Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice

Audrius Kilikevicius, Jun Wang, Xiulong Shen, Frank Rigo, Thahza P. Prakash, Marek Napierala & David R. Corey (2022); RNA Biology, 19:1, 364-372, DOI: 10.1080/15476286.2022.2043650 

 In this study, we investigate the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. After confirming successful in vivo delivery of oligonucleotides using a benchmark gapmer targeting the nuclear noncoding RNA Malat1, we tested anti-FXN oligonucleotides designed to function by various mechanisms. None of these strategies yielded enhanced expression of FXN in the model mice. Our inability to translate activation of FXN expression from cell culture to mice may be due to inadequate potency of our compounds or differences in the molecular mechanisms governing FXN gene repression and activation in FA model mice.

Bone Mineral Density and Current Bone Health Screening Practices in Friedreich’s Ataxia

Dunn J, Tamaroff J, DeDio A, Nguyen S, Wade K, Cilenti N, Weber DR, Lynch DR and McCormack SE (2022) Bone Mineral Density and Current Bone Health Screening Practices in Friedreich’s Ataxia. Front. Neurosci. 16:818750. doi: 10.3389/fnins.2022.818750 

 Low aBMD is prevalent in FRDA, but few of even the highest risk individuals are undergoing screening. Our findings highlight potential missed opportunities for the screening and treatment of low aBMD in FRDA.

Friedreich’s Ataxia Related Diabetes: Epidemiology and Management Practices

Jaclyn Tamaroff, Anna DeDio, Kristin Wade, McKenzie Wells, Courtney Park, Karla Leavens, Christian Rummey, Andrea Kelly, David R. Lynch, Shana E. McCormack; Diabetes Research and Clinical Practice, 2022, 109828, doi.org/10.1016/j.diabres.2022.109828. 

FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common, and newer glucose-lowering agents were used rarely.

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

Vavla M, Arrigoni F, Peruzzo D, Montanaro D, Frijia F, Pizzighello S, De Luca A, Della Libera E, Tessarotto F, Guerra P, Harding IH and Martinuzzi A (2022); Front. Neurol. 12:802496. doi: 10.3389/fneur.2021.802496 

fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.

Cur@SF NPs alleviate Friedreich’s ataxia in a mouse model through synergistic iron chelation and antioxidation

Li Xu, Zichen Sun, Zhiyao Xing, Yutong Liu, Hongting Zhao, Zhongmin Tang, Yu Luo, Shuangying Hao & Kuanyu Li; J Nanobiotechnol 20, 118 (2022). doi;10.1186/s12951-022-01333-9 

 Cur@SF NPs exhibited a powerful effect in reducing the oxidative stress level and removing the accumulated iron in the myocardial tissue of FRDA mice. The behavioral and histological assays exhibited excellent therapeutic efficacy of Cur@SF NPs in improving neurological deficits and cardiomyopathy. Thus, we provide evidence for low-cost agent Cur@SF NPs by increasing their bioavailability, suggesting their potential in the treatment of FRDA disease.

Should Advanced Friedreich’s Ataxia Be a Contraindication for Heart Transplantation? A Case Report of a Successful Procedure in a 58-Year-Old Patient

Valero, M.J.; Muñoz-Blanco, J.L.; Sanchez, A.G.; Cuerpo, G.; Castrodeza, J.; Navas, P.; Sousa, I.; Villa, A.; Fernández-Avilés, F.; Martínez-Sellés; J. Cardiovasc. Dev. Dis. 2022, 9, 80. doi:10.3390/jcdd9030080

We conclude that HT is a safe option for end-stage heart disease in selected patients with FA. A multidisciplinary team should assess utility, justice, quality of life, and life expectancy. Patient involvement in the decision is essential.

The Cognitive Profile of Friedreich Ataxia: A Systemic Review and Meta-Analysis

Naeije g, Schul JB, Corben L.; Research Square; 2022. DOI: 10.21203/rs.3.rs-1010466/v1. 

Individuals with FRDA display significantly lower performances in many cognitive domains compared to control participants. The spectrum of the cognitive profile alterations in FRDA and its correlation with disease severity and cerebellar structural parameters suggest a cerebellar role in the pathophysiology of FRDA cognitive impairments. (Preprint)

Naeije G, Schulz JB, Corben LA. The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis. BMC Neurol. 2022 Mar 17;22(1):97. doi: 10.1186/s12883-022-02615-3. PMID: 35300598.

Clinilabs is currently recruiting volunteers for DT-216 Clinical trial

March 8th, 2022

Gene therapy for Friedreich ataxia: Too much, too little, or just right?

R. Mark Payne, Molecular Therapy - Methods & Clinical Development, Volume 25, 2022, Pages 1-2, doi:10.1016/j.omtm.2022.02.008 

Defining minimal expression levels for normal cell function in different tissues, including brain, will be needed to develop effective therapies. These experiments are an important contribution to the field of FA, because they define toxicity of FXN overexpression and, more importantly, identify mechanisms underlying this toxicity.

1st Hellenic Friedreich's Ataxia Conference

7.3.2022; The Hellenic Friedreich's Ataxia Association plans to conduct on 6th May the 1st Hellenic Friedreich's Ataxia Conference, both, in person and virtual, with the kind and very strong support of US FARA.