Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

PT Pierce, X Wang, A Rivera, A Cooper, H Van Remmen, J Brown, PF Vitiello, The American Journal of the Medical Sciences, Volume 365, Supplement 1, 2023, Pages S194-S195, ISSN 0002-9629, doi:10.1016/S0002-9629(23)00372-5. 

Since mitochondrial complex activities of cardiac fibers from FRDAkD mice were impaired without changes in mitochondrial mass, we hypothesize that bioenergetic changes could be attributable to altered fragmentation of the mitochondrial network. This is the first set of data providing ex vivo evidence of mitochondrial respiratory defects during FXN knockdown associated with FRDA. Furthermore, these findings highlight that there are tissue-specific mechanisms during FXN loss since cardiac and skeletal muscle fibers had differential bioenergetic responses.

Foot and Ankle Biomechanics

Morgan E. Leslie, Joseph M. Iaquinto, Chapter 31 - Neurological Foot Pathology, Editor(s): William R. Ledoux, Scott Telfer, Academic Press, 2023, Pages 489-506, ISBN 9780128154496, doi:10.1016/B978-0-12-815449-6.00047-0. 

This chapter provides an overview of pathologies involving neurological mechanisms affecting foot and ankle biomechanics including stroke, cerebral palsy, toe walking, peripheral neuropathy, foot drop, tarsal tunnel syndrome, Morton’s neuroma, Charcot foot, Charcot-Marie-Tooth disease, Friedreich’s ataxia, and poliomyelitis.

Interactions of reactive sulfur species with metalloproteins

ndrea Domán, Éva Dóka, Dorottya Garai, Virág Bogdándi, György Balla, József Balla, Péter Nagy; Redox Biology, 2023, 102617, ISSN 2213-2317, doi:10.1016/j.redox.2023.102617. 

The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in H2S-related drug development and the advancement of redox medicine.

Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders

Bianca Seminotti, Mateus Grings, Nícolas Manzke Glänzel, Jerry Vockley, Guilhian Leipnitz; Biochemical Pharmacology, 2023, 115433, ISSN 0006-2952, doi:10.1016/j.bcp.2023.115433. 

Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.

A new FRDA mouse model [Fxnnull:YG8s(GAA) > 800] with more than 800 GAA repeats

Kalef-Ezra E, Edzeamey FJ, Valle A, Khonsari H, Kleine P, Oggianu C, Al-Mahdawi S, Pook MA and Anjomani Virmouni S (2023) . Front. Neurosci. 17:930422. doi: 10.3389/fnins.2023.930422 

We found statistically significant behavioral deficits, together with reduced levels of frataxin mRNA and protein, and aconitase activity in YG8JR mice compared with control Y47JR mice. YG8JR mice exhibit intergenerational GAA repeat instability by the analysis of parent and offspring tissue samples. Somatic GAA repeat instability was also detected in individual brain and cerebellum tissue samples. In addition, increased DNA methylation of CpG U13 was identified in FXN GAA repeat region in the brain, cerebellum, and heart tissues. Furthermore, we show decreased histone H3K9 acetylation and increased H3K9 methylation of YG8JR cerebellum tissues within the FXN gene, upstream and downstream of the GAA repeat region compared to Y47JR controls.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

By: Rebecca Roberts - Jan. 23, 2023. Professor Stephanie Cherqui of University of California San Diego’s School of Medicine recently received a prestigious grant from the Californian Institute of Regenerative Medicine, which will allow her and her team to bring her novel CRISPR therapy for the fatal neurodegenerative disease Friedreich’s ataxia to the clinic. Cherqui’s novel treatment for FRDA is an ex vivo gene-edited autologous cell therapy. The process begins with extracting haematopoietic stem and progenitor cells (HSPCs) from the peripheral blood of patients before excising the trinucleotide repeat hyperexpansion in intron 1 of the FXN gene from the cells. This edit involves delivering a ribonucleoprotein (RNP) complex consisting of Cas9 and two sgRNAs – one guide for either end of the trinucleotide expansion. In their original proof-of-concept study, the team were able to achieve editing efficiencies of more than 50% in the HSPCs of FRDA patients. Edited HSPCs display restored expression of frataxin and mitochondrial function, and can be transplanted back to patients as a one-time, curative therapy. »Because this mutation is located within an intron in the FXN gene, it is a good target for gene correction by removing this expansion using CRISPR-Cas9. In addition, this approach would be valid for all FRDA patients, because they all carry a trinucleotide expansion mutation,« Cherqui elaborates. Edited HSPCs are currently used for the treatment of blood disorders such as sickle cell disease and β-thalassemia. However, Cherqui’s work is novel because it offers proof that these cells can be used to treat conditions like FRDA. Edited HSPCs are able to proliferate and differentiate into macrophages and microglia in vivo in mice, and traffic to the necessary tissues throughout the body and brain of FRDA patients. The early data shows that transplantation of the corrected HSPCs in mice prevents disease progression. The therapy will be aimed at the treatment of babies and children in whom the disease has not yet caused significant damage, however, Cherqui says they may also be able to halt disease progression in adult patients.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

Bernardo-Seisdedos G, Schedlbauer A, Pereira-Ortuzar T, Mato JM, Millet O.; Life (Basel). 2023 Jan 12;13(1):222. doi: 10.3390/life13010222. PMID: 36676171. 

We demonstrate that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase.

Small-molecule inhibitors of proteasome increase CjCas9 protein stability

Yaméogo P, Majeau N, Mbakam CH, Tremblay JP (2023) . PLoS ONE 18(1): e0280353. doi:10.1371/journal.pone.0280353 

We observed that the CjCas9 protein expressed in HEK293T cells after transfection of this transgene under a CMV promoter was much lower than the SpCas9 protein in the same conditions. We thus evaluated the effect of proteasome inhibitors on CjCas9 protein stability and its efficiency on FXN gene editing. Western blotting showed that the addition of MG132 or bortezomib, significantly increased CjCas9 protein levels in HEK293T and HeLa cells. Moreover, bortezomib increased the level of CjCas9 protein expressed under promoters weaker than CMV such as CBH or EFS but which are specific for certain tissues. Finally, ddPCR quantification showed that bortezomib treatment enhanced CjCas9 efficiency to delete GAA repeat region of FXN gene in HEK293T cells. The improvement of CjCas9 protein stability would facilitate its used in CRISPR/Cas system.

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Jackson Ping Kei Chan, Suran Nethisinghe, Stavros Athanasopoulos, Valeria Ricotti, Thomas Voit, Paola Giunti, Richard Festenstein & A. Aldo Faisal; Nat Med (2023). doi:10.1038/s41591-022-02159-6

Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.

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

Chiara Dionisi, Marine Chazalon, Myriam Rai, Céline Keime, Virginie Imbault, David Communi, Hélène Puccio, Serge N Schiffmann, Massimo Pandolfo; Brain Communications, 2023;, fcad007, doi:10.1093/braincomms/fcad007 

 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.

Form S-1/A JUPITER NEUROSCIENCES

As filed with the U.S. Securities and Exchange Commission on January 17, 2023. 

JOTROL™ is a micellar non-aqueous solution of resveratrol delivered in a softgel capsule. Each capsule includes 100mg of resveratrol. Pre-clinical trials in mice and rats were conducted comparing JOTROL™ to micronized resveratrol, labeled to have the highest bioavailability in the nutritional market, to demonstrate that we could achieve a significantly higher bioavailability.

Neurobehavioral deficits of mice expressing a low level of G127V mutant frataxin

Daniel Fil, Robbie L. Conley, Aamir R. Zuberi, Cathleen M. Lutz, Terry Gemelli, Marek Napierala, Jill S. Napierala; Neurobiology of Disease, Volume 177, 2023, 105996, ISSN 0969-9961, doi:10.1016/j.nbd.2023.105996. 

 Results of these studies provide insight into the unique pathogenic mechanism of the FXN G130V mechanism and the tolerable limit of Fxn/FXN expression in vivo.

Quantitative Oculomotor Assessment in Hereditary Ataxia: Discriminatory Power, Correlation with Severity Measures, and Recommended Parameters for Specific Genotypes

Pilar Garces, Chrystalina A. Antoniades, Anna Sobanska, Norbert Kovacs, Sarah H. Ying, Anoopum S. Gupta, Susan Perlman, David J. Szmulewicz, Chiara Pane, Andrea H. Németh, Laura B. Jardim, Giulia Coarelli, Michaela Dankova, Andreas Traschütz & Alexander A. Tarnutzer; Cerebellum (2023). doi:10.1007/s12311-023-01514-8 

Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Ketolysis is Required for the Proper Development and Function of the Somatosensory Nervous System

Jonathan Enders, Jarrid Jack, Sarah Thomas, Paige Lynch, Sarah Lasnier, Xin Cao, M Taylor Swanson, Janelle M Ryals, John P Thyfault, Patrycja Puchalska, Peter A Crawford, Douglas E Wright; bioRxiv 2023.01.11.523492; doi:10.1101/2023.01.11.523492 

We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

FXN gene methylation determines carrier status in Friedreich ataxia

Lam C, Gilliam KM, Rodden LN, Schadt KA, Lynch DR, Bidichandani S.; J Med Genet. 2023 Jan 12:jmedgenet-2022-108742. doi: 10.1136/jmg-2022-108742. Epub ahead of print. PMID: 36635061. 

 FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE.

Prime Medicine (PRME) Announces Recent Progress and Highlights 2023 Strategic Priorities

January 9, 2023; “Today, we are pleased to announce accomplishments across our portfolio and platform, including new preclinical proof-of-concept data in Friedrich’s ataxia and cystic fibrosis showing restoration of genetic function.

In preclinical studies, Prime Medicine is using its technology to precisely remove the GAA pathological repeats at the FXN gene, restoring Frataxin protein expression and sensory neuron function in patient dorsal root ganglia. Today, Prime Medicine announced new preclinical data demonstrating that Prime Editing-mediated removal of pathological repeats in vitro results in correction of hypermethylation at the FXN gene, restoring genetic function back to wild-type levels. The company believes these data also support the evaluation of Prime Editing for the potential treatment of other repeat expansion diseases, many of which exhibit hypermethylation as a key feature of the underlying pathogenesis.

S-Glutathionylation and S-Nitrosylation in Mitochondria: Focus on Homeostasis and Neurodegenerative Diseases

Vrettou S, Wirth B.; International Journal of Molecular Sciences. 2022 Dec;23(24):15849. DOI: 10.3390/ijms232415849. PMID: 36555492; PMCID: PMC9779533. 

We discuss how S-glutathionylation and S-nitrosylation interfere in mitochondrial homeostasis and how the deregulation of these modifications is associated with Alzheimer's, Parkinson's, amyotrophic lateral sclerosis and Friedreich's ataxia.

ODs with a positive TPR conclusion, not subject to a conditional approval, and approved without requering a pass would be more likely to be reimbursed in Spain

José Luis Poveda, Claudia Gómez, Alicia Gil & Xavier Badia; Orphanet J Rare Dis 18, 4 (2023). doi:10.1186/s13023-022-02610-4 

This study shows that the TPR plays a key role in the P&R process in Spain and highlights that traditional evaluation tools, such us safety and efficacy, were the main drivers of P&R decisions for ODs. A positive conclusion of the TPR, non-conditional approval by the EMA and no obligation for a PASS seems to favourably affect P&R decisions in Spain.

Open Innovation for an Inclusive Labor Market for University Students with Disabilities

Espada-Chavarria, R.; Diaz-Vega, M.; González-Montesino, R.H.; J. Open Innov. Technol. Mark. Complex. 2021, 7, 217. doi:10.3390/joitmc7040217 

 This descriptive and quantitative study discusses the results obtained after implementing an open innovation program to promote access to internships for university students with disabilities, in which three multi-national companies have participated. We used the Job Typicalness, Quality of Work Life and Employment Maturity Interview Questionnaires to collect information. The results show that the jobs performed by disabled participants are similar to those of other workers. This job typicality positively influences their perception of quality of life and job satisfaction. The open innovation process has focused on collaboration to provide accessibility and equity to the procedures of human resources departments for access to employment, that is, external collaboration has been used to offer an equal-opportunity hiring process. The information obtained allows us to conclude that companies need to increase their training and/or knowledge in the fields of diversity and inclusion to eliminate the barriers of access to employment found in hiring processes. This study reveals the importance of this type of open innovation among companies and organizations, not only for establishing diversity-sensitive human resources policies, but also for promoting the talent attraction with equal opportunities and an inclusive labour market.

Iron-frataxin involved in the protective effect of quercetin against alcohol-induced liver mitochondrial dysfunction

Liu J, Chen H, Lin H, Peng S, Chen L, Cheng X, Yao P, Tang Y.; J Nutr Biochem. 2022 Dec 29:109258. doi: 10.1016/j.jnutbio.2022.109258. Epub ahead of print. PMID: 36587874. 

 Frataxin deficiency reduced the protective effects of quercetin on mitochondria disordered by ethanol.

Drosophila melanogaster frataxin: protein crystal and predicted solution structure with identification of the iron-binding regions

Rodrigues AV, Batelu S, Hinton TV, Rotondo J, Thompson L, Brunzelle JS, Stemmler TL.; Acta Crystallogr D Struct Biol. 2023 Jan 1;79(Pt 1):22-30. doi: 10.1107/S2059798322011639. Epub 2023 Jan 1. PMID: 36601804. 

 The goal of this report is to provide structural details of the Drosophila melanogaster frataxin ortholog (Dfh), using both X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, in order to provide the foundational insight needed to understand the structure-function correlation of the protein.

Histopathology of the cerebellar cortex in essential tremor and other neurodegenerative motor disorders: comparative analysis of 320 brains

Elan D. Louis, Regina T. Martuscello, John T. Gionco, Whitney G. Hartstone, Jessica B. Musacchio, Marisa Portenti, Morgan McCreary, Sheng-Han Kuo, Jean-Paul G. Vonsattel & Phyllis L. Faust; Acta Neuropathol (2023). doi:10.1007/s00401-022-02535-z 

We conducted comparative analyses in a postmortem series of 320 brains on the severity and patterning of cerebellar cortex degenerative changes in ET (n = 100), other neurodegenerative disorders of the cerebellum [spinocerebellar ataxias (SCAs, n = 47, including 13 SCA3 and 34 SCA1, 2, 6, 7, 8, 14); Friedreich’s ataxia (FA, n = 13); multiple system atrophy (MSA), n = 29], and other disorders that may involve the cerebellum [Parkinson’s disease (PD), n = 62; dystonia, n = 19] versus controls (n = 50).