C-Path partners with FARA to fortify RDCA-DAP and further accelerate drug development with new Friedreich’s Ataxia Data

TUCSON, Ariz., June 18, 2024 — Critical Path Institute (C-Path), a leader in accelerating drug development for rare diseases, today announced the targeted integration of additional Friedreich’s ataxia (FA) datasets into C-Path’s Rare Disease Cures Accelerator-Data and Analytics Platform (RDCA-DAP®) as part of a partnership with Friedreich’s Ataxia Research Alliance (FARA). 

“RDCA-DAP’s extensive resources can amplify the impact of the existing data and foster new discoveries in FA research. This collaboration will build upon our strong, sustained, and productive partnership with the C-Path team,” said Farmer.

Friedreich’s Ataxia and Cesarean Delivery: A Case Report of Epidural Anesthesia With Ropivacaine

Theodosopoulou P, Mavromati M, Paraskeva A (June 06, 2024) Friedreich’s Ataxia and Cesarean Delivery: A Case Report of Epidural Anesthesia With Ropivacaine. Cureus 16(6): e61776. doi:10.7759/cureus.61776 

Overall management and the choice to proceed with neuraxial anesthesia in a woman with FRDA should be based on comprehensive consultations in both cardio-obstetrics and pre-anesthetic evaluations.

Microfluidic Formulation of Diazoxide-Loaded Solid Lipid Nanoparticles as a Novel Approach for Friedreich's Ataxia Treatment

Ilaria Arduino, Antonella Santoro, Silvia De Santis, Rosa Maria Iacobazzi, Angela Assunta Lopedota, Eleonora Paradies, Giuseppe Merla, Sara Anjomani Virmouni, Luigi Palmieri, Carlo Marya Thomas Marobbio, Nunzio Denora, Microfluidic Formulation of Diazoxide-Loaded Solid Lipid Nanoparticles as a Novel Approach for Friedreich's Ataxia Treatment, Journal of Drug Delivery Science and Technology, 2024, 105837, ISSN 1773-2247, doi: 10.1016/j.jddst.2024.105837. 

 These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue - Broad Energy Barriers and the General Properties of the Transition State

Pietrangeli P, Marcocci L, Pennacchietti V, Diop A, Di Felice M, Pagano L, Malagrinò F, Toto A, Brunori M, Gianni S. The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue - Broad Energy Barriers and the General Properties of the Transition State. J Mol Biol. 2024 May 15;436(10):168555. doi: 10.1016/j.jmb.2024.168555. Epub 2024 Mar 27. PMID: 38552947. 

 We compared results from yeast and human frataxin providing insights into the impact of native topology on the folding mechanism and elucidating the properties of the underlying free energy landscape. The findings are discussed in the context of the funneled energy landscape theory of protein folding.

The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population

Mahdieh N, Heidari M, Rezaei Z, et al. The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population. Human Genomics. 2024 Apr;18(1):35. DOI: 10.1186/s40246-024-00598-5. PMID: 38570878; PMCID: PMC10988936.

 Friedreich ataxia (FA), ataxia telangiectasia (AT), ataxia with oculomotor apraxia (AOA), and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) are among the most common forms of ARCA. These conditions typically present with a complicated phenotype. For instance, FA, the most prevalent recessive ataxia affecting 1 in 50,000 individuals in white populations, is caused by homozygous expansions of an intronic GAA trinucleotide repeat in the FXN gene

Mitochondrial calcium regulation of cardiac metabolism in health and disease

Balderas E, Lee SH, Rai NK, et al. Mitochondrial calcium regulation of cardiac metabolism in health and disease. Physiology (Bethesda, Md.). 2024 May. DOI: 10.1152/physiol.00014.2024. PMID: 38713090. 

In this review, we delve into recent insights further defining the relationship between mitochondrial Ca2+ dynamics and oxidative phosphorylation. Our focus is on how such regulation affects cardiac function in health and disease, including heart failure, ischemia-reperfusion, arrhythmias, catecholaminergic polymorphic ventricular tachycardia, mitochondrial cardiomyopathies, Barth syndrome, and Friedreich's ataxia.

Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics

Mahale R, Purushottam M, Singh R, Yelamanchi R, Kamble N, Holla V, Pal PK, Jain S, Yadav R. Revisiting Friedreich's Ataxia: Phenotypic and Imaging Characteristics. Ann Indian Acad Neurol. 2024 Mar-Apr;27(2):152-157. doi: 10.4103/aian.aian_1001_23. Epub 2024 Apr 12. PMID: 38751907; PMCID: PMC11093178.

A retrospective cross-sectional, descriptive analysis of genetically proven FRDA patients was performed. A detailed review of all the hospital case records was done to analyze the clinical, radiologic, and electrophysiologic details.

Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions

Etienne Gnimpieba, D M Diing, Jared Ailts et al. Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions, 26 April 2024, PREPRINT (Version 1) available at Research Square doi: 10.21203/rs.3.rs-4259413/v1] 

Our data has demonstrated the strengths of employing complementary methods to identify a unique interactome for FXN. Our data provides new insights into FXN function and regulation, a potential direct interaction between FXN and NFS1, and pathway interactions between FXN and Prdx3.

Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview

Mantle D, Hargreaves IP. Efficacy and Safety of Coenzyme Q10 Supplementation in Neonates, Infants and Children: An Overview. Antioxidants (Basel, Switzerland). 2024 Apr;13(5):530. DOI: 10.3390/antiox13050530. PMID: 38790635; PMCID: PMC11117623. 

 Contradictory outcomes have been described regarding the effect of supplementation with the CoQ10 analogue idebenone on cardiac function or neurological function in younger Friedreich’s ataxia patients. Thus, in an open study, supplementation with idebenone (5 mg/kg/day for 6 months) in eight children (age range 4–12 years) with Friedreich’s ataxia resulted in improved cardiac indices (left ventricular mass, left ventricular posterior wall thickness, shortening fraction). An open study of Friedreich’s ataxia patients, including 15 children (ages 4–12 years), found improved cardiac indices (left ventricular posterior wall thickness, interventricular septum thickness) following supplementation with idebenone (20 mg/kg/day). However, in a randomised controlled trial comprising 70 paediatric patients, supplementing idebenone (450–2250 mg/day for 6 months) did not result in any significant benefit on left ventricular hypertrophy or other cardiac function parameters. Similarly, with regard to neurological function, an open study by Pineda et al. comparing younger (ages 8–18 years) and adult (ages 18–46 years) patients with Friedreich’s ataxia found supplementation with idebenone (5–20 mg/kg/day for 3–5 years) stabilised neurological function in younger subjects, but not in adults. However, a randomised controlled trial supplementing idebenone (450–2250 mg/day for 6 months) in a series of 70 children/adolescents (aged 8–18 years) did not result in any significant improvement in neurological function. In addition, a randomised controlled trial, supplementation with idebenone (5–45 mg/kg/day for 6 months) in a cohort of 42 children/adolescents (aged 9–17 years) with Friedreich’s ataxia did not result in any improvement in exercise capacity.

CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias

Perlman SL. CRPD frontiers in movement disorders Therapeutics: From evidence to treatment and applications: Addressing Patients' Needs in the Management of the Ataxias. Clinical Parkinsonism & Related Disorders. 2024 ;10:100255. DOI: 10.1016/j.prdoa.2024.100255. PMID: 38798918; PMCID: PMC11126860. 

The genetic ataxias have no cures and no proven ways to delay progression (no disease-modifying therapies). The acquired ataxias may have treatments that address the underlying cause and may slow or stop progression, but will not reverse damage already sustained. The idiopathic ataxias (of unknown genetic or acquired cause) also have no proven disease-modifying therapies. However, for all patients with ataxia of any cause, there is always something that can be done to improve quality of life-treat associated symptoms, provide information and resources, counsel patient and family, help with insurance and disability concerns, be available to listen and answer the many questions they will have.

Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol

Braymer JJ, Stehling O, Stümpfig M, et al. Requirements for the biogenesis of [2Fe-2S] proteins in the human and yeast cytosol. Proceedings of the National Academy of Sciences of the United States of America. 2024 May;121(21):e2400740121. DOI: 10.1073/pnas.2400740121. PMID: 38743629; PMCID: PMC11126956. 

The most critical GSH requirement was assigned to Atm1-dependent export, i.e. a step before GSH-dependent cGrxs function. Our findings extend the general model of eukaryotic Fe/S protein biogenesis by adding the molecular requirements for cytosolic [2Fe-2S] protein maturation.