Ectopic Burden via Holter Monitors in Friedreich Ataxia.

Erika Mejia,Abigail Lynch,Patrick Hearle,Oluwatimilehin Okunowo,Heather Griffis,Maully Shah,David Lynch,Kimberly Y Lin; Physician's Weekly; Mar 4, 2021

Using a natural history study of patients with Friedreich ataxia at a single center, we analyzed portable heart rhythm monitors (Holters). Ectopic burden was defined as the proportion of atrial or ventricular ectopic beats over total beats.
Of 456 patients, 131 had Holters. Sixty-eight (52.0%) were male, median age of symptom onset was 8.0 years (5.0 to 13.0, n = 111), median age at time of Holter was 17.3 years (interquartile range [IQR] 12.9 to 22.8, n = 129), and median duration of illness was 8.7 years (IQR 5.3 to 11.6, n = 110). Median GAA length on the shorter FXN allele was 706.0 (IQR 550.0 to 840.0, n = 112). Eight (7.8%, n = 103) had diminished cardiac function, and 74 (74.0%, n = 100) had ventricular hypertrophy. Ninety patients (83.0%) had atrial ectopy (supraventricular ectopy [SVE]): 85 (78.0%) with rare SVE (>0% to 5%) and five (5.0%) with frequent SVE (>10%). Twenty-five (19.0%) had supraventricular runs, and one (0.8%) had atrial fibrillation/flutter. Forty-five (41.0%) had ventricular ectopy (VE): 43 (39.0%) with rare VE (0% to 5%) and two (2.0%) with moderate VE (5% to 10%). Compared with patients with none and rare SVE, patients with frequent SVE had longer disease duration (18.3 versus 4.6 versus 9.0 years, P = 0.0005).
Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification; however, longitudinal analysis is needed.

Larimar Therapeutics Reports Fourth Quarter and Full Year 2020 Operating and Financial Results

BioSpace.com, Published: Mar 04, 2021​. 

 

Reported preliminary Phase 1 findings from a Single Ascending Dose (SAD) trial that suggest single subcutaneous injections of CTI-1601 were well tolerated at doses up to 100 mg in Friedreich'sataxia (FA) patients Placebo-controlled Phase 1 trials in FA patients remain on track for topline data in Q2 2021

LEXEO Therapeutics Announces License Agreement and Consolidation of Comprehensive Pre-clinical Data Package to Support Cardiac Friedreich's Ataxia Gene Therapy Program (LX2006)

Published: Mar 01, 2021 NEW YORK, March 01, 2021 (GLOBE NEWSWIRE) -- LEXEO Therapeutics, a clinical-stage gene therapy company, today announced it has licensed worldwide intellectual property rights and pre-clinical data from Adverum Biotechnologies to its Friedreich's ataxia gene therapy program. With exclusive rights to data from seven pre-clinical studies now combined, LEXEO will advance LX2006 through final IND-enabling studies and into a planned Phase 1 clinical trial in 2021.

The displacement of frataxin from the mitochondrial cristae correlates with abnormal respiratory supercomplexes formation and bioenergetic defects in cells of Friedreich ataxia patients

Davide Doni, Giovanni Rigoni, Elisa Palumbo, Elisa Baschiera, Roberta Peruzzo, Edith De Rosa, Federico Caicci, Leonardo Passerini, Daniela Bettio, Antonella Russo, Ildiko Szabò, Maria Eugenia Soriano, Leonardo Salviati, Paola Costantini; The FASEB Journal. 2021; 35:e21362. doi:10.1096/fj.202000524RR

In this work, we performed a comparative analysis of the mitochondrial phenotype of cell lines from FRDA patients, either homozygous for the expansion or compound heterozygotes for the G130V mutation. We found that, in healthy cells, FXN and two key proteins of the FeS‐cluster assembly machinery are enriched in mitochondrial cristae, the dynamic subcompartment housing the respiratory chain. On the contrary, FXN widely redistributes to the matrix in FRDA cells with defects in respiratory supercomplexes assembly and altered respiratory function. We propose that this could be relevant for the early mitochondrial defects afflicting FRDA cells and that perturbation of mitochondrial morphodynamics could in turn be critical in terms of disease mechanisms.

Retrotope Granted Rare Pediatric Disease Designation from FDA for Lead Development Candidate, RT001, in Two Life-Threatening Neurodegenerative Indications

LOS ALTOS, Calif., Feb. 25, 2021 (GLOBE NEWSWIRE) -- Retrotope, a clinical-stage biopharmaceutical company focused on the development of novel, first-in-class therapies for degenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted two rare pediatric disease designations to RT001, the company’s lead development candidate. The first rare pediatric disease designation is for the treatment of infantile neuroaxonal dystrophy (INAD), with the second covering the treatment of Friedreich’s ataxia (FA). In addition, RT001 has been granted Fast Track designation by the FDA for the treatment of FA and orphan drug designation by the European Medicines Agency (EMA) for the treatment of INAD. RT001 has previously been granted orphan drug designation in the U.S. for the treatment of multiple diseases, including FA, progressive supranuclear palsy (PSP) and PLA2G6-associated neurodegeneration, which includes INAD.

Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington's Disease

Zhao X, Kumari D, Miller CJ, Kim GY, Hayward B, Vitalo AG, Pinto RM, Usdin K.; J Huntingtons Dis. 2021;10(1):149-163. doi: 10.3233/JHD-200423. PMID: 33579860.

In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

Petrillo S, Santoro M, La Rosa P, Perna A, Gallo MG, Bertini ES, Silvestri G and Piemonte F; Front. Neurosci. 15:638810. (2021) doi:10.3389/fnins.2021.638810

Under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.

Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery

Uceda, A.B.; Donoso, J.; Frau, J.; Vilanova, B.; Adrover, M.; Antioxidants 2021, 10, 315. doi:10.3390/antiox10020315 

Consequently, our work proves that Yfh1 and Hfra are essential components of the intracellular antioxidant machinery, not only because they are able to regulate the detoxifying enzymatic mechanisms, but also because they directly act against the production of ROS. This latter mechanism also has further consequences since both proteins are able to unspecifically inhibit the oxidation of α-syn, which prove that they could act as molecular shields to protect a broad set of intracellular oxidation-prone proteins.

Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

Cesar Vasquez, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeova, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert; bioRxiv 2020.06.12.148361; doi:10.1101/2020.06.12.148361 

 The lack of overt cardiac hypertrophy, consistent with lower global protein translation, suggests that ISR predominated over mTORC1 activation. Suppression of a major ATP demanding process could benefit the FXN-depleted heart, at least short term. Thus, the FXN-depleted heart may enter a protective state, not necessarily linked to a major energy deficit. Finally, we propose the model used here as a pre-clinical model of cardiomyopathy in FRDA.

Friedreich’s Ataxia and Auditory Processing Disorder

Teive, H.A., Iliadou, V.M. & Manto, M.; Cerebellum (2021). doi:10.1007/s12311-021-01238-7

The link between auditory deprivation (in this case of the form of APD) and cognition has long-term outcomes and should not be thought as a cross-sectional one [17, 18]. Thus, it is of outmost importance to longitudinally evaluate patients with ATX-FXN, document the cognitive deficits when identifying APD at an early stage, and provide appropriate management for these challenging patients. Could this improve patients’ quality of life? This remains to be confirmed. Furthermore, the issue of a possible use of these findings as a biomarker for longitudinal or therapeutic studies remains open and requires novel studies.