BALA CYNWYD, Pa., Aug. 3, 2017 /PRNewswire/ -- Chondrial Therapeutics, Inc., an emerging biotechnology company focused on the treatment of rare mitochondrial diseases, announced today that the US Food and Drug Administration (FDA) has granted orphan drug designation to its lead investigational drug candidate, CTI-1601, being developed for the treatment of Friedreich's Ataxia.
Friday, August 4, 2017
Tuesday, August 1, 2017
The importance of international collaboration for rare diseases research: a European perspective
D Julkowska, C P Austin, C M Cutillo, D Gancberg, C Hager, J Halftermeyer, A H Jonker, L P L Lau, I Norstedt, A Rath, R Schuster, E Simelyte and S van Weely; Gene Therapy advance online publication 27 July 2017; doi: 10.1038/gt.2017.29
Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.
Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.
Sunday, July 30, 2017
Impact of diabetes in the Friedreich ataxia clinical outcome measures study
Ashley McCormick, Jennifer Farmer, Susan Perlman, Martin Delatycki, George Wilmot, Katherine Matthews, Grace Yoon, Chad Hoyle, Sub H. Subramony, Theresa Zesiewicz, David R. Lynch and Shana E. McCormack; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.439
DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.
DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.
Saturday, July 22, 2017
Pharmacological therapeutics in Friedreich Ataxia: The present state
Cassandra Strawser, Kimberly Schadt, Lauren Hauser, Ashley McCormick, Mckenzie Wells, Jane Larkindale, Hong Lin & David R Lynch; Expert Review of Neurotherapeutics Vol. 0 , Iss. ja,0, Accepted author version posted online: 20 Jul 2017 doi: 10.1080/14737175.2017.1356721
Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.
Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA. The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.
Friday, July 21, 2017
Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model
Angelical S. Martin, Dennis M. Abraham, Kathleen A. Hershberger, Dhaval P. Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J. Muehlbauer, Paul A. Grimsrud, Jason W. Locasale, R. Mark Payne, and Matthew D. Hirschey, JCI Insight. 2017;2(14):e93885. doi: 10.1172/jci.insight.93885.
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. Our data define a clear role for SIRT3 in mediating the beneficial effects of NMN in this HF model; thus, future studies in the FXN-KO and dKO models would be of interest to evaluate the consequences of manipulating of redox-induced acetylation versus SIRT3-regulated acetylation. These studies include studies dedicated to varying the NMN dosing regimen, as well as acetyl-proteomic analysis of hearts from these NMN-treated mice. Our findings presented here serve as important preclinical data to highlight NMN supplementation and/or SIRT3 agonist treatment as potential therapeutic strategies in FRDA patients and HF.
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich’s ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. Our data define a clear role for SIRT3 in mediating the beneficial effects of NMN in this HF model; thus, future studies in the FXN-KO and dKO models would be of interest to evaluate the consequences of manipulating of redox-induced acetylation versus SIRT3-regulated acetylation. These studies include studies dedicated to varying the NMN dosing regimen, as well as acetyl-proteomic analysis of hearts from these NMN-treated mice. Our findings presented here serve as important preclinical data to highlight NMN supplementation and/or SIRT3 agonist treatment as potential therapeutic strategies in FRDA patients and HF.
Wednesday, July 19, 2017
Interrogating the “unsequenceable” genomic trinucleotide repeat disorders by long-read sequencing
Qian Liu, Peng Zhang, Depeng Wang, Weihong Gu and Kai Wang; Genome Medicine 20179:65 DOI: 10.1186/s13073-017-0456-7
Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably.
In this study, we have developed RepeatHMM to detect repeat counts of microsatellites from long-read sequencing data. RepeatHMM was evaluated on both simulation data and real data and our results suggested that RepeatHMM was effective and efficient to quantify repeat counts. RepeatHMM is flexible to handle repeat patterns of any length beyond trinucleotide repeats and can incorporate different error profiles. With the wider application of long-read sequencing techniques in research and clinical settings, RepeatHMM is expected to contribute to the quantification of repeat counts and to facilitate the analysis of genotype-phenotype relationships for disease-related microsatellites.
Microsatellite expansion, such as trinucleotide repeat expansion (TRE), is known to cause a number of genetic diseases. Sanger sequencing and next-generation short-read sequencing are unable to interrogate TRE reliably.
In this study, we have developed RepeatHMM to detect repeat counts of microsatellites from long-read sequencing data. RepeatHMM was evaluated on both simulation data and real data and our results suggested that RepeatHMM was effective and efficient to quantify repeat counts. RepeatHMM is flexible to handle repeat patterns of any length beyond trinucleotide repeats and can incorporate different error profiles. With the wider application of long-read sequencing techniques in research and clinical settings, RepeatHMM is expected to contribute to the quantification of repeat counts and to facilitate the analysis of genotype-phenotype relationships for disease-related microsatellites.
Wednesday, July 12, 2017
Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients
M. Seco-Cervera, D. González-Rodríguez, J. S. Ibáñez-Cabellos, L. Peiró-Chova, P. González-Cabo, E. García-López, J. J. Vílchez, I. Sanz-Gallego, F. V. Pallardó & J. L. García-Giménez; Scientific Reports 7, Article number: 5237 (2017) doi:10.1038/s41598-017-04996-9
miR-323a-3p as a biomarker for diagnosis of cardiomyopathy in FRDA
Circulating miRNAs can detect pathological events, and could also monitor molecular signals participating in cardiomyopathy even before the appearance of clinical cardiac manifestations. To maximize the likelihood of detecting the onset or progression of cardiomyopathy, we suggest combining standard cardiac diagnostic procedures with the use of circulating microRNAs. This approach could provide more clinical information for evaluating cardiomyopathy progression in FRDA. In summary, miRNAs obtained in this study show new candidates for personalized therapy in FRDA patients.
miR-323a-3p as a biomarker for diagnosis of cardiomyopathy in FRDA
Circulating miRNAs can detect pathological events, and could also monitor molecular signals participating in cardiomyopathy even before the appearance of clinical cardiac manifestations. To maximize the likelihood of detecting the onset or progression of cardiomyopathy, we suggest combining standard cardiac diagnostic procedures with the use of circulating microRNAs. This approach could provide more clinical information for evaluating cardiomyopathy progression in FRDA. In summary, miRNAs obtained in this study show new candidates for personalized therapy in FRDA patients.
Tuesday, July 11, 2017
How does performance of the Friedreich Ataxia Functional Composite compare to rating scales?
Geneieve Tai, Eppie M. Yiu, Martin B. Delatycki, Louise A. Corben; J Neurol (2017). doi:10.1007/s00415-017-8566-0
The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components.
The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components.
Sunday, July 9, 2017
Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity
Pablo Calap-Quintana, Javier González-Fernández, Noelia Sebastiá-Ortega, José Vicente Llorens, Orcid and María Dolores Moltó; Int. J. Mol. Sci. 2017, 18(7), 1456; doi:10.3390/ijms18071456
Drosophila models of FRDA support the proposal that iron plays a major role in FRDA physio-pathology. Although reduction in iron levels by iron chelation has been relatively successful in clinical trials, genetic or pharmacological intervention through the sphingolipid/Pdk1/Mef-2 pathway and pathways regulating iron homeostasis are new approaches to be explored in preclinical studies.
Drosophila models of FRDA support the proposal that iron plays a major role in FRDA physio-pathology. Although reduction in iron levels by iron chelation has been relatively successful in clinical trials, genetic or pharmacological intervention through the sphingolipid/Pdk1/Mef-2 pathway and pathways regulating iron homeostasis are new approaches to be explored in preclinical studies.
Wednesday, July 5, 2017
Selected missense mutations impair frataxin processing in Friedreich ataxia
Elisia Clark, Jill S. Butler, Charles J. Isaacs, Marek Napierela and David R. Lynch; Annals of Clinical and Translational Neurology. doi: 10.1002/acn3.433
FXNI154F and FXNG130V missense mutations decrease FXN81–210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.
FXNI154F and FXNG130V missense mutations decrease FXN81–210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.
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