Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica

Alfaro-Olivera M, Calle-Nuñez A, Uribe-León A, Aguirre-Quispe W, Sarapura-Castro E, Cornejo-Olivas M. Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica. Revista de Neuro-Psiquiatría [Internet]. 27abr.2023 [citado 7jun.2023];86(1):45-1. Available from: https://revistas.upch.edu.pe/index.php/RNP/article/view/4466 

 La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países.

XC-103 by Ixchel Pharma for Friedreich Ataxia: Likelihood of Approval

June 5, 2023. XC-103 is under clinical development by Ixchel Pharma and currently in Phase I for Friedreich Ataxia. According to GlobalData, Phase I drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the IXC-103 LoA Report.

Amplifying gene expression with RNA-targeted therapeutics

Khorkova O, Stahl J, Joji A, Volmar CH, Wahlestedt C. Amplifying gene expression with RNA-targeted therapeutics. Nature reviews. Drug Discovery. 2023 May. DOI: 10.1038/s41573-023-00704-7. PMID: 37253858; PMCID: PMC10227815. 

This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report

M. Sneyers Closa, A. Pérez Requena, S. Sánchez García, J. Sistac Ballarín, Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report, Revista Española de Anestesiología y Reanimación (English Edition), 2023, doi:10.1016/j.redare.2023.06.002.

 A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm. Thyroid storm is an endocrine emergency that is associated with high morbidity and mortality. Early diagnosis and treatment, which is of vital importance to improve survival, includes symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment. 

 Paciente de 26 años afecto de ataxia de Friederich con una miocardiopatía hipertrófica obstructiva sometido a una tiroidectomía total por tirotoxicosis secundaria a amiodarona persistente (a pesar de elevadas dosis de antitiroideos y corticoides) que intraoperatoriamente presentó un episodio sugestivo de tormenta tiroidea. La tormenta tiroidea es una emergencia endocrinológica que asocia una elevada morbimortalidad. Para mejorar la supervivencia es de vital importancia un diagnóstico y tratamiento precoz que incluya: un tratamiento sintomático; el tratamiento de las manifestaciones cardiovasculares, neurológicas y/o hepáticas y de la tirotoxicosis; y así como suprimir o evitar estímulos desencadenantes y practicar un tratamiento definitivo.

Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia

Tslil Ast, Hong Wang, Eizo Marutani, Fumiaki Nagashima, Rajeev Malhotra, Fumito Ichinose, Vamsi K Mootha, Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia, Human Molecular Genetics, 2023;, ddad091, doi:10.1093/hmg/ddad091 

 The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?

Francisco Figueroa, Lili Salinas, Claire Montgomery, Phung N. Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena Dedkova, PO-01-126 SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S141, doi.:10.1016/j.hrthm.2023.03.489. 

Our study revealed sexual dimorphism and significant impairment in electrical and contractile function in FXN cKO males compared to females. A detailed characterization of impaired electrical signals in FA hearts will build a platform for drug testing to treat lethal cardiomyopathy in FA.

THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA

Bojjibabu Chidipi, Roman Czornobil, Elizabeth Remily-Wood, David R. Lynch, Sami F. Noujaim, PO-01-124 THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S140, doi:10.1016/j.hrthm.2023.03.487. 

The development of left ventricular contractile dysfunction in FA is associated with reduced expression of calcium handling proteins, abnormal calcium cycling, and mitochondrial dysfunction.

Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy

Chellapandi, D.M., Mosbach, V., Paschaki, M., Puccio, H. (2023). Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. doi:10.1007/978-3-031-24345-5_23 

 In this chapter, we discuss recent therapeutic approaches, including a proof-of-concept study for gene therapy, drug development targeting the affected downstream pathways, paving the way for the first disease-modifying therapeutic approaches.

Therapeutic Use of Interferon Gamma in Friedreich Ataxia

Martinuzzi, A., Paparella, G., Vavla, M., D’Angelo, M.G., Arrigoni, F., Testi, R. (2023). Therapeutic Use of Interferon Gamma in Friedreich Ataxia. In: Soong, Bw., Manto, M., Brice, A., Pulst, S.M. (eds) Trials for Cerebellar Ataxias. Contemporary Clinical Neuroscience. Springer, Cham. doi:10.1007/978-3-031-24345-5_24 

In patients with FRDA, IFN-γ upregulated frataxin levels in cells from FRDA patients and increased frataxin expression in dorsal root ganglia neurons. In this chapter we review the basic science behind the proposal of IFN-γ as a potential treatment for FRDA and summarize the clinical studies related to the use of IFN-γ in FRDA, outlining critical lessons that have been learned in terms of drug efficacy and tolerability.

Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich’s Ataxia Pre-Clinical Models and Clinical Trials

Tiberi J, Segatto M, Fiorenza MT, La Rosa P. Apparent Opportunities and Hidden Pitfalls: The Conflicting Results of Restoring NRF2-Regulated Redox Metabolism in Friedreich's Ataxia Pre-Clinical Models and Clinical Trials. Biomedicines. 2023 Apr;11(5):1293. DOI: 10.3390/biomedicines11051293. PMID: 37238963.

 The issues discussed here indicate that there are still many dark spots that require elucidation in order for FRDA patients to benefit from effective antioxidant therapy. However, although the relationship between the lack of FXN in FRDA and the benefits of NRF2–ARE axis activation have not yet been fully elucidated, it is important to highlight the significant correlation found between FXN expression and NRF2 activity, which is associated with the presence of three highly conserved ARE sequences on the FXN gene promoter, which are crucial for the binding of the NRF2–sMaf complex to promote the transcription of detoxification and antioxidant genes [105,106]. In light of this, by addressing the limitations that currently separate pre-clinical models from patient trials and improving early diagnostic systems, it is auspicial that new treatments or molecules, especially in conjunction with other therapeutic approaches (i.e., lentivirus-mediated FXN gene delivery [228] or human embryonic stem cell (hESC) therapy [229]), may pave the way for effective treatments of this pathology.