Nature Biotechnology 35,103 (2017) doi:10.1038/nbt0217-103b Published online 08 February 2017
The Shire deal includes preclinical drug programs in cystic fibrosis and urea cycle disorders to augment RaNa’s pipeline. In 2015, RaNa raised $55 million in venture capital to continue development of epigenetic gene upregulation and mRNA stabilization technologies and support the company’s programs in spinal muscular dystrophy and Friedreich’s ataxia.
Thursday, February 9, 2017
Wednesday, February 8, 2017
Comparison of Two Different PCR-based Methods for Detection of GAA Expansions in Frataxin Gene
Mona ENTEZAM, Akbar AMIRFIROOZI, Mansoureh TOGHA, Mohammad KERAMATIPOUR; Iranian Journal of Public Health 2017. 46(2):222-228.
The presence or absence of expanded alleles can be identified correctly by TP-PCR. Performing long-PCR and Fluorescent-long-PCR enables accurate genotyping in all samples. This approach is highly reliable. It could be successfully used for detection of GAA expansion repeats.
The presence or absence of expanded alleles can be identified correctly by TP-PCR. Performing long-PCR and Fluorescent-long-PCR enables accurate genotyping in all samples. This approach is highly reliable. It could be successfully used for detection of GAA expansion repeats.
Tuesday, February 7, 2017
Chondrial Therapeutics Secures Up to $22.6 Million in Series A Financing and Licenses Novel Technology for the Treatment of Friedreich's Ataxia
PR Newswire, News provided by Chondrial Therapeutics, Inc. Feb 06, 2017, Company Plans to Advance Pipeline of Product Candidates Focused on the Treatment of Rare Mitochondrial Diseases, Carole Ben-Maimon, MD, Named President & CEO
Discovered by Dr. Payne while at Wake Forest Baptist Medical Center, CTI-1601 utilizes a carrier protein to deliver frataxin, the deficient protein in Friedreich's Ataxia, to the mitochondria where researchers believe it is processed to mature frataxin and becomes active in mitochondrial metabolism. People with Friedreich's Ataxia have very low levels of frataxin, which is active in the mitochondria and assists in energy production. Chondrial's premise in the research program is that by replacing the deficient protein the mitochondria will resume normal function, patients' symptoms may be minimized, and disease progression may be curtailed.
This comes a few months after Horizon Pharma’s Actimmune missed the primary endpoint in a phase 3 trial in the rare neurodegenerative movement disorder, sparking a 20% drop in its stock price.
Discovered by Dr. Payne while at Wake Forest Baptist Medical Center, CTI-1601 utilizes a carrier protein to deliver frataxin, the deficient protein in Friedreich's Ataxia, to the mitochondria where researchers believe it is processed to mature frataxin and becomes active in mitochondrial metabolism. People with Friedreich's Ataxia have very low levels of frataxin, which is active in the mitochondria and assists in energy production. Chondrial's premise in the research program is that by replacing the deficient protein the mitochondria will resume normal function, patients' symptoms may be minimized, and disease progression may be curtailed.
This comes a few months after Horizon Pharma’s Actimmune missed the primary endpoint in a phase 3 trial in the rare neurodegenerative movement disorder, sparking a 20% drop in its stock price.
Friday, February 3, 2017
MiRNA-145 Regulates the Development of Congenital Heart Disease Through Targeting FXN
Lei Wang, Danqiu Tian, Jihua Hu, Haijian Xing, Min Sun, Juanli Wang, Qiang Jian, Hua Yang. Pediatr Cardiol (2016) 37: 629. doi:10.1007/s00246-015-1325-z
we examined the effect of miRNA-145 and miRNA-182 on cell apoptosis, aconitase activity and ROS, and the results showed that transfection of miRNA-145 significantly activated caspase-3, which promotes apoptosis, and meanwhile suppressed aconitase activity and ROS formation, while miRNA-182 showed no such differences. These results indicate that the regulation of miRNA-145 on FXN influences the multiple aspects of cellular physiology.
we examined the effect of miRNA-145 and miRNA-182 on cell apoptosis, aconitase activity and ROS, and the results showed that transfection of miRNA-145 significantly activated caspase-3, which promotes apoptosis, and meanwhile suppressed aconitase activity and ROS formation, while miRNA-182 showed no such differences. These results indicate that the regulation of miRNA-145 on FXN influences the multiple aspects of cellular physiology.
Thursday, February 2, 2017
Estudio piloto sobre los valores acústicos de las vocales en español como indicadores de la gravedad de la disartria
Pilot study of the acoustic values of the vowels in Spanish as indicators of the severity of dysarthria. (Article in Spanish; Abstract available in Spanish from the publisher.)
Delgado-Hernandez J.; Rev Neurol. 2017 Feb 1;64(3):105-111. PMID: 28128427
El análisis acústico es una herramienta que proporciona datos objetivos sobre las alteraciones del habla en la disartria. Los sujetos con disartria atáxica presentan un menor contraste vocálico y una centralización en la realización de las vocales. Las medidas acústicas estudiadas en este trabajo preliminar tienen una alta sensibilidad en la detección de la disartria, pero sólo el VSA y la media de las distancias primarias informan sobre la gravedad de este tipo de alteración del habla.
The acoustic analysis is a tool that provides objective data on changes of speech in dysarthria. Ataxic dysarthria subjects have lower contrast and vowel centralization in carrying out the vowels. The acoustic measures studied in this preliminary work have a high sensitivity in the detection of dysarthria but only the VSA and the mean of primary distances provide information on the severity of this type of speech disturbance.
Delgado-Hernandez J.; Rev Neurol. 2017 Feb 1;64(3):105-111. PMID: 28128427
El análisis acústico es una herramienta que proporciona datos objetivos sobre las alteraciones del habla en la disartria. Los sujetos con disartria atáxica presentan un menor contraste vocálico y una centralización en la realización de las vocales. Las medidas acústicas estudiadas en este trabajo preliminar tienen una alta sensibilidad en la detección de la disartria, pero sólo el VSA y la media de las distancias primarias informan sobre la gravedad de este tipo de alteración del habla.
The acoustic analysis is a tool that provides objective data on changes of speech in dysarthria. Ataxic dysarthria subjects have lower contrast and vowel centralization in carrying out the vowels. The acoustic measures studied in this preliminary work have a high sensitivity in the detection of dysarthria but only the VSA and the mean of primary distances provide information on the severity of this type of speech disturbance.
Tuesday, January 31, 2017
Using the shared genetics of dystonia and ataxia to unravel their pathogenesis
Esther A.R. Nibbeling, Cathérine C.S. Delnooz, Tom J. de Koning, Richard J. Sinke, Hyder A. Jinnah, Marina A.J. Tijssen, Dineke S. Verbeek, Neuroscience & Biobehavioral Reviews, Available online 28 January 2017, ISSN 0149-7634, doi:10.1016/j.neubiorev.2017.01.033.
In this review we explore the similarities between spinocerebellar ataxias and dystonias, and suggest potentially shared molecular pathways using a gene co-expression network approach. Many patients show a combination of cerebellar ataxia and dystonia. Dystonia is frequently seen in SCA2 (14%), SCA3 (24%) and SCA17 (53%), and regularly seen in SCA types 1, 6, 12, 14, 15/16 and 20, in ataxia telangiectasia, in Friedreich’s ataxia, and in ataxia with oculomotor apraxia. Taken into account the clinical and etiological heterogeneity, the exact pathophysiological mechanisms of SCA and dystonia are not exactly clear. For SCA, several etiological roles have been identified that lead to neurotransmission deficits and result in PC death, including transcriptional dysregulation, autophagy, mitochondrial defects and alterations in calcium homeostasis.In dystonia, the basal ganglia have classically been attributed a key role.
In this review we explore the similarities between spinocerebellar ataxias and dystonias, and suggest potentially shared molecular pathways using a gene co-expression network approach. Many patients show a combination of cerebellar ataxia and dystonia. Dystonia is frequently seen in SCA2 (14%), SCA3 (24%) and SCA17 (53%), and regularly seen in SCA types 1, 6, 12, 14, 15/16 and 20, in ataxia telangiectasia, in Friedreich’s ataxia, and in ataxia with oculomotor apraxia. Taken into account the clinical and etiological heterogeneity, the exact pathophysiological mechanisms of SCA and dystonia are not exactly clear. For SCA, several etiological roles have been identified that lead to neurotransmission deficits and result in PC death, including transcriptional dysregulation, autophagy, mitochondrial defects and alterations in calcium homeostasis.In dystonia, the basal ganglia have classically been attributed a key role.
Monday, January 30, 2017
miRNAs as biomarkers of neurodegenerative disorders
Vijitha Viswambharan, Ismail Thanseem, Mahesh M Vasu, Suresh A Poovathinal, and Ayyappan Anitha; Biomarkers in Medicine, February 2017 ,Vol. 11, No. 2 , Pages 151-167 doi: 10.2217/bmm-2016-0242
The potential role of epigenetic changes associated with FRDA including miRNA-based regulatory mechanisms is being studied now. Genetic variations that create miRNA target sites in the 3′-UTR of FXN have been found to affect frataxin expression in FRDA. For example, miRNA-145 has been found to directly bind to the 3′-UTR region of FXN, negatively regulating its expression.
The potential role of epigenetic changes associated with FRDA including miRNA-based regulatory mechanisms is being studied now. Genetic variations that create miRNA target sites in the 3′-UTR of FXN have been found to affect frataxin expression in FRDA. For example, miRNA-145 has been found to directly bind to the 3′-UTR region of FXN, negatively regulating its expression.
Sunday, January 29, 2017
Targeting Class I Histone Deacetylases in a “Complex” Environment
Christopher J. Millard, Peter J. Watson, Louise Fairall, John W.R. Schwabe, Trends in Pharmacological Sciences, Available online 28 January 2017, ISSN 0165-6147, doi:10.1016/j.tips.2016.12.006.
Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Due to their nonselective nature, many patients experience significant side effects.
The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.
Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Due to their nonselective nature, many patients experience significant side effects.
The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.
Friday, January 27, 2017
New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins involved in Iron Sulfur Cluster Biogenesis
Marco Fantini, Duccio Malinverni, Paolo De Los Rios, Annalisa Pastore, bioRxiv 103283; doi:10.1101/103283
We have used DCA to analyse three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that, although based on a relatively small number of sequences due to its distribution in genomes, we can correctly recapitulate all the features of the fold of the CyaY/frataxin family, a protein involved in the human disease Friedreich's ataxia.
We have used DCA to analyse three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that, although based on a relatively small number of sequences due to its distribution in genomes, we can correctly recapitulate all the features of the fold of the CyaY/frataxin family, a protein involved in the human disease Friedreich's ataxia.
Wednesday, January 25, 2017
Influence of substituent heteroatoms on the cytoprotective properties of pyrimidinol antioxidants
Arnaud Chevalier, Omar M. Khdour, Margaret Schmierer, Indrajit Bandyopadhyay, Sidney M. Hecht, Bioorganic & Medicinal Chemistry, Available online 23 January 2017, ISSN 0968-0896, doi:10.1016/j.bmc.2017.01.030.
Defects in mitochondrial function are linked to numerous neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Friedreich’s ataxia, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. In this context, improvements in mitochondrial function and cellular bioenergetics represent potential targets for therapeutic intervention in mitochondrial diseases.
These compounds are able to quench ROS and lipid peroxidation, maintain mitochondrial membrane potential and confer cytoprotection to cultured cells under conditions of induced oxidative stress. These properties are related to their ability to quench reactive oxygen radicals; therefore, the compounds have been denoted multifunctional radical quenchers (MRQs).
The ability of these compounds to quench lipid peroxidation induced by depletion of glutathione with diethyl maleate (DEM) was evaluated in Friedreich’s ataxia (FRDA) lymphocytes.
Defects in mitochondrial function are linked to numerous neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Friedreich’s ataxia, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. In this context, improvements in mitochondrial function and cellular bioenergetics represent potential targets for therapeutic intervention in mitochondrial diseases.
These compounds are able to quench ROS and lipid peroxidation, maintain mitochondrial membrane potential and confer cytoprotection to cultured cells under conditions of induced oxidative stress. These properties are related to their ability to quench reactive oxygen radicals; therefore, the compounds have been denoted multifunctional radical quenchers (MRQs).
The ability of these compounds to quench lipid peroxidation induced by depletion of glutathione with diethyl maleate (DEM) was evaluated in Friedreich’s ataxia (FRDA) lymphocytes.
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