Creigh, P. D., Mountain, J. , Sowden, J. E., Eichinger, K. , Ravina, B. , Larkindale, J. and Herrmann, D. N. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50865
MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.
Saturday, August 17, 2019
Exicure, Inc.Announced important preclinical data supporting development of SNA technology in the central nervous system (CNS)
Exicure, Inc. (Nasdaq: XCUR), 8 Aug 2019, pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA™) constructs, today reported financial results for the second quarter ended June 30, 2019 and provided an update on corporate progress.
The first half of 2019 continued to bring advancements across our pipeline,”said Dr. David Giljohann, Exicure’s chief executive officer. “We are extremely pleased with the strong progress in both our neurology and oncology franchises, while we simultaneously strengthened our board leadership and balance sheet. Our non-human primate data confirmed our enthusiasm for neurological applications of our SNA platform. Our recent $63.3 million public offering, which closed on August 2, 2019 provides the financial resources to advance these opportunities,” he added.
Presented results from a biodistribution study of SNAs in the CNS of non-human primates.
SNAs were observed in all 46 regions of the brain examined.
Preclinical research underway in indications including Huntington’s disease, spinocerebellar ataxia type 3 (SCA3), SCA2, SCA1, Friedreich's ataxia and Batten disease.
Expect to nominate first candidate for neurological conditions late in 2019.
The first half of 2019 continued to bring advancements across our pipeline,”said Dr. David Giljohann, Exicure’s chief executive officer. “We are extremely pleased with the strong progress in both our neurology and oncology franchises, while we simultaneously strengthened our board leadership and balance sheet. Our non-human primate data confirmed our enthusiasm for neurological applications of our SNA platform. Our recent $63.3 million public offering, which closed on August 2, 2019 provides the financial resources to advance these opportunities,” he added.
Presented results from a biodistribution study of SNAs in the CNS of non-human primates.
SNAs were observed in all 46 regions of the brain examined.
Preclinical research underway in indications including Huntington’s disease, spinocerebellar ataxia type 3 (SCA3), SCA2, SCA1, Friedreich's ataxia and Batten disease.
Expect to nominate first candidate for neurological conditions late in 2019.
Thursday, August 15, 2019
Mitochondrial disorders and drugs: what every physician should know
Orsucci D, Caldarazzo Ienco E, Siciliano G, Mancuso M.; Drugs in Context 2019; 8: 212588. DOI: 10.7573/dic.212588
In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.
In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.
Wednesday, August 14, 2019
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
Natalia Robledinos-Antón, Raquel Fernández-Ginés, Gina Manda, and Antonio Cuadrado, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9372182, 20 pages, 2019. doi:10.1155/2019/9372182.
Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.
Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.
Tuesday, August 13, 2019
Compassionate use of human recombinant insulin-like growth factor-1 therapy in Friedreich's ataxia
García Ron A, Rodriguez Mesa M. , Compassionate use of human recombinant insulin-like growth factor-1 therapy in Friedreich's ataxia del tratamiento como uso compasivo de mecasermina (factor de crecimiento insulínico recombinante humano tipo 1) en ataxia de Friedreich. Neurología. 2019. doi:10.1016/j.nrl.2017.11.004
As no curative treatment is currently available for FA, we believe that any drug potentially capable of halting or delaying disease progression without causing severe adverse effects merits further research. Further randomised controlled trials are needed to confirm the benefits obtained in our case, to try to determine the action mechanism of rhIGF-1, and to establish what can be expected during the long-term treatment of this and other neurodegenerative diseases.
As no curative treatment is currently available for FA, we believe that any drug potentially capable of halting or delaying disease progression without causing severe adverse effects merits further research. Further randomised controlled trials are needed to confirm the benefits obtained in our case, to try to determine the action mechanism of rhIGF-1, and to establish what can be expected during the long-term treatment of this and other neurodegenerative diseases.
Sunday, August 11, 2019
Exploring the Potential of Small Molecule-Based Therapeutic Approaches for Targeting Trinucleotide Repeat Disorders
Arun Kumar Verma & Eshan Khan & Sonali R. Bhagwat & Amit Kumar; Mol Neurobiol (2019). doi:10.1007/s12035-019-01724-4
In recent years, neurological disorders have globally become a leading cause of disability and death. Neurological disorders are very common in both high- and low-income countries, and the number of patients is predicted to increase in the coming decades. Disorders caused by the expanded trinucleotide repeats (CAG, CGG, CCG, CTG, CUG, GAA, and GCN) in the genome, also described as trinucleotide repeat expansion disorders (TREDs), comprise of the major class of neurological diseases. Various TREDs have different modes of pathogenesis, but the severity and time of onset of disease depends on the trinucleotide repeat numbers. Numerous therapeutic strategies, including symptomatic treatment, blockage of mutant protein synthesis, targeting the toxic protein aggregates and degradation of RNA transcripts have been developed for the treatment of these diseases. However, various limitations to these therapeutic strategies have been reported, and therefore, researchers are exploring different avenues of therapeutics development. One of the recent developments include targeting the expanded repeats with small molecules. Small molecule binds with the secondary/tertiary structure of RNA (like bulges, loops, and hairpins) irrespective of its sequences. Altogether, small molecule-based therapeutics may have the advantage over others to be able to overcome the hurdles of the blood–brain barrier, poor absorption, and allergic reactions. In this review, we have summarized various TREDs and envisage the potential of small molecule-based therapeutics for targeting these hitherto incurable neurological disorders.
In recent years, neurological disorders have globally become a leading cause of disability and death. Neurological disorders are very common in both high- and low-income countries, and the number of patients is predicted to increase in the coming decades. Disorders caused by the expanded trinucleotide repeats (CAG, CGG, CCG, CTG, CUG, GAA, and GCN) in the genome, also described as trinucleotide repeat expansion disorders (TREDs), comprise of the major class of neurological diseases. Various TREDs have different modes of pathogenesis, but the severity and time of onset of disease depends on the trinucleotide repeat numbers. Numerous therapeutic strategies, including symptomatic treatment, blockage of mutant protein synthesis, targeting the toxic protein aggregates and degradation of RNA transcripts have been developed for the treatment of these diseases. However, various limitations to these therapeutic strategies have been reported, and therefore, researchers are exploring different avenues of therapeutics development. One of the recent developments include targeting the expanded repeats with small molecules. Small molecule binds with the secondary/tertiary structure of RNA (like bulges, loops, and hairpins) irrespective of its sequences. Altogether, small molecule-based therapeutics may have the advantage over others to be able to overcome the hurdles of the blood–brain barrier, poor absorption, and allergic reactions. In this review, we have summarized various TREDs and envisage the potential of small molecule-based therapeutics for targeting these hitherto incurable neurological disorders.
Saturday, August 10, 2019
Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes
Jixue Li, Natalia Rozwadowska, Amanda Clark, Daniel Fil, Jill S. Napierala, Marek Napierala; Stem Cell Research, 2019, 101529, doi:10.1016/j.scr.2019.101529.
Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.
Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.
Friday, August 9, 2019
Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin
Sylvain Gervason, Djabir Larkem, Amir Ben Mansour, Thomas Botzanowski, Christina S. Müller, Ludovic Pecqueur, Gwenaelle Le Pavec, Agnès Delaunay-Moisan, Omar Brun, Jordi Agramunt, Anna Grandas, Marc Fontecave, Volker Schünemann, Sarah Cianférani, Christina Sizun, Michel B. Tolédano & Benoit D’Autréaux;Nature Communicationsvolume 10, Article number: 3566 (2019), doi:10.1038/s41467-019-11470-9
Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich’s ataxia therapies.
Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich’s ataxia therapies.
Thursday, August 8, 2019
A Collaborative-Filtering-Based Data Collection Strategy for Friedreich’s Ataxia
Wenbin Yue, Zidong Wang, Bo Tian, Annette Payne, Xiaohui Liu. Cogn Comput (2019). doi:10.1007/s12559-019-09674-8
We propose a novel data collection strategy for the FRDA baseline data by using the collaborative filtering (CF) approaches. This strategy is motivated by the popularity of the nowadays “Recommendation System” whose central idea is based on the fact that similar patients have similar symptoms on each test item. By doing so, instead of having no data at all, the FRDA researchers would be provided with certain predicted baseline data on patients who cannot attend the assessments for physical/psychological reasons, thereby helping with the data analysis from the researchers’ perspective. It is shown that the CF approaches are capable of predicting baseline data based on the similarity in test items of the patients, where the prediction accuracy is evaluated based on three rating scales selected from the EFACTS database. Experimental results demonstrate the validity and efficiency of the proposed strategy.
We propose a novel data collection strategy for the FRDA baseline data by using the collaborative filtering (CF) approaches. This strategy is motivated by the popularity of the nowadays “Recommendation System” whose central idea is based on the fact that similar patients have similar symptoms on each test item. By doing so, instead of having no data at all, the FRDA researchers would be provided with certain predicted baseline data on patients who cannot attend the assessments for physical/psychological reasons, thereby helping with the data analysis from the researchers’ perspective. It is shown that the CF approaches are capable of predicting baseline data based on the similarity in test items of the patients, where the prediction accuracy is evaluated based on three rating scales selected from the EFACTS database. Experimental results demonstrate the validity and efficiency of the proposed strategy.
Wednesday, August 7, 2019
Reata gets another shot in Friedreich’s ataxia
EvaluatePharma. August 06, 2019.
Pharmaceuticals will soon find out if its decision to persevere with omaveloxolone despite an earlier failure has paid off.
The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).
Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.
Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.
Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”
Pharmaceuticals will soon find out if its decision to persevere with omaveloxolone despite an earlier failure has paid off.
The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).
Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.
Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.
Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”
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