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.

Friedreich ataxia: clinical features and new developments

Medina Keita, Kellie McIntyre, Layne N Rodden, Kim Schadt, and David R Lynch; Neurodegenerative Disease Management 0 0:0. Published Online:29 Jun 2022 ; doi:10.2217/nmt-2022-0011 

 Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000–100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.

What role can decentralized trial designs play to improve rare disease studies?

Moore, J., Goodson, N., Wicks, P. et al.; Orphanet J Rare Dis 17, 240 (2022). doi:10.1186/s13023-022-02388-5

DCT approaches have been shown to be more resilient to changes in enrolment and attrition during COVID-19 than traditional designs and offer benefits in terms of patient burden, convenience, inclusion, and data quality. Digital tools such as wearable devices and electronic clinical outcome assessments may also provide more convenient and environmentally valid measures of how a condition affects the life of an individual in their regular environment (e.g. mobility around the home versus a hospital corridor). Digital solutions have greater ability to support language localization, accessibility, and may lead to increase access to global rare disease trials. In parallel, challenges exist, such as the technical support, the digital divide, ensuring high quality data, and delivering safe trials.

Discovery of Therapeutics Targeting Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic Review

Lew, S.Y.; Phang, M.W.L.; Chong, P.S.; Roy, J.; Poon, C.H.; Yu, W.S.; Lim, L.W.; Wong, K.H.; Pharmaceuticals 2022, 15, 764. doi:10.3390/ph15060764 

We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.