Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201)

Chiara Pane1, Alberto M. Marra, Ludovica Aliberti, Mario Campanile, Federica Coscetta, Giulia Crisci, Roberta D'Assante, Angela Marsili, Giorgia Puorro, Andrea Salzano, Antonio Cittadini, Francesco Saccà; Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201). Front. Neurosci. Sec. Neuropharmacology, Volume 17 - 2023 | doi: 10.3389/fnins.2023.1260977 

 Conclusions: this is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Luffarelli, R.; Panarello, L.; Quatrana, A.; Tiano, F.; Fortuni, S.; Rufini, A.; Malisan, F.; Testi, R.; Condò, I. Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells. Int. J. Mol. Sci. 2023, 24, 12687. doi:10.3390/ijms241612687 

The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.

Omaveloxolone for the Treatment of Friedreich’s Ataxia

Riley Kessler, Sonal Sharma, David R Lynch, Omaveloxolone for the Treatment of Friedreich’s Ataxia, Published Online: Aug 9th 2023 touchREVIEWS in Neurology. 2023;19(2):Online ahead of journal publication. 

 This review discusses the underlying cellular pathology and proposed mechanism of omaveloxolone in FRDA. The MOXIe study is presented in detail, including a discussion of the challenges faced in clinical trials in FRDA, and rare diseases more broadly. Finally, other therapies under investigation are reviewed briefly.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective

Sahel DK, Vora LK, Saraswat A, et al. CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective. Advanced Science (Weinheim, Baden-wurttemberg, Germany). 2023 Jul;10(19):e2207512. DOI: 10.1002/advs.202207512. PMID: 37166046; PMCID: PMC10323670. 

Despite DSBs, they have also been explored through epigenome editing and biosensor applications. However, its in vivo delivery is still a major challenge. Interestingly, ample nonviral nanocarriers have been developed and explored for the in vivo delivery of CRISPR components, but they are limited to some immune-prone organs of the body, such as the liver, lungs, or spleen. 

However, various pharmaceutical companies are showing interest in the CRISPR therapeutics area, and therefore, it will be interesting to watch the progress in this field. Since both ethical and social implications are associated with the usage of CRISPR, we need to move forward very responsibly.

Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

Maas RPPWM. Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose? Movement Disorders : Official Journal of the Movement Disorder Society. 2023 Jun;38(6):917-923. DOI: 10.1002/mds.29388. PMID: 37475615.

Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia

Adanyeguh IM, Joers JM, Deelchand DK, et al. Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia. Brain Communications. 2023 ;5(4):fcad196. DOI: 10.1093/braincomms/fcad196. PMID: 37483529. 

 We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Recent advances in small molecules for improving mitochondrial disorders

Meng L, Wu G. Recent advances in small molecules for improving mitochondrial disorders. RSC Advances. 2023 Jul;13(30):20476-20485. DOI: 10.1039/d3ra03313a. PMID: 37435377; PMCID: PMC10331567. 

 This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app

Buchholz M, Weber N, Borel S, et alPatient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health appBMJ Open 2023;13:e075736. doi: 10.1136/bmjopen-2023-075736 

The symptoms affect the patients’ health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app).

The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review

Poleur, M., Markati, T. & Servais, L. The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review. Orphanet J Rare Dis 18, 224 (2023). doi:10.1186/s13023-023-02813-3 

 We found two studies of patients with FRDA that used inertial technology. Remote monitoring of several voice parameters, upper limb function through 14 parameters that can be grouped into parameters related to movement velocity, spectral frequency, and parameters related to deviation of the ideal trajectory, and 15 spatiotemporal gait parameters was feasible over 1 week. The sensitivity of an upper limb composite score, the AIM-S, obtained through sensors contained in a spoon designed to detect deterioration in upper limb function, was greater than other measures.

Biogen to Acquire Reata Pharmaceuticals

CAMBRIDGE, Mass. and PLANO, Texas, July 28, 2023 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) and Reata Pharmaceuticals, Inc. (Nasdaq: RETA) today announced the companies have entered into a definitive agreement under which Biogen has agreed to acquire Reata for $172.50 per share in cash, reflecting an enterprise value of approximately $7.3 billion. 

Reata has made significant advancements developing therapeutics that regulate cellular metabolism and inflammation in serious neurologic diseases. Reata’s FDA-approved SKYCLARYS® (omaveloxolone) is the first and only approved treatment for Friedreich’s ataxia (FA) in the United States, with a commercial launch underway, and European regulatory review ongoing. In addition, Reata is developing a portfolio of innovative products for a range of neurological diseases.