Brain Structure and Degeneration Staging in Friedreich Ataxia: MRI Volumetrics from the ENIGMA-Ataxia Working Group

Harding IH, Chopra S, Arrigoni F, Boesch S, Brunetti A, Cocozza S, Corben LA, Deistung A, Delatycki M, Diciotti S, Dogan I, Evangelisti S, França MC Jr, Göricke SL, Georgiou-Karistianis N, Gramegna LL, Henry PG, Hernandez-Castillo CR, Hutter D, Jahanshad N, Joers JM, Lenglet C, Lodi R, Manners DN, Martinez AR, Martinuzzi A, Marzi C, Mascalchi M, Nachbauer W, Pane C, Peruzzo D, Pisharady PK, Pontillo G, Reetz K, Rezende TJ, Romanzetti S, Saccà F, Scherfler C, Schulz JB, Stefani A, Testa C, Thomopoulos SI, Timmann D, Tirelli S, Tonon C, Vavla M, Egan GF, Thompson PM.; Ann Neurol. 2021 Aug 26. doi: 10.1002/ana.26200. Epub ahead of print. PMID: 34435700. 

The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed greatest reductions in volume relative to controls (Cohen's d = 1.5-2.6). Cerebellar grey matter alterations were most pronounced in lobules I-VI (d = 0.8), while cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax = 0.35) and peduncles (rmax = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral grey matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course.

Treatment with ROS detoxifying gold quantum clusters alleviates the functional decline in a mouse model of Friedreich ataxia

CHIARA VILLA, MARIELLA LEGATO, ALESSANDRO UMBACH, CHIARA RIGANTI, REBECCA JONES, BEATRICE MARTINI, MARINA BOIDO, CLAUDIO MEDANA, IRENE FACCHINETTI, DARIO BARNI, MILENA PINTO, TANIA ARGUELLO, MARZIA BELICCHI, GIGLIOLA FAGIOLARI, CARLA LIACI, MAURIZIO MOGGIO, RICCARDO RUFFO, CARLOS T. MORAES, ANGELO MONGUZZI, GIORGIO R. MERLO, YVAN TORRENTE; Science Translational Medicine 18 Aug 2021: Vol. 13, Issue 607, eabe1633 DOI: 10.1126/scitranslmed.abe1633 

Patients with Friedreich ataxia (FRDA) present neurological deficits and impaired muscle coordination. Mitochondrial energy conversion and oxidative phosphorylation have been shown to contribute to disease pathophysiology. Now, Villa et al. tested whether gold cluster superstructures (Au8-pXs), previously shown to have antioxidant properties, could be effective in reducing the hallmarks of FRDA in vitro and in vivo. Au8-pXs improved mitochondrial function, rescued autophagy flux, and increased FXN protein expression in mesenchymal stem cells from patients. In vivo, the treatment had therapeutic effects in a mouse mode, suggesting that Au8-pXs might be effective in reducing FRDA symptoms.

Data-derived wearable digital biomarkers predict Frataxin gene expression levels and longitudinal disease progression in Friedreich’s Ataxia

Aldo Faisal, Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Ping Kei Jackson Chan, Stavros Athanasopoulos, Paola Giunti, Valeria Ricotti, Thomas Voit, Richard Festenstein; Research Square; 2021. DOI: 10.21203/rs.3.rs-737100/v1. 

Our wearable digital biomarker can accurately predict for each patient their personal FXN gene expression levels, demonstrating the sensitivity of our approach and the importance of FXN levels in FA. Therefore, our data-derived biomarker approach can not only cross-sectionally predict disease and their gene expression levels but also their longitudinal disease trajectory: it is sensitive and accurate enough to detect disease progression with much fewer subjects or shorter time scales than existing primary endpoints. Our work demonstrates that data-derived wearable biomarkers have the potential to substantially reduce clinical trial durations and a first in-human demonstration of reconstructing FXN gene expression levels from behavioral data alone.

SS-31 efficacy in a mouse model of Friedreich ataxia by upregulation of frataxin expression

Liu Y, Cai J, Shen J, Dong W, Xu L, Fang M, Lin Y, Liu J, Ding Y, Qiao T, Li K.; Hum Mol Genet. 2021 Aug 13:ddab232. doi: 10.1093/hmg/ddab232. Epub ahead of print. PMID: 34387346. 

We found that SS-31 treatment upregulated FXN expression not only at translational levels as observed in cell culture, but also at mRNA levels in vivo. Consequently, mitochondrial morphology and function were greatly improved in all tested tissues. Importantly, our data provided additional evidence that the maintenance of the therapeutic benefits needed continuous drug administration. Taken together, our findings have demonstrated the effectiveness of SS-31 treatment through the upregulation of FXN in vivo and offer guidance of the potential usage in clinical application for FRDA.

CRISPR/Cas9 gene-edited HSPCs for Friedreich’s ataxia

Stephanie Cherqui, PhD, University of California, San Diego, La Jolla, CA, describes a CRISPR/Cas9 gene-edited hematopoietic stem and progenitor cell (HSPC)-based therapy for Friedreich’s ataxia (FRDA)

Exicure, Inc. Reports Second Quarter 2021 Financial Results and Corporate Progress

CHICAGO & CAMBRIDGE, Mass.--(BUSINESS WIRE)​; XCUR-FXN 

– Friedreich’s Ataxia 

 The Company hosted a virtual R&D Day on July 15, 2021 to present new and previously unreleased preclinical data and discuss progress with XCUR-FXN: Observed 2-3x fold change in measurable Frataxin protein in the cerebellum and dorsal root ganglia (amongst other important brain and spinal regions) in Pook800J mouse model indicating potential for disease resolution; Showed no adverse, test-related histopathological findings in repeat dose range finding rat study. The Company continues to expect to file for an IND for XCUR-FXN in FA by the end of 2021 and to dose the first human patient in the first half of 2022.

Larimar Therapeutics Reports Second Quarter 2021 Operating and Financial Results

BALA CYNWYD, Pa., Aug. 12, 2021 (GLOBE NEWSWIRE), “We finished the second quarter in a strong financial position and with a compelling clinical data set that demonstrates proof-of-concept for CTI-1601, which to our knowledge is the only clinical-stage candidate designed to address the root cause of Friedreich’s ataxia,” said Carole Ben-Maimon, MD, President and Chief Executive Officer of Larimar. “These positive Phase 1 data along with non-clinical pharmacology data demonstrate proof-of-concept, and CTI-1601’s differentiated mechanism of action helped us to earn a PRIME designation from the European Medicines Agency, providing us with valuable regulatory benefits and important external validation. Looking forward, we continue to collect and analyze data from our 180-day non-human primate toxicology study and remain confident that there is a path forward through the resolution of the CTI-1601 clinical hold and towards the initiation of our Jive open-label extension and pediatric multiple ascending dose trials.”

Reata Pharmaceuticals, Inc. Announces Second Quarter 2021 Financial Results and Provides an Update on Clinical Development Programs

August 09, 2021, PLANO, Texas--(BUSINESS WIRE)--Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a clinical-stage biopharmaceutical company, today announced financial results for the quarter ended June 30, 2021, and provided an update on the Company’s business operations and clinical development programs. 

Omaveloxolone in Patients with Friedreich’s Ataxia (“FA”). Based on a communication received from the U.S. Food and Drug Administration (“FDA”) regarding omaveloxolone for the treatment of FA, we withdrew our request for a Type C meeting and requested a pre-NDA meeting with the FDA. The pre-NDA meeting request has been granted, a pre-NDA meeting has been scheduled during the third quarter of this year, and we have submitted briefing materials for the meeting. We recently received a communication from the FDA requesting the estimated date of our New Drug Application (“NDA”) for its planning purposes. We plan to submit the NDA during the first quarter of 2022.

Design Therapeutics Reports GeneTAC™ Portfolio Progress and Second Quarter 2021 Results

CARLSBAD, Calif., Aug. 09, 2021 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a biotechnology company developing treatments for degenerative genetic disorders, today reported recent progress with its portfolio of novel small molecule gene targeted chimeras (GeneTACsTM), as well as business highlights and second quarter 2021 financial results. New Data from IND-enabling Studies with GeneTAC Product Candidate for Friedreich Ataxia (FA) Support Initiation of Clinical Trial in First Half of 2022: Data from IND-enabling studies in rodents and non-human primates showed that multidose systemic administration of the company’s FA GeneTAC was well tolerated and achieved higher concentrations in the CNS (cerebrum, cerebellum, brainstem and spinal cord), heart, and skeletal muscle than needed to restore frataxin (FXN) gene expression. In addition, the company observed that exposure to low nanomolar (nM) concentrations of its FA GeneTAC in neurons and cardiomyocytes derived from FA patient stem cells in in vitro experiments led to robust and durable increases in FXN mRNA, as well as an increase in endogenous protein reaching levels comparable to unaffected individuals.

Diagnostic and Prognostic Value of Cardiovascular Magnetic Resonance in Neuromuscular Cardiomyopathies

Almogheer B, Antonopoulos AS, Azzu A, Al Mohdar S, Vlachopoulos C, Pantazis A, Mohiaddin RH.; Pediatr Cardiol. 2021 Aug 3. doi: 10.1007/s00246-021-02686-y. Epub ahead of print. PMID: 34342696. 

We present data from a unique cohort of NMD patients and provide evidence on the incidence, patterns, and the prognostic value of LGE in NMD-related cardiomyopathy. LGE is variably present in NMD subtypes and correlates with LV remodelling, dysfunction, and clinical outcomes in patients with NMD. The study included retrospective analysis of a cohort of 111 patients with various forms of NMD; mitochondrial: n = 14, Friedreich's ataxia (FA): n = 27, myotonic dystrophy: n = 27, Becker/Duchenne's muscular dystrophy (BMD/DMD): n = 15, Duchenne's carriers: n = 6, other: n = 22.

Un bri d’esperança

Dissabte, 7 agost 2021, El Punt Avui.

L’atàxia de Friedreich provoca problemes de coordinació, força muscular i cor i escurça l’esperança de vida fins als 40 anys. L’objectiu del fàrmac, que ja està en fase clínica, és aturar la progressió d’aquestes malalties o, almenys, alentir-la. “No és el mateix treballar desenvolupant medicaments per a malalties on hi ha moltes opcions terapèutiques que aquí, on si no te’n surts els malalts no tenen res més. La pressió és molt alta però també la motivació”, reflexiona el CEO de Minoryx.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich’s ataxia

Arne Mueller, Elaine Paterson, Avery McIntosh, Jens Praestgaard, Mary Bylo, Holger Hoefling, McKenzie Wells, David R. Lynch, Christian Rummey, Michelle L. Krishnan, Meredith Schultz, C. J. Malanga; Ann Clin Transl Neurol. doi:10.1002/acn3.51438

Deploying digital endpoints in home settings is feasible in this population, results in meaningful and robust data collection, and may allow for frequent sampling over longer periods of time to track disease progression. Care must be taken when training participants, and investigators should consider the complexity of the tasks and equipment used.

The Role of Voltage-Dependent Anion Channel in Mitochondrial Dysfunction and Human Disease

Varughese J, Buchanan S, Pitt A., Cells. 2021 Jul;10(7). PMCID: PMC8305817 doi:10.3390/cells10071737

The voltage-dependent anion channel (VDAC) is a β-barrel membrane protein located in the outer mitochondrial membrane (OMM). VDAC has two conductance states: an open anion selective state, and a closed and slightly cation-selective state. VDAC conductance states play major roles in regulating permeability of ATP/ADP, regulation of calcium homeostasis, calcium flux within ER-mitochondria contact sites, and apoptotic signaling events. Three reported structures of VDAC provide information on the VDAC open state via X-ray crystallography and nuclear magnetic resonance (NMR). Together, these structures provide insight on how VDAC aids metabolite transport. The interaction partners of VDAC, together with the permeability of the pore, affect the molecular pathology of diseases including Parkinson’s disease (PD), Friedreich’s ataxia (FA), lupus, and cancer.

Determining the Validity of Conducting Rating Scales in Friedreich Ataxia through Video

Tai, G., Corben, L.A., Woodcock, I.R., Yiu, E.M. and Delatycki, M.B. (2021); Mov Disord Clin Pract, 8: 688-693. doi:10.1002/mdc3.13204 

Excellent test–retest reliability was demonstrated in the majority of the mFARS sections, and in the total mFARS and SARA scores, suggesting that video is a valid method of conducting these scales. This method enables inclusion of participants who are unable to travel to study sites. A larger cohort will be required to further validate the use of video mFARS and SARA for future studies.

Polyuria and Acute Hyperglycemia Secondary to New-Onset Diabetes in a Young Woman With Friedreich’s Ataxia

Santos J, Woloski J R, Wu N (June 29, 2021); Cureus 13(6): e16032. doi:10.7759/cureus.16032 

Diabetes is a common complication in patients with FRDA and should be routinely screened for by healthcare providers, preferably via an OGTT. Treatment of diabetes can be challenging due to neurodegenerative symptoms that may interfere with the ability to self-administer insulin. Additionally, close follow-up with cardiology is important to monitor for any signs or symptoms of cardiomyopathy, especially after the initiation of diabetes medications. Once diabetes is diagnosed, an individualized treatment plan along with efficient coordination of care is essential for successful diabetes management in patients with FRDA.