Mikhail S. Shchepinov, Trends in Pharmacological Sciences, 2020, doi:10.1016/j.tips.2020.01.010.
Regioselective deuteration that reinforces oxidation-prone, bis-allylic sites of PUFAs is a novel, nonantioxidant treatment modality that dramatically reduces LPO, potentially mitigating numerous diseases through preservation of membrane properties and amelioration of oxidative stress. Animal disease models and several ongoing human clinical trials highlight the potential of the deuterated-PUFA (D-PUFA) drug candidates currently in development.
Thursday, March 5, 2020
Wednesday, March 4, 2020
Identification of Frataxin as a regulator of ferroptosis
Jing Du, Yi Zhou, Yanchun Li, Jun Xia, Yongjian Chen, Sufeng Chen, Xin Wang, Weidong Sun, Tongtong Wang, Xueying Ren, Xu Wang, Yihan An, Kang Lu, Wanye Hu, Siyuan Huang, Jianghui Li, Xiangmin Tong, Ying Wang; Redox Biology, 2020, 101483, doi:10.1016/j.redox.2020.101483.
This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
This paper suggests that FXN is a novel ferroptosis modulator, as well as a potential provided target to improve the antitumor activity based on ferroptosis.
Tuesday, March 3, 2020
An Overview of the Current State and the Future of Ataxia Treatments
Kimberly Tsu Kwei, Sheng-Han Kuo; Neurologic Clinics, 2020, doi:10.1016/j.ncl.2020.01.008.
Keywords: Cerebellum; Ataxia; Multiple system atrophy; Spinocerebellar ataxia; Friedreich ataxia; Ataxia treatment
Keywords: Cerebellum; Ataxia; Multiple system atrophy; Spinocerebellar ataxia; Friedreich ataxia; Ataxia treatment
Sunday, March 1, 2020
Epigenetic regulation of clinical manifestations of Friedreich's disease
Nuzhny EP, Abramycheva NY, Nikolaeva NS, Ershova MV, Klyushnikov SA, Illarioshkin SN, Fedotova EY.; Zh Nevrol Psikhiatr Im S S Korsakova. 2020;120(1):20-26. doi: 10.17116/jnevro202012001120. [Article in Russian; Abstract available in Russian from the publisher]
Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed.
Correlations between the methylation level of CpG-sites in UP-GAA and DOWN-GAA and the number of GAA repeats in both expanded FXN alleles in patients with FD were found. An analysis revealed an earlier onset and a more severe course of FD in cases with hypermethylation of several CpG-sites in the UP-GAA region. The correlation between the methylation pattern and the presence of extraneural manifestations of FD was also revealed. In FD patients with cardiomyopathy, a hypomethylated CpG-site in the promoter region was found. In FD patients with carbohydrate metabolism disorders, two hypomethylated CpG-sites in the DOWN-GAA region were observed.
Sunday, February 23, 2020
Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases
Perez, B.A.; Shutterly, A.; Chan, Y.K.; Byrne, B.J.; Corti, M.; Brain Sci. 2020, 10, 119; doi:10.3390/brainsci10020119 (registering DOI)
Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.
Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.
Monday, February 17, 2020
A Phase 2 Clinical Trial to Test the Safety and Efficacy of Etravirine in Friedreich Ataxia Patients (FAEST1)
ClinicalTrials.gov Identifier: NCT04273165. February 17, 2020, Sponsor: IRCCS Eugenio Medea, Collaborator: University of Rome Tor Vergata.
A drug repositioning effort provided evidence supporting the possible use of Etravirine, a drug approved for the treatment of HIV infections in patients starting from 2 years of age, as a treatment for FA. We found that Etravirine is able to increase Frataxin protein both in vitro - in cells derived from FA patients - and in vivo - in the heart and skeletal muscle of Frataxin-deficient YG8 mice. Because of these findings, and since Etravirine displays a generally favorable safety profile, we plan to launch an open-label, phase 2 clinical trial aimed at assessing the safety and efficacy of Etravirine in FA patients. We aim at recruiting 30 FA patients. 15 will be treated with Etravirine for 4 months at 200 mcg/day and 15 will be treated with Etravirine for 4 months at 400 mg/day. Efficacy primary endpoint will be represented changes in peak VO2 as measured by incremental cycle ergometer exercise test. Secondary endpoints will include maximal workload, SARA score, cardiac measures, Frataxin protein levels in peripheral blood mononuclear cells and molecular analysis of Frataxin mRNA translation efficiency. Complete sets of data will be collected 4 months before the start of the treatment (T -4), at the start (T0), after 2 months (T2), at the end of the treatment (T4) and 4 months after the termination of the treatment (T8).
A drug repositioning effort provided evidence supporting the possible use of Etravirine, a drug approved for the treatment of HIV infections in patients starting from 2 years of age, as a treatment for FA. We found that Etravirine is able to increase Frataxin protein both in vitro - in cells derived from FA patients - and in vivo - in the heart and skeletal muscle of Frataxin-deficient YG8 mice. Because of these findings, and since Etravirine displays a generally favorable safety profile, we plan to launch an open-label, phase 2 clinical trial aimed at assessing the safety and efficacy of Etravirine in FA patients. We aim at recruiting 30 FA patients. 15 will be treated with Etravirine for 4 months at 200 mcg/day and 15 will be treated with Etravirine for 4 months at 400 mg/day. Efficacy primary endpoint will be represented changes in peak VO2 as measured by incremental cycle ergometer exercise test. Secondary endpoints will include maximal workload, SARA score, cardiac measures, Frataxin protein levels in peripheral blood mononuclear cells and molecular analysis of Frataxin mRNA translation efficiency. Complete sets of data will be collected 4 months before the start of the treatment (T -4), at the start (T0), after 2 months (T2), at the end of the treatment (T4) and 4 months after the termination of the treatment (T8).
Friday, February 14, 2020
Instrumented Data Exchange for Ataxia Study (IDEA)
ClinicalTrials.gov Identifier: NCT04268147. Sponsor: University of Chicago. Collaborators: Pfizer, Biogen, APDM Wearable Technologies.
This research study is testing body-worn sensors to measure movement during simple tests of coordination, in order to evaluate the progression and severity of ataxia.
Condition or disease: Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia Type 3, Spinocerebellar Ataxia Type 6, Friedreich Ataxia.
This research study is testing body-worn sensors to measure movement during simple tests of coordination, in order to evaluate the progression and severity of ataxia.
Condition or disease: Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia Type 3, Spinocerebellar Ataxia Type 6, Friedreich Ataxia.
Tuesday, February 11, 2020
Loss of mitochondrial localization of human FANCG causes defective FANCJ helicase
Sudit S Mukhopadhyay, Jagadeesh Chandra Bose K, Bishwajit Singh Kapoor, Kamal Mandal, Subhrima Ghosh, Raveendra B Mokhamatam, Sunil K Manna; bioRxiv 2020.01.15.907303; doi:10.1101/2020.01.15.907303
Mitochondrial instability in the FANCGR22P cell causes the transcriptional down-regulation of mitochondrial iron-sulphur cluster biogenesis protein Frataxin (FXN) and resulting iron deficiency of FA protein FANCJ, an iron-sulphur containing helicase involved in DNA repair.
Despite of DNA repair ability the Fanconi anemia mutant protein FANCGR22P destabilizes mitochondria and leads to genomic instability via FANCJ helicase . Preprint from bioRxiv, 15 Jan 2020
DOI: 10.1101/2020.01.15.907303
Mitochondrial instability in the FANCGR22P cell causes the transcriptional down-regulation of mitochondrial iron-sulphur cluster biogenesis protein Frataxin (FXN) and resulting iron deficiency of FA protein FANCJ, an iron-sulphur containing helicase involved in DNA repair.
Despite of DNA repair ability the Fanconi anemia mutant protein FANCGR22P destabilizes mitochondria and leads to genomic instability via FANCJ helicase . Preprint from bioRxiv, 15 Jan 2020
DOI: 10.1101/2020.01.15.907303
Monday, February 10, 2020
NAD+ therapy in age-related degenerative disorders: A benefit/risk analysis
Nady Braidy, Yue Liu; Experimental Gerontology, 2020, 110831, doi:10.1016/j.exger.2020.110831.
While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.
NOTE: NAD+ and Exercise in FA (ExRx in FA)
While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.
NOTE: NAD+ and Exercise in FA (ExRx in FA)
Sunday, February 9, 2020
The Potential of the Novel NAD+ Supplementing Agent, SNH6, as a Therapeutic Strategy for the Treatment of Friedreich’s Ataxia
Shannon Chiang, Danuta S. Kalinowski, Mahendiran Dharmasivam, Nady Braidy, Des R. Richardson, Michael L.-H. Huang, Pharmacological Research, 2020, 104680, doi:10.1016/j.phrs.2020.104680
SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.
SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD+ and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties.
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