Early Genetic Testing Avoids Treatment Delays for Patients with Friedreich Ataxia

EMJ. 2024;9[3]:14-23. doi:10.33590/emj/RSCJ7037 

This industry-sponsored symposium took place during the European Association of Neurology (EAN) Congress held in Helsinki, Finland, 29 June−2 July, 2024.

At the 2024 European Association of Neurology (EAN) Congress, one satellite symposium discussed the recognition, diagnosis, and treatment of Friedreich ataxia (FA), the most common hereditary ataxia. This condition is characterised by progressive neurodegeneration, multisystem complications, loss of ambulation, and reductions in the ability to carry out activities of daily living (ADL). For many, there is also a premature death. FA is caused by guanine-adenine-adenine triplet (GAA) repeat expansions in the gene FXN. This codes for the protein frataxin, loss of which is associated with impaired mitochondrial function, increased sensitivity to oxidative stress and reactive oxygen species levels, increased inflammation, and cell death.

Papillon Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for PPL-001 for the Treatment of Friedreich's Ataxia

SAN DIEGO--(BUSINESS WIRE)--Sep 17, 2024-- Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 is an experimental gene-corrected CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. This therapeutic’s novel approach utilizes targeted excision to correct the GAA repeat expansion in Intron 1 of the FXN gene.

Mitotech Presents Promising Results in Friedreich's Ataxia

LONDON, Sept. 17, 2024 /PRNewswire-PRWeb/ -- Mitotech Ltd, a mitochondria-focused clinical-stage biotechnology company, presented new data for its mitochondria-targeted ferroptosis inhibitor in Friedreich's Ataxia (FA) model at the 149th annual meeting of the American Neurological Association. The conference took place on September 14-17, 2024, in Orlando, FL. 

Those new data demonstrated high level of efficacy of the company's lead compound SkQ1 – a mitochondria-targeted ferroptosis inhibitor – against ferroptosis and oxidative stress at strikingly low doses.The Friedreich's Ataxia-specific model has not only demonstrated SkQ1's great potential as a monotherapy for FA, but also highlighted its MoA as complementary to that of the currently available therapy – omaveloxolone. The latter aspect of our latest dataset opens the door for studying SkQ1 in a combination treatment in the clinic,"

Skeletal Muscle Involvement in Friedreich Ataxia

Indelicato, E.; Wanschitz, J.; Löscher, W.; Boesch, S. Skeletal Muscle Involvement in Friedreich Ataxia. Int. J. Mol. Sci. 2024, 25, 9915. doi:10.3390/ijms25189915 

 Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response

Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Fabien Delaspre, Maria Pazos-Gil, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol, Deciphering the ferroptosis pathways in dorsal root ganglia of Friedreich ataxia models. The role of LKB1/AMPK, KEAP1, and GSK3β in the impairment of the NRF2 response, Redox Biology, Volume 76, 2024, 103339, ISSN 2213-2317, doi:10.1016/j.redox.2024.103339

Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia

Scarabino D, Veneziano L, Nethisinghe S, Mantuano E, Fiore A, Granata G, Solanky N, Zanni G, Cavalcanti F, Corbo RM, Giunti P. Unusual Age-Dependent Behavior of Leukocytes Telomere Length in Friedreich's Ataxia. Mov Disord. 2024 Sep 5. doi: 10.1002/mds.29976. Epub ahead of print. PMID: 39235665. 

 The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease.

A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients

Paparella, G.; Stragà, C.; Pesenti, N.; Dal Molin, V.; Martorel, G.A.; Merotto, V.; Genova, C.; Piazza, A.; Piccoli, G.; Panzeri, E.; et al. A Pilot Phase 2 Randomized Trial to Evaluate the Safety and Potential Efficacy of Etravirine in Friedreich Ataxia Patients. Children 2024, 11, 958, doi:10.3390/children11080958.

Etravirine was well tolerated. Etravirine completely stopped the progression of the SARA score during the 4-months treatment period, compared to the 4 months pre and post treatment. It increased peak workload, while the improvement of peak oxygen uptake was not statistically significant. No changes in the cardiac measures were observed. Health and QoL measures showed a worsening at the suspension of the drug. In this open trial etravirine significantly improved neurological function and was generally safe and reasonably tolerated. This suggests that etravirine represents a potential therapeutic agent in FRDA deserving testing in a randomized placebo controlled clinical trial.

Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model

Wu, L., Huang, F., Yang, L. et al. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model. Sci Rep 14, 19876 (2024). doi:10.1038/s41598-024-71099-7

We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.

A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia

Valentine Mosbach, Hélène Puccio, A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1871, Issue 7, 2024, 119809, ISSN 0167-4889, doi:10.1016/j.bbamcr.2024.119809. 

 Over the years, several cellular and animal models for FA have been developed. These models are all complementary and possess their own strengths to investigate different aspects of the disease, such as the epigenetics of the locus or the pathophysiology of the disease, as well as being used to developed novel therapeutic approaches. This review will explore the recent advancements in the different mammalian models developed for FA.

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich’s Ataxia

NAD+ precursors prolong survival and improve cardiac phenotypes in a mouse model of Friedreich’s Ataxia, Caroline E. Perry, … , David R. Lynch, Joseph A. Baur. Published August 22, 2024, Citation Information: JCI Insight. 2024;9(16):e177152. doi:10.1172/jci.insight.177152. 

Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.