pract. 2023 Dec;13(6):e200199. doi: 10.1212/CPJ.0000000000200199. Epub 2023 Oct 16. PMID: 37854177; PMCID: PMC10581072. DIRAGENE is an observational, cross-sectional, mixed-methods study with a patient-centered component and a primary caregiver-centered component. Observations include disease severity, psychosocial, and emotional scales; in-house questionnaires; and semidirected interviews.

 

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.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Elisabetta Indelicato, Klaus Faserl, Matthias Amprosi, Wolfgang Nachbauer, Rainer Schneider, Julia Wanschitz, Bettina Sarg, Sylvia Boesch. Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia; Front. Neurosci. Sec. Neuropharmacology Volume 17 - 2023 | doi: 10.3389/fnins.2023.1289027. 

Principal component analysis showed a clear separation between FRDA and control samples. Interactome analysis revealed clustering of DE proteins in oxidative phosphorylation, ribosomal elements, mitochondrial architecture control and fission/fusion pathways. DE findings in the muscle-specific proteomics suggested a shift towards fasttwitching glycolytic fibers. Notably, most DE proteins (169/228, 74%) are target of the transcription factor nuclear factor-erythroid 2.Our data corroborate a mitochondrial biosignature of FRDA, which extends beyond a mere oxidative phosphorylation failure. Skeletal muscle proteomics highlighted a derangement of mitochondrial architecture and maintenance pathways and a likely adaptive metabolic shift of contractile proteins.The present findings are relevant for the design of future therapeutic strategies and highlight the value of skeletal muscle -omics as disease state readout in FRDA.

Skeletal muscle proteome analysis underpins multifaceted mitochondrial dysfunction in Friedreich´s Ataxia

Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study)

Lynch D. Correction to Safety and Efficacy of Omaveloxolone in Friedreich Ataxia (MOXIe Study). Ann Neurol. 2023 Oct 5. doi: 10.1002/ana.26808. Epub ahead of print. Erratum for: Ann Neurol. 2021 Feb;89(2):212-225. PMID: 37795909.

 In the Results section, the text should read: “Within the mFARS assessment, omaveloxolone improved each component (bulbar, upper limb coordination, lower limb coordination, and upright stability) relative to placebo, although the greatest effects were on upper limb coordination, followed by upright stability.

Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics

Schultz BG, Joukhader Z, Nattala U, et al. Disease Delineation for Multiple Sclerosis, Friedreich Ataxia, and Healthy Controls Using Supervised Machine Learning on Speech Acoustics. IEEE Transactions on Neural Systems and Rehabilitation Engineering : a Publication of the IEEE Engineering in Medicine and Biology Society. 2023 Oct;PP. DOI: 10.1109/tnsre.2023.3321874. PMID: 37792655.

 Results showed that Friedreich ataxia, multiple sclerosis and healthy controls were all identified with high accuracy (over 82%). Twenty-one acoustic features were strong markers of neurodegenerative diseases, falling under the categories of spectral qualia, spectral power, and speech rate. We demonstrated that speech markers can delineate neurodegenerative diseases and distinguish healthy speech from pathological speech with high accuracy.

Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman

Fernández, A.G. Vestibular Pathology as Early Finding of Friedreich’s Ataxia in a 16 Years Old Woman. Indian J Otolaryngol Head Neck Surg (2023). doi:10.1007/s12070-023-04249-4 

Friedreich’s ataxia is degenerative disease frequently starting around puberty and it’s characterized by a progressive gait ataxia, limb weakness, apparition of Babinsky sign, loss of deep tendon reflex, dysarthria and skeletal deformities. The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich’s ataxia diagnosis is reported.

Social cognition in degenerative cerebellar ataxias

Simona Karamazovova, Veronika Matuskova, Natalie Svecova, Martin Vyhnalek, Social cognition in degenerative cerebellar ataxias, Current Opinion in Behavioral Sciences, Volume 54, 2023, 101313, doi:10.1016/j.cobeha.2023.101313.

Social cognition (SC) refers to a set of skills necessary for successful social communication and interpersonal relationships. Accumulating evidence points toward a crucial role of the cerebellum in SC. This narrative review summarizes and discusses the social cognitive impairment in cerebellar ataxias (CA), a group of hereditary neurodegenerative diseases of the cerebellum. Substantial impairment in emotion recognition and theory of mind, two essential components of SC, is present in CA. The social cognitive impairment is largely independent of the motor disability, general cognitive deficit, or neuropsychiatric symptoms. Since the impairment reaches comparable levels to autism or schizophrenia, it can substantially impact patients’ quality of life and deserves further attention in future research.

FDA Clears Exploration Trial for Higher Dose of CTI-1601 for Friedreich Ataxia

October 2, 2023. After the company released positive phase 2 data earlier this year, Larimar Therapeutics announced that the FDA has cleared a 4-week, placebo-controlled exploration trial (NCT05579691) assessing its investigational Friedrich ataxia (FA) agent CTI-1601 in doses of 50 mg. The company’s open-label extension (OLE), which will assess 25 mg of CTI-1601 daily, was also cleared for initiation by the FDA.

The OLE, expected to begin in Q1 2024, will include those who completed treatment in the phase 2 dose exploration trial or a prior trial of CTI-1601. In the OLE, investigators will assess safety, tolerability, and pharmacokinetics of the agent, as well as measures of frataxin (FXN) levels and other pharmacodynamic markers. Other objectives include the evaluation of the effects of long-term subcutaneous administration of CTI-1601 on measures of clinical function. Data from the OLE will be compared with a matched set of untreated patients from the Friedreich’s Ataxia Clinical Outcome Measures Study (FACOMS) database.

Neurologic orphan diseases: Emerging innovations and role for genetic treatments

Kioutchoukova IP, Foster DT, Thakkar RN, Foreman MA, Burgess BJ, Toms RM, Molina Valero EE, Lucke-Wold B. Neurologic orphan diseases: Emerging innovations and role for genetic treatments. World J Exp Med 2023; 13(4): 59-74  doi: 10.5493/wjem.v13.i4.59

 Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.

Benefits of Adaptive Sport on Physical and Mental Quality of Life in People with Physical Disabilities: A Meta-Analysis

Isidoro-Cabañas E, Soto-Rodríguez F, Morales-Rodríguez F, Pérez-Mármol J. Benefits of Adaptive Sport on Physical and Mental Quality of Life in People with Physical Disabilities: A Meta-Analysis; Healthcare (Basel, Switzerland). 2023 Sep;11(18). PMCID: PMC10531072. doi:10.3390/healthcare11182480 

The engagement in adaptive sports showed a positive impact on the mental quality of life among adults with physical disabilities. However, the positive effect of adaptive sports practice on physical quality of life was shown only in the pre–post-test analysis. Further studies are required to validate the obtained findings.

Comparison of Live and Remote Video Ratings of the Scale for Assessment and Rating of Ataxia

Taheri Amin A, Faber J, Önder D, et al. Comparison of Live and Remote Video Ratings of the Scale for Assessment and Rating of Ataxia; Movement Disorders Clinical Practice. 2023 Aug;10(9):1404-1407. PMCID: PMC10525045. DOI: 10.1002/mdc3.13843 

Live and remote video ratings showed a high level of agreement for the complete score (bias = 0.09, with standard deviation = 2.00) and all single SARA items (bias<0.20 for all items).

Conclusion: Remote video ratings of SARA are a reliable means to assess severity of ataxia.

Pre-Validation of a Virtual Reality Tool to Quantify the Severity of Friedreich's Ataxia

K. Chenier, A. Duquette, L. Touma, M. T. Le and D. R. Labbe, "Pre-Validation of a Virtual Reality Tool to Quantify the Severity of Friedreich's Ataxia," 2023 IEEE 11th International Conference on Serious Games and Applications for Health (SeGAH), Athens, Greece, 2023, pp. 1-7, doi: 10.1109/SeGAH57547.2023.10253802.

 The results of this study demonstrate the feasibility of using VR with FA patients, although adaptation of the technology may be necessary for those with more severe impairments.