Identifying project topics and requirements in a citizen science project in rare diseases: a participative study

Michaela Neff, Holger Storf, Jessica Vasseur, Jörg Scheidt, Thomas Zerr, Andreas Khouri & Jannik Schaaf. Orphanet J Rare Dis 17, 357 (2022). doi:10.1186/s13023-022-02514-3 

Due to their low prevalence (< 5 in 10,000), rare diseases are an important area of research, with the active participation of those affected being a key factor. In the Citizen Science project “SelEe” (Researching rare diseases in a citizen science approach), citizens collaborate with researchers using a digital application, developed as part of the project together with those affected, to answer research questions on rare diseases. The aim of this study was to define the rare diseases to be considered, the project topics and the initial requirements for the implementation in a digital application.

Advancing qualitative rare disease research methodology: a comparison of virtual and in-person focus group formats

Andrew A. Dwyer, Melissa Uveges, Samantha Dockray & Neil Smith; Orphanet J Rare Dis 17, 354 (2022). doi:10.1186/s13023-022-02522-3 

Geographically dispersed patients have posed significant roadblocks for rare disease research resulting in small sample sizes and underpowered studies. As rare disease patients have been referred to as internet “power users”, web-enabled technologies hold promise for reaching dispersed rare disease patients and surmounting geographic barriers for many. To our knowledge, the present study is the first to support the validity of virtual focus groups for qualitative rare disease research. Moreover, the present findings suggest the anonymity afforded by the internet can facilitate discussion of highly sensitive and intimate topics. This observation is important as feelings of stigma and shame are frequently experienced by patients living with a rare disease—particularly in a condition like CHH that has a psychosexual/sexual health component. The present findings support methodologic rigor of using web-enabled technologies for qualitative research using focus groups in rare diseases.

A promissing mouse model for Friedreich Ataxia progressing like human patients

Catherine Gérard, Annabelle Fortin Archambault, Camille Bouchard, Jacques P. Tremblay; Behavioural Brain Research, 2022, 114107, doi:10.1016/j.bbr.2022.1141

Jackson Laboratories Inc. developed a new mouse model that has 800 GAA repeats. We demonstrate here that these mice accurately reflect the human disease with a progressive neuromuscular degeneration highlighted by the two beam tests and the beginning of heart hypertrophy at 26 weeks. YG8-800 mice are thus currently a promising mouse model for FRDA.

Larimar Therapeutics Announces FDA Clearance to Initiate the 25 mg Cohort of a Phase 2 Dose Exploration Trial of CTI-1601 in Friedreich’s Ataxia Patients

BALA CYNWYD, Pa., Sept. 14, 2022 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) today announced that the U.S. Food and Drug Administration (FDA) has cleared the initiation of the 25 mg cohort of a Phase 2, four-week, placebo-controlled, dose exploration trial of CTI-1601 in Friedreich’s ataxia (FA) patients. In a written communication to Larimar, the FDA indicated it was lifting its full clinical hold on the CTI-1601 program and imposing a partial hold. The design of the upcoming Phase 2 trial is identical to the design proposed by Larimar, with the exception of a requirement for the FDA to review data from the 25 mg cohort prior to escalating the dose in the second cohort. Larimar expects to begin the Phase 2 trial in Q4 2022, with top-line data expected in 2H 2023.

The C-Terminal Cross-linked Telopeptide of Type I Collagen (CTX-I) as a Potential Cardiomyopathy Biomarker in Friedreich Ataxia Patients

Chiara Pane, Assunta Trinchillo, Andrea Salzano, Angela Marsili, Giorgia Puorro, Antonio Cittadini, Francesco Saccà & Cinzia Valeria Russo; Cerebellum (2022). doi:10.1007/s12311-022-01475-4 

CTX-I, a biomarkers of collagen turnover, is elevated in FRDA and should provide complementary information to identify patients with high cardiological risk even if longitudinal studies are needed to define the role of this serologic marker of collagen metabolism in the natural history of cardiomyopathy in FRDA patients.

A non-synonymous single nucleotide polymorphism in SIRT6 predicts neurological severity in Friedreich ataxia

Rodden LN, Rummey C, Dong YN, Lagedrost S, Regner S, Brocht A, Bushara K, Delatycki MB, Gomez CM, Mathews K, Murray S, Perlman S, Ravina B, Subramony SH, Wilmot G, Zesiewicz T, Bolotta A, Domissy A, Jespersen C, Ji B, Soragni E, Gottesfeld JM and Lynch DR; (2022). Front. Mol. Biosci. 9:933788. doi: 10.3389/fmolb.2022.933788

People with FRDA in the CT SIRT6 group have less severe neurological and visual dysfunction than those in the TT SIRT6 group. Biochemical analyses indicate that the benefit conferred by T to C SNP in SIRT6 does not come from altered expression or enzymatic activity of SIRT6 or frataxin but is associated with changes in the transcriptome.

Hyperactivation of mTOR and AKT in a cardiac hypertrophy animal model of Friedreich ataxia

Wing-Hang Tong, Hayden Ollivierre, Audrey Noguchi, Manik C. Ghosh, Danielle A. Springer, Tracey A. Rouault; Heliyon, Volume 8, Issue 8, 2022. 

 We observed increased phosphorylation of AKT and dysregulation of multiple downstream effectors of mTORC1, including S6K1, S6, ULK1 and 4EBP1, in a cardiac/skeletal muscle specific FRDA conditional knockout (cKO) mouse model and in human cell lines depleted of ISC biogenesis factors.

Respiratory Function in Friedreich’s Ataxia

Vinante, E.; Colombo, E.; Paparella, G.; Martinuzzi, M.; Martinuzzi, A. Children 2022, 9, 1319. https://doi.org/10.3390/children9091319

Respiratory function is impaired at various degrees in FRDA. The complex condition of inco-ordination and hyposthenia in FRDA affects daytime and night-time respiratory efficiency. We believe that the respiratory deficit and the inefficiency of cough are indeed a clinical problem deserving consideration, especially in the context of the concomitant postural difficulty and the possible presence of dysphagia. Therefore, the rehabilitation project for the subject with FRDA should also consider the respiratory function.

Preservation of bioenergetics and inhibition of ferroptosis with the novel compound SBT-588 in Friedreich’s ataxia cell models

Laura E. Kropp, Hatim Zariwala, Yunmi Park, Martin Redmon, David A. Brown, Alyssa Handler; Biochimica et Biophysica Acta (BBA) - Bioenergetics, Volume 1863, Supplement, 2022, doi:10.1016/j.bbabio.2022.148869.

Frataxin deficiency disrupts mitochondrial respiration and pulmonary endothelial cell function

Miranda K Culley, Monica Mehta, Jingsi Zhao, Dror Perk, Yi Yin Tai, Ying Tang, Sruti Shiva, Marlene Rabinovitch, Mingxia Gu, Thomas Bertero, Stephen Y Chan; bioRxiv 2022.08.22.504849; doi:org/10.1101/2022.08.22.504849

Our data highlight an Fe-S-driven metabolic shift separate from previously described replication stress whereby FXN knockdown diminished mitochondrial respiration and increased glycolysis and oxidative species production. In turn, FXN-deficient endothelial cells exhibited a vasoconstrictive phenotype consistent with PH. These data were observed in both primary pulmonary endothelial cells after pharmacologic inhibition of FXN and inducible pluripotent stem cell-derived endothelial cells from patients with FXN mutations. Altogether, this study defines FXN as a shared upstream driver of pathologic aberrations in both metabolism and genomic stability. Moreover, our study highlights FXN-specific vasoconstriction, suggesting available and future therapies may be beneficial and targeted for PH subtypes with FXN deficiency.