Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters

Petrillo, S.; Perna, A.; Quatrana, A.; Silvestri, G.; Bertini, E.; Piemonte, F.; Santoro, M. Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters. Int. J. Mol. Sci. 2024, 25, 11615. doi:10.3390/ijms252111615  

The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention.

Navigating the Orphan Medicinal Product Designation: Evidence Requirements for Gene Therapies in Europe

Palomo, G.M. et al., Navigating the Orphan Medicinal Product Designation: Evidence Requirements for Gene Therapies in Europe. Molecular Therapy, Volume 0, Issue 0. DOI: 10.1016/j.ymthe.2024.10.015 

To provide insight into regulatory decision-making at the time of granting initial orphan designation by the Committee for Orphan Medicinal Products, we have conducted a retrospective analysis for viral vector-mediated gene therapies in rare non-oncological conditions with respect to the data provided to support the criteria to be met in successful applications.

At-home wearable-based monitoring predicts clinical measures and biological biomarkers of disease severity in Friedreich’s Ataxia

Mishra, R.K., Nunes, A.S., Enriquez, A. et al. At-home wearable-based monitoring predicts clinical measures and biological biomarkers of disease severity in Friedreich’s Ataxia. Commun Med 4, 217 (2024). Doi:10.1038/s43856-024-00653-1 

This results establish the initial clinical validity of using wearable sensors in assessing disease severity and monitoring motor dysfunction in FRDA.

Uniparental IsoDisomy: a case study on a new mechanism of Friedreich ataxia

Sperelakis-Beedham, B., Gitiaux, C., Rajaoba, M. et al. Uniparental IsoDisomy: a case study on a new mechanism of Friedreich ataxia. Eur J Hum Genet (2024). Doi:10.1038/s41431-024-01728-2 

The identification of a deletion in the primer-annealing region of the TP-PCR explained the initial TP-PCR failure. This is the first documented case of FRDA caused by segmental UPiD. This case highlights the complexity of the molecular diagnosis of FRDA, and emphasises the importance of integrating results from various technical diagnostic approaches.

Utility of Optical Genome Mapping in Repeat Disorders

Mutlu MB, Karakaya T, Çelebi HBG, Duymuş F, Seyhan S, Yılmaz S, Yiş U, Atik T, Yetkin MF, Gümüş H. Utility of Optical Genome Mapping in Repeat Disorders. Clin Genet. 2024 Oct 22. doi: 10.1111/cge.14633. Epub ahead of print. PMID: 39435674. 

We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.

Design and validation of cell-based potency assays for frataxin supplementation treatments

Design and validation of cell-based potency assays for frataxin supplementation treatments; Shibani Mukherjee, Larisa Pereboeva, Daniel Fil, Achisha Saikia, Jeon Lee, Jixue Li, M. Grazia Cotticelli, Elisabetta Soragni, Robert B. Wilson, Marek Napierala, Jill S. Napierala. Molecular Therapy Methods & Clinical Development, Volume 32, Issue 4, 101347 DOI: 10.1016/j.omtm.2024.101347

Immortalized MUT MEFs are an excellent tool for developing potency assays to validate novel FRDA therapies. Care needs to be exercised while utilizing these cell lines, as extended passaging results in molecular changes that spontaneously reverse FRDA-like phenotypes without increasing Fxn expression. Based on transcriptome analyses, we identified the Warburg effect as the mechanism allowing cells expressing a minimal level of Fxn to thrive under standard cell culture conditions.

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

October 15, 2024. SAN DIEGO--Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 has previously received Orphan Drug designation. 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.

PTC Therapeutics Announces Positive Results from Long-Term Treatment Studies and Updates on Regulatory Progress for Vatiquinone Friedreich Ataxia Program

WARREN, N.J., Oct. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. provided today several positive updates on the vatiquinone Friedreich ataxia (FA) program. The pre-specified endpoint for two different FA long-term extension studies was met, with highly statistically significant evidence of durable treatment benefit on disease progression. In addition, PTC recently aligned with FDA on key aspects of the planned NDA submission for vatiquinone.

Analysis of the MOVE-FA long-term extension study demonstrated that 144 weeks of vatiquinone treatment resulted in a 3.7-point benefit (p<0.0001, N=70) on the modified Friedreich Ataxia Rating Scale (mFARS) relative to a matched natural history cohort from the FACOMS (Friedreich Ataxia Clinical Outcome Measures) disease registry. This treatment difference on the primary endpoint represents a clinically meaningful 50% slowing in disease progression over 3 years. These results confirm that the slowing of disease progression recorded in the 72-week placebo-controlled MOVE-FA trial are maintained over 144 weeks of treatment. In addition, vatiquinone continued to be safe and well tolerated without any treatment-related serious adverse events reported.In addition, PTC analyzed long-term open-label data from an earlier study of vatiquinone in adults with FA. Following 24-months of treatment with vatiquinone, subjects had a 4.8-point benefit on the mFARS relative to a matched natural history population (p<0.0001, N=41).

The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders

Pranshul Sethi, Sidharth Mehan, Zuber Khan, Pankaj Kumar Maurya, Nitish Kumar, Aakash Kumar, Aarti Tiwari, Tarun Sharma, Ghanshyam Das Gupta, Acharan S Narula, Reni Kalfin, The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders, Behavioural Brain Research, 2024, 115280, ISSN 0166-4328, doi:10.1016/j.bbr.2024.115280. 

SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling

Pepin XJH, Hynes SM, Zahir H, Walker D, Semmens LQ, Suarez-Sharp S. Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling. CPT Pharmacometrics Syst Pharmacol. 2024 Sep 2. doi: 10.1002/psp4.13221. Epub ahead of print. PMID: 39219492. 

Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.