Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies

Santos C, Malheiro S, Correia M, Damásio J. Gene Suppression Therapies in Hereditary Cerebellar Ataxias: A Systematic Review of Animal Studies. Cells. 2023; 12(7):1037. https://doi.org/10.3390/cells12071037 

In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed. Conclusion: The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype in vivo. Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.

Traitement somatosensoriel proprioceptif et tactile chez les personnes atteintes d’ataxie de Friedreich, une étude d’imagerie par résonance magnétique fonctionnelle

Virginie Destrebecq, Valérie Martinet, Antonin Rovai, Nicolas Trotta, Gilles Naeije, Traitement somatosensoriel proprioceptif et tactile chez les personnes atteintes d’ataxie de Friedreich, une étude d’imagerie par résonance magnétique fonctionnelle, Volume 8063, Issue 100, 04/2023, Pages S1-S210, ISSN 0035-3787, doi: 10.1016/j.neurol.2023.01.629 

Discussion Ces paradigmes d’IRMf capturent la dichotomie entre les déficiences tactiles et proprioceptives chez les personnes atteintes de FRDA. L’altération proprioceptive prédominante rappelle le patron lié au vieillissement. Conclusion L’âge et la FRDA pourraient se potentialiser et rendre les déficits de perception tactile cliniquement pertinents.

Clinically meaningful metrics of speech in neurodegenerative disease: Quantification of speech intelligibility and naturalness in ataxia

Clinically meaningful metrics of speech in neurodegenerative disease: Quantification of speech intelligibility and naturalness in ataxia Adam P Vogel, Paul Maruff, Hannah Reece, Hannah Carter, Geneieve Tai, Benjamin G Schultz, Louise Corben, Martin B Delatycki, Athanasios Tsanas; medRxiv 2023.03.28.23287878; doi:10.1101/2023.03.28.23287878

We demonstrate a subset of measures are strongly associated with all four clinical scales. Objective speech data replicated expert assessments of naturalness and intelligibility. These scores represent a lower level of variability than observed between subjective listener ratings. Findings provide evidence there are specific objective markers of speech that change over time and reflect clinical aspects of the disease. Discussion: The use of a large dataset yielded a speech assay capable of accurately approximating expert listener ratings of key clinical aspects of dysarthria severity. Distinct but complementary subsets align with disease severity and speech related quality of life.

Sequencing through hyperexpanded Friedreich’s ataxia-GAA repeats by nanopore technology: implications in genotype–phenotype correlation

Bharathram Uppili, Pooja Sharma, Istaq Ahmad, Shweta Sahni, Vivekanand Asokachandran, Anil B Nagaraja, Achal K Srivastava, Mohammed Faruq, Sequencing through hyperexpanded Friedreich’s ataxia-GAA repeats by nanopore technology: implications in genotype–phenotype correlation, Brain Communications, Volume 5, Issue 2, 2023, fcad020, doi:10.1093/braincomms/fcad020

The total throughput achievable through our protocol can allow for screening of up to 96 samples per flow cell in less than 24 h. The proposed method is clinically scalable and deployable for day-to-day diagnostics. In this paper, we demonstrate to resolve the genotype–phenotype correlation of Friedreich’s ataxia patients with better accuracy.

Dimorphic frataxin and its gene regulation by sex steroids in hamsters

Ramos L. (2023). Dimorphic frataxin and its gene regulation by sex steroids in hamsters. Molecular genetics and genomics : MGG, 10.1007/s00438-023-02004-6.  Advance online publication. doi:10.1007/s00438-023-02004-6 

 The mRNA expression results indicated that Harderian FXN may play a dynamic role in intracellular Fe of heme required for processing cytochromes and other hemeproteins, also suggesting that the moderate sexual dimorphism present in the HG and gonads could be regulated by androgens, while sexually dimorphic expression of FXN in the female pancreas may be controlled by sex steroids.

Skyclarys' Positive Reception By FDA And Medical Community Bolsters Reata's Future

Seeking Alpha. Mar. 23, 2023. Reata Pharmaceuticals recently received FDA approval for Skyclarys, the first drug approved to treat Friedreich's ataxia (FA) in adults and adolescents aged 16 years and older. Skyclarys is expected to experience significant utilization among FA patients, with a potential peak annual revenue between $800 million and $1 billion in the US alone. 

According to the Friedreich's Ataxia Research Alliance, there are several potential competitors in the pipeline for FA treatment, including one Phase 3 candidate and a few in Phase 2. At first glance, the competitive risk to Reata's Skyclarys seems relatively low, but it's essential to remain cautious as the landscape can change. PTC Therapeutics' Phase 3 candidate, vatiquinone, failed to meet its Phase 2 study endpoints related to FA. Phase 3 data is expected in Q2 2023. Leriglitazone did not meet endpoints in a Phase 2 proof-of-concept study. The HIV antiviral drug, etravirine, demonstrated increased frataxin levels in FA patient-derived cells but is awaiting Phase 2 clinical trial results. Most other drugs are in Phase 1, while gene therapy is in pre-clinical development.

Assessment of Hepatic Safety in Patients with Friedreich’s Ataxia in the MOXIe Trial of Omaveloxolone

S.H. Subramony, MD, University of Florida Health System, David Lynch, MD, PhD, Children's Hospital of Philadelphia, Martin Delatycki, MD, PhD, Murdoch Children’s Research Institute, Deborah Ferguson, PhD, Reata Pharmaceuticals, Angie Goldsberry, MS, Reata Pharmaceuticals, Seemi Khan, MD, Reata Pharmaceuticals, Caterina Mariotti, MD, Istituto Neurologico Carlo Besta, Katherine Mathews, MD, FAAN, University of Iowa, Colin Meyer, MD, Reata Pharmaceuticals, Masako Murai, MD, Reata Pharmaceuticals, Wolfgang Nachbauer, MD, PhD, Medical University Innsbruck, Lorenzo Nanetti, MD, Istituto Neurologico Carlo Besta, Susan Perlman, MD, University of California Los Angeles, Isaac Trevino, Reata Pharmaceuticals, Christian Wigley, PhD, Reata Pharmaceuticals, George Wilmot, MD, PhD, Emory University School of Medicine, Theresa Zesiewicz, MD, University of South Florida Ataxia Research Center. Muscular Dystrophy Association, conference posters 2023. Here, we present analyses of laboratory parameters associated with hepatic functio (MOXIe Part 2 (NCT02255435)). 

The majority of AEs were mild to moderate in severity. There were no deaths. The distribution of hepatobiliary disorder AEs was similar between treatment groups, with 2 events in the omav group (n=51) and 1 in the placebo group (n=52). ALT increases were reported as AEs in 37.3% of patients in the omav group versus 1.9% of patients in the placebo group. AST increases were reported as AEs in 21.6% of patients in the omav group versus 1.9% of patients in the placebo group. GGT increases were reported in 5.9% of patients in the omav group versus no patients in the placebo group. Discontinuations due to ALT or AST elevation occurred in one patient in the omav group (2%) and no patients in the placebo group. Among omav-treated patients, most (68.6%) had maximum ALT and AST increases of ≤ 3 times the upper limit of normal (ULN). None had ALT and AST increases of ≥10 times the ULN. ALT and AST elevations were mild to moderate, transient, and reversible after drug discontinuation. Maximal values occurred within the first 12 weeks of treatment. No aminotransferase increase was associated with concurrent increases in total bilirubin, and no Hy’s Law cases were observed. Nonclinical data show omav modulates aminotransferase gene expression. No new safety signals were observed in the OLE, at the last data-cut (March 24th, 2022). 

Conclusions Omav was well tolerated and had a manageable hepatic safety profile in clinical studies in patients with FA.

Assessment of Cardiac Safety in Patients with Friedreich’s Ataxia in the MOXIe Trial of Omaveloxolone

S.H. Subramony, MD, University of Florida Health System, David Lynch, MD, PhD, Children's Hospital of Philadelphia, Martin Delatycki, MD, PhD, Murdoch Children’s Research Institute, Angie Goldsberry, MS, Reata Pharmaceuticals, Seemi Khan, MD, Reata Pharmaceuticals, Caterina Mariotti, MD, Istituto Neurologico Carlo Besta, Katherine Mathews, MD, FAAN, University of Iowa, Colin Meyer, MD, Reata Pharmaceuticals, Masako Murai, MD, Reata Pharmaceuticals, Wolfgang Nachbauer, MD, PhD, Medical University Innsbruck, Lorenzo Nanetti, MD, Istituto Neurologico Carlo Besta, Susan Perlman, MD, University of California Los Angeles, George Wilmot, MD, PhD, Emory University School of Medicine, Theresa Zesiewicz, MD, University of South Florida Ataxia Research Center. Muscular Dystrophy Association, conference posters 2023. 

Here, we present post-hoc analyses of cardiac safety assessments performed during MOXIe Part 2. Cardiac adverse events (AEs) occurred in 9.8% of patients receiving omav (n=51) as compared to 13.5% of those receiving placebo (n=52). A standardized medical query revealed no imbalances for arrhythmia-related AEs (5 in omav group and 5 in placebo group). In patients with a medical history of cardiomyopathy, no imbalances in cardiovascular AEs were observed (12% in omav group and 13.3% in placebo group). Only one cardiac serious AE (SAE), atrial fibrillation, was reported in more than one patient, and it was reported in one patient each in placebo and omav groups. Two additional patients in the omav group reported cardiac SAEs. No clinically significant changes were observed between groups in echocardiogram, electrocardiogram, heart rate and blood pressure assessments. Slight increases in BNP and NT-Pro-BNP were observed only in the omav-treatment group but occurred without signs or symptoms of fluid retention. Mean values remained below the ULN of 100 pg/mL. Although mean cholesterol values were higher in the omav group than in the placebo group, the values remained within normal limits. The OLE trial is ongoing, with data in MOXIe accrued up to 4.3 years, as of the last data-cut of March 24th, 2022. No new cardiac safety signals have been observed. There were no deaths in the study and the majority of all adverse events were mild to moderate in severity. 

Conclusions Omav was well tolerated and had a manageable cardiac safety profile in MOXIe Part 2.

Ataxia Scales for the Clinical Evaluation

Bürk, K. (2023). Ataxia Scales for the Clinical Evaluation. In: Gruol, D.L., Koibuchi, N., Manto, M., Molinari, M., Schmahmann, J.D., Shen, Y. (eds) Essentials of Cerebellum and Cerebellar Disorders. Springer, Cham. doi:10.1007/978-3-031-15070-8_76 

The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS), the Scale for the Assessment and Rating of Ataxia (SARA), the Brief Ataxia Rating Scale (BARS), and the Unified Multiple System Atrophy Rating Scale (UMSARS) represent validated scales for the assessment of disease severity and progression in cerebellar disorders. Each scale has its strengths and weaknesses.

A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia

Rodden, L. N., Rummey, C., Kessler, S., Wilson, R. B., & Lynch, D. R. (2023). A Novel Metric for Predicting Severity of Disease Features in Friedreich's Ataxia. Movement disorders : official journal of the Movement Disorder Society, 10.1002/mds.29370. Advance online publication. https://doi.org/10.1002/mds.29370 

FRDA DB is a novel metric of disease severity that has utility in small datasets to demonstrate correlations that would not otherwise be evident with either GAA-TR or DD alone. This is important for discovering new biomarkers, as well as improving the prediction of severity of disease features in FRDA.

Vesigen Therapeutics Awarded Grant from Friedreich’s Ataxia Research Alliance (FARA) to Develop a Targeted Genome Editing Therapeutic Strategy

March 14 2023. Vesigen Therapeutics, a biotechnology company developing targeted therapies by engineering a distinct class of human extracellular vesicles called ARMMs (ARrestin-domain 1 Mediated Microvesicles), is pleased to announce receipt of a FARA (Friedreich’s Ataxia Research Alliance) General Research Grant. Vesigen will evaluate its proprietary technology to deliver CRISPR-Cas genome editing complexes as a non-viral disease-modifying strategy for patients diagnosed with the neurodegenerative disease Friedreich’s Ataxia (FA).

Sensoren in der Kleidung plus KI: Erfolgversprechende Diagnosetechnologie: Bei Friedreich-Ataxie und Duchenne-Muskeldystrophie getestet

Patzer, K.-H. (2023). Sensoren in der Kleidung plus KI: Erfolgversprechende Diagnosetechnologie: Bei Friedreich-Ataxie und Duchenne-Muskeldystrophie getestet. MMW Fortschritte der Medizin, 165(S1), 46–46. doi:10.1007/s15006-023-2393-2

CRISPR/Cas9-based edition of frataxin gene in Dictyostelium discoideum for Friedreich’s Ataxia disease modeling

Gentili, H. G., Pignataro, M. F., Olmos, J., Pavan, M. F., Ibanez, L. I., Santos, J., & Velazquez, F. (2023). CRISPR/Cas9-based edition of frataxin gene in Dictyostelium discoideum for Friedreich’s Ataxia disease modeling. doi:10.1101/2023.02.27.530330

Here we present the development of a new model system for Friedreich's Ataxia (FA) using D. discoideum (Dd). FA is a rare disease caused by disfunction of frataxin (FXN), a protein involved in Fe-S cluster assembly machinery.

Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia

Kerestes, R., Cummins, H., Georgiou-Karistianis, N., Selvadurai, L. P., Corben, L. A., Delatycki, M. B., Egan, G. F., & Harding, I. H. (2023). Reduced cerebello-cerebral functional connectivity correlates with disease severity and impaired white matter integrity in Friedreich ataxia. Journal of neurology, 10.1007/s00415-023-11637-x. Advance online publication. https://doi.org/10.1007/s00415-023-11637-x

Compared to controls, people with FRDA showed significantly reduced connectivity between the anterior cerebellum and bilateral pre/postcentral gyri, and between the superior posterior cerebellum and left dorsolateral PFC. Greater disease severity correlated with lower connectivity in these circuits. Lower anterior cerebellum-motor cortex functional connectivity also correlated with slower speeded finger tapping and less fractional anisotropy in the superior cerebellar peduncles, internal capsule, and precentral white matter in the FRDA cohort. There were no significant between-group differences in inferior posterior cerebellar or dentate nucleus connectivity. This study indicates that altered cerebello-cerebral functional connectivity is associated with functional status and white matter damage in cerebellar efferent pathways in people with FRDA, particularly in motor circuits.

Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties

Dionisi, C., Chazalon, M., Rai, M., Keime, C., Imbault, V., Communi, D., Puccio, H., Schiffmann, S. N., & Pandolfo, M. (2023). Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties. Brain communications, 5(1), fcad007. https://doi.org/10.1093/braincomms/fcad007

The analysis of the transcriptomic and proteomic profile suggests an impairment of cytoskeleton organization at the growth cone, neurite extension and, at later stages of maturation, synaptic plasticity. Alterations in the spiking profile of tonic neurons are also observed at the electrophysiological analysis of mature neurons. Despite the reversal of the repressive epigenetic state at the FXN locus and the restoration of FXN expression, isogenic control neurons retain many features of Friedreich ataxia neurons. Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals. It also highlights the need for further investigations to better understand the mechanistic link between FXN silencing and proprioceptive degeneration in Friedreich ataxia.

FDA has approved Skyclarys (omaveloxolone) as the first treatment for Friedreich’s ataxia

 FDA approves first treatment for Friedreich’s ataxia

FDA Widens Path for Rare-Disease Treatments With New Approval

Reata Pharmaceuticals Announces FDA Approval of SKYCLARYS™ (Omavaloxolone), the First and Only Drug Indicated for Patients with Friedreich’s Ataxia

What is SKYCLARYS?

https://s27.q4cdn.com/486207181/files/doc_presentations/2023/20230228_RETA_Deck_SKYCLARYS_Approval_for_Patients_with_Friedreich%E2%80%99s_Ataxia.pdf