Importance of an echocardiogram in the evaluation of ataxia

Stokreef S, Lemos M, Quintas S.; BMJ Case Reports CP 2022;15:e248691. doi:10.1136/bcr-2021-248691

We present the case of a boy in his middle childhood with gait ataxia and loss of reflexes with a 1-year onset. He had a background of an autism spectrum disorder but was otherwise healthy. A paediatric cardiology assessment was requested to investigate possible cardiac involvement associated to his neurological symptoms. Even though he had no cardiac symptoms and a normal electrocardiography, the echocardiogram revealed severe asymmetric left ventricle hypertrophy consistent with hypertrophic cardiomyopathy. This prompted genetic testing and the diagnosis of Friedreich’s ataxia was confirmed.

Unleashing the potential of AAV gene therapy

Biopharma Dealmakers (Biopharm Deal). 18/7/2022.

Voyager Therapeutics is unlocking the potential of adeno-associated virus gene therapy to treat a range of neurological disorders, broadening the therapeutic window while ensuring efficacy and safety. The company has already secured capsid option and license agreements with Novartis and Pfizer for target-specific use with CNS and cardiac muscle targets. Voyager also has an ongoing collaboration with Neurocrine Biosciences on a preclinical Friedreich’s ataxia (FA) program and two undisclosed discovery programs in which the company’s novel capsids may be deployed.

SCouT: Synthetic Counterfactuals via Spatiotemporal Transformers for Actionable Healthcare

Bhishma Dedhia, Roshini Balasubramanian, Niraj K. Jha; arXiv:2207.04208v1 [cs.AI] for this version); doi:10.48550/arXiv.2207.04208 (Computer Science > Artificial Intelligence)

We also generate actionable healthcare insights at the population and patient levels by simulating a state-wide public health policy to evaluate its effectiveness, an in silico trial for asthma medications to support randomized controlled trials, and a medical intervention for patients with Friedreich's ataxia to improve clinical decision-making and promote personalized therapy.

We simulate synthetic counterfactuals under a Calcitriol supplement intervention for a Friedreich’s ataxia (FA) patient.

Cardiovascular Research in Friedreich Ataxia

R. Mark Payne; J Am Coll Cardiol Basic Trans Science. null2022, 0 (0); doi:10.1016/j.jacbts.2022.04.005

Patients can develop a cardiomyopathy associated with heart failure and death. • A single gene defect decreases expression of FXN and may be amenable to therapy. • A need exists for greater basic and clinical investigations to advance therapies.

Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation

Imbault, Virginie; Dionisi, Chiara; Naeije, Gilles; Communi, David; Pandolfo, Massimo (2022). Frontiers. Collection. doi:10.3389/fnins.2022.885313 

This study supports the hypothesis that the quantitative analysis CSF proteins may provide robust biomarkers for clinical trials as well as shed light on pathogenic mechanisms. Interestingly, DEPs in FA patients CSF point to neurodegeneration and neuroinflammation processes that may respond to treatment.

EE146 Cost and Resource Utilization in Friedreich Ataxia: A Systematic Literature Review

R Zhang, K Buesch; Value in Health, Volume 25, Issue 7, Supplement, 2022, Page S363, doi:10.1016/j.jval.2022.04.396. 

The search retrieved 57 studies, of which 5 fulfilled the eligibility criteria. Among these, 2 reported resource utilization, and 5 reported cost data. No economic evaluation was identified. Neurologists and cardiologists were the most frequently visited physicians, seen by 61-86% and 57-86% of FA patients, respectively. About 23-46% of FA patients were hospitalized for an average of 5-9 days per year. Mean annual direct medical and non-medical cost per patient ranged from £8.893 in the UK to...

CO49 Clinical Efficacy and Safety of Therapeutic Interventions Used in Friedreich Ataxia: A Systematic Review

P Jain, L Badgujar, JA Spoorendonk, K Buesch; Value in Health, Volume 25, Issue 7, Supplement, 2022, Pages S312-S313, doi:10.1016/j.jval.2022.04.147. 

 In total, 32 relevant publications were identified, of which 24 were randomized controlled trials. These publications investigated idebenone (n=11), recombinant erythropoietin (n=6), omaveloxolone (n=3), amantadine hydrochloride (n=2), and A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, L-cartinine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, vatiquinone (all n=1). Age of study participants ranged from 8 to 73 years and disease duration ranged from 4 to 19.

Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design

Christian Rummey, Louise A Corben, Martin Delatycki, George Wilmot, Sub H Subramony, Manuela Corti, Khalaf Bushara, Antoine Duquette, Christopher Gomez, J Chad Hoyle, Richard Roxburgh, Lauren Seeberger, Grace Yoon, Katherine Mathews, Theresa Zesiewicz, Susan Perlman, David R Lynch; Neurology Jul 2022, 10.1212/WNL.0000000000200913; DOI: 10.1212/WNL.0000000000200913

Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

Rare motor disorder: International study investigates living situation of people with Friedreich’s Ataxia

AAAS and EurekAlert. NEWS RELEASE 11-JUL-2022 DZNE - GERMAN CENTER FOR NEURODEGENERATIVE DISEASES 

The study aims to investigate and evaluate the health-related, psychosocial and economic impacts of the disease. The results of the interdisciplinary project, which combines clinical expertise with expertise in health economics, health care research and psychosocial research, are intended to provide a basis for improving treatment, care and support. In this project, the DZNE works closely with international partners from France (Paris Brain Institute) and Canada (McMaster University) as well as with the healthtech company Aparito and various European university hospitals. "PROFA" is being carried out in six study centers in Europe. It is planned that more than 200 patients aged 12 years and older will participate in the study.

셀리버리 “올해 코로나19·아토피 2상 진입 기대…무증 적절”

[KBIC 2022] 조대웅 대표 발표 

프리드리히 운동실조증(FRDA) 치료제 ‘AAV-FXN-aMTD‘는 TSDT를 적용한 세포·조직투과성 aMTD-융합 Frataxin(FXN) 재조합단백질이다. 조 대표는 “현재 다케다 제약과 공동 연구개발을 진행하고 있다”며 “3단계 마일스톤 효능평가를 미국에서 진행하고 있으며, 기술이전 협의도 동시에 진행 중”이라고 했다.

HTA decision-making for drugs for rare diseases: comparison of processes across countries

Tania Stafinski, Judith Glennie, Andrea Young & Devidas Menon; Orphanet J Rare Dis 17, 258 (2022). doi:10.1186/s13023-022-02397-4 

There is no “magic bullet” solution to address the challenges inherent in the HTA evaluation and reimbursement of DRDs. A variety of approaches are being used by different jurisdictions to address the evaluation of DRDs, in additional to various mechanisms for enabling reimbursement and patient access. As reimbursement and pricing processes for DRDs are being revisited in Canada, the insights gleaned related to stakeholder engagement, the collection of robust real-world data to support innovative reimbursement schemes, and the role that different financing models could play in efforts to achieve equitable access should be considered.

A Phase 1/2 Study of the Safety and Efficacy of LX2006 Gene Therapy in Participants With Cardiomyopathy Associated With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT05445323; Sponsor: Lexeo Therapeutics

Intervention/treatment: 

Genetic: Low dose LX2006 Adeno-associated viral vector encoding the FXN gene (AAVrh.10hFXN) Genetic: High Dose LX2006 Adeno-associated viral vector encoding the FXN gene (AAVrh.10hFXN)

Large-scale expansions of Friedreich′s ataxia GAA·TTC repeats in human cells are prevented by LNA-DNA oligonucleotides and PNA oligomers

Anastasia Rastokina, Negin Mozafari, Jorge Cebrian, Edvard Smith, Sergei M. Mirkin, Rula Zain; bioRxiv 2022.07.04.498742; doi:10.1101/2022.07.04.498742 

The human disease Friedreich′s ataxia (FRDA) is caused by expansions of GAA·TTC repeats in the first intron intron of the frataxin (FXN) gene, and both intergenerational and somatic expansions are crucial for disease development. We and others have shown earlier that expanded GAA·TTC repeats can form an intramolecular triplex structure (H-DNA). Here we studied the effects of locked nucleic acid (LNA)-DNA mixmer oligonucleotides and peptide nucleic acid (PNA) oligomers on the expansion of GAA·TTC repeats in cultured human cells. Our experimental system employes a mammalian/yeast shuttle plasmid containing a selectable cassette to detect repeat expansions. Using our in-house in vitro triplex-specific DNA cleavage assay, we first confirmed H-DNA formation by the (GAA)100·(TTC)100 repeat in the selectable cassette and demonstrated that the designed LNA-DNA oligonucleotides as well as PNA oligomers are able to disrupt this structure. We then found that both LNA-DNA mixmers and PNA oligomers prevent repeat expansions in human cells. In the accompanying paper, we show that expansions of GAA·TTC repeats in this experimental system occur during replication fork stalling, regression and restart at the repetitive run. We hypothesize, therefore, that triplex DNA formation by the GAA·TTC repeats is a key to their instability, while LNA-DNA oligonucleotides and PNA oligomers counteract repeat expansions by disrupting the triplex at the fork or preventing triplex formation upon fork reversal.

Efficacy of plant extracts against Friedreich’s ataxia

Magisetty Obulesu, Plant Extracts in Neurodegenerative Diseases, Academic Press, Chapter 4, Pages 47-60, 2022, doi:10.1016/B978-0-323-95762-5.00006-0.

Friedreich’s ataxia (FA) is a rare neurodegenerative disease (ND). Its prevalence is usually found in those of Indo-European and Afro-Asiatic origin. Frataxin (FXN), a low-molecular-weight protein of 23kDa found in mitochondria, plays a pivotal role in the etiopathogenesis of FA. Therefore, a wide array of therapeutics has been targeted at FXN. This chapter throws light on multifarious therapeutics employed to combat FA in cell and animal models and human subjects. A few possible mechanistic roles of plant-based compounds and dietary ingredients have been discussed. It also emphasizes the pitfalls in current therapeutics that need more attention. 

Clinical and Molecular Spectrum of Degenerative Cerebellar Ataxia: A Single Centre Study

Balakrishnan S, Aggarwal S, Muthulakshmi M, Meena AK, Borgohain R, Mridula KR, Yareeda S, Ranganath P, Dalal A.  Neurol India 2022;70:934-42 DOI: 10.4103/0028-3886.349660 

SCA 1, 2, 3 and FRDA were the most common causes of ataxia. SCA 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. NGS testing revealed several rare forms of ataxia. Clinical features based testing is cost-effective, achieves good genotype-phenotype correlation, and prioritizes variants for further studies.

Safety and pharmacokinetics of a highly bioavailable resveratrol preparation (JOTROL TM)

Kemper, Christopher; Benham, Dariush; Brothers, Shaun; Wahlestedt, Claes; Volmar, Claude-Henry; Bennett, Daniel; et al. (2022). figshare. Collection. doi:10.6084/m9.figshare.c.6074992.v1 

This paper describes a first in human study (FIH) to evaluate the bioavailability of resveratrol after ascending, single oral doses up to 700 mg resveratrol as JOTROLTM. After a single 500 mg dose of JOTROLTM, a Cmax of 455 ng/mL was observed, vs. 85 ng/mL Cmax after a 1 g encapsulated dose (Turner et al., Neurology 85:1383-91, 2015) and 1942 ng/mL after a 2.5 g micronized dose (Howells et al., Cancer Prev Res (Phila) 4:1419-1425, 2011). In this study, resveratrol exposures (AUCs and Cmax) increased with increasing doses. This increase appears to be higher than dose-proportional for AUC0-t and Cmax. Resveratrol and its three major conjugates accounted for 40 to 55% of the dose in urine, consistent with a high extent of absorption, but < 1% of drug-related material was intact relative to key metabolites in plasma and urine.