The power and the promise of CRISPR/Cas9 genome editing for clinical application with gene therapy

Ning Guo, Ji-Bin Liu, Wen Li, Yu-Shui Ma, Da Fu; Journal of Advanced Research, Volume 40, 2022, Pages 135-152, doi:10.1016/j.jare.2021.11.018. 

CRISPR/Cas9 also provides a possible therapeutic strategy for Friedreich's ataxia (FRDA). For example, removing the GAA expansions of the frataxin gene (FXN) in vitro and in vivo alleviates related symptoms dramatically but with some unexpected side effects like p53-mediated cell proliferation delay.

A Study to Assess the Safety and Efficacy of Vatiquinone in Participants With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05515536

The primary objective of this study is to assess the long-term safety of vatiquinone in participants with Friedreich ataxia (FA) previously exposed to vatiquinone in Study PTC743-NEU-003-FA (NCT04577352) or Study PTC743-NEU-005-FA

Phase 3 

Study Type : Interventional (Clinical Trial) 

Estimated Enrollment : 140 participants 

Allocation: N/A 

Intervention Model: Single Group Assignment 

Masking: None (Open Label) 

Primary Purpose: Treatment 

Official Title: Long-Term Open-Label Study to Assess the Safety and Efficacy of Vatiquinone in Patients With Friedreich Ataxia 

Estimated Study Start Date : November 1, 2022 

Estimated Primary Completion Date : December 31, 2027 

Estimated Study Completion Date : December 31, 2027

Consideration of oral health in rare disease expertise centres: a retrospective study on 39 rare diseases using text mining extraction method

Friedlander, L., Vincent, M., Berdal, A. et al.; Orphanet J Rare Dis 17, 317 (2022). doi:10.1186/s13023-022-02467-7 

Five networks we studied fill in the patient database while their phenotypes predict that dental and oral phenotypes may raise difficulties. The analysis of the collected data suggests a lack of connection with oral professionals during early childhood and adult transition. These networks are BRAIN-TEAM with Friedreich ataxia (Rare diseases with motor or cognitive expression of the central nervous system)......

Resveratrol from Dietary Supplement to a Drug Candidate: An Assessment of Potential

Khattar, Shivani, Sauban Ahmed Khan, Syed Amir Azam Zaidi, Mahdi Darvishikolour, Uzma Farooq, Punnoth Poonkuzhi Naseef, Mohamed Saheer Kurunian, Mohammed Zaafar Khan, Athar Shamim, Mohd Masih Uzzaman Khan, Zeenat Iqbal, and Mohd. Aamir Mirza. 2022.; Pharmaceuticals 15, no. 8: 957. doi:10.3390/ph15080957

In Australia, RVT as an option for the treatment of Friedreich ataxia was assessed ( NCT01339884, A Study of Resveratrol as Treatment for Friedreich Ataxia, Phase 1, Phase 2)

Perspectives on current models of Friedreich's ataxia

Kelekçi S, Yıldız AB, Sevinç K, Çimen DU, Önder T. Perspectives on current models of Friedreich's ataxia. Frontiers in Cell and Developmental Biology. 2022 ;10:958398. DOI: 10.3389/fcell.2022.958398 

We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

Comorbidities in Friedreich ataxia: incidence and manifestations from early to advanced disease stages

Fichera M, Castaldo A, Mongelli A, Marchini G, Gellera C, Nanetti L, Mariotti C.; Neurol Sci. 2022 Sep 2. doi: 10.1007/s10072-022-06360-w 

 Incidence of FA-related medical conditions varies according to disease duration. In patients with very long disease duration, we observed an unexpectedly high incidence of visual and auditory pseudo-hallucinations that were not previously reported in FA patients. We hypothesized that these late complications may be possibly related to the severe sensory deafferentation syndrome observed in the advanced stages of FA disease.

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence

Hanaford A, Johnson SC. Orphanet Journal of Rare Diseases. 2022 Sep;17(1):335. DOI: 10.1186/s13023-022-02495-3.

Inflammation appears to play a role in the pathogenesis of the mitochondria-associated iron accumulation disease Friedreich ataxia (FRDA). Microgliosis has been reported in the dorsal root ganglia of FRDA patients, a known site of FRDA neuropathology. Microglial activation has also been reported in FRDA patients in brain regions associated with neuropathology using PET scanning for 18F-FEMPA, a high-affinity ligand for the microglia-specific 18-kDa Translocator protein (TPSO). 18F-FEMPA signal intensity correlates with age of disease onset, supporting a causal role for neuroinflammation in FRDA symptoms. FRDA patients also show elevated plasma IL-6, and FRDA patient blood transcriptomic profiles show upregulated innate immune responses.

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.