Mechanisms of impaired mitochondrial homeostasis and NAD+ metabolism in a model of mitochondrial heart disease exhibiting redox active iron accumulation

Chiang S, Braidy N, Maleki S, Lal S, Richardson DR, Huang ML.; Redox Biol. 2021 Jun 10;46:102038. doi: 10.1016/j.redox.2021.102038. Epub ahead of print. PMID: 34416478; PMCID: PMC8379503. 

This investigation examined the muscle creatine kinase conditional frataxin knockout mouse, which closely mimics FA cardiomyopathy, to dissect the mechanisms of dysfunctional mitochondrial homeostasis. Dysfunction of key mitochondrial homeostatic mechanisms were elucidated in the knockout hearts relative to wild-type littermates, namely: (1) mitochondrial proliferation with condensed cristae; (2) impaired NAD+ metabolism due to perturbations in Sirt1 activity and NAD+ salvage; (3) increased mitochondrial biogenesis, fusion and fission; and (4) mitochondrial accumulation of Pink1/Parkin with increased autophagic/mitophagic flux. Immunohistochemistry of FA patients' heart confirmed significantly enhanced expression of markers of mitochondrial biogenesis, fusion/fission and autophagy. These novel findings demonstrate cardiac frataxin-deficiency results in significant changes to metabolic mechanisms critical for mitochondrial homeostasis. This mechanistic dissection provides critical insight, offering the potential for maintaining mitochondrial homeostasis in FA and potentially other cardio-degenerative diseases by implementing innovative treatments targeting mitochondrial homeostasis and NAD+ metabolism.

Retrotope eyes $100m raise for neurodegenerative disease platform

https://www.clinicaltrialsarena.com   27 Aug 2021 California-based Retrotope aims to expand its investor pool as it prepares to potentially go public in the coming years. 

Currently, Retrotope has ongoing trials for RT001 in three of the four most common orphan neurodegenerative diseases— amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP) and Friedreich’s ataxia (FA). The ALS and PSP trials are Phase II, while the FA trial is a Phase II/III potentially IND-enabling study, company president Anil Kumar said.

Determine Range of Tissue Frataxin Concentrations and Other Potential Biomarkers

ClinicalTrials.gov Identifier: NCT05028764, First Posted : August 31, 2021; Sponsor: Larimar Therapeutics, Inc. 

Brief Summary: To examine range of tissue frataxin (FXN) concentrations, specific ribonucleic acids, other proteins and specialized lipids in the buccal cells, blood, and skin cells of normal healthy volunteers without Friedreich's ataxia (FRDA).

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.”