Publication date: 2016-03-17 Patent application number: 20160075745
The method according to claim 19, wherein said functional protein is frataxin, respectively OTC, and said mitochondrial disorder is Friedreich's ataxia or any other disorder associated with deficiency of frataxin or with defective frataxin or, respectively, a disorder associated with a deficiency of OTC or with defective OTC.
Friday, March 18, 2016
Thursday, March 10, 2016
New Clinical Trial: Rosuvastatin (Crestor) in Friedreich Ataxia
ClinicalTrials.gov Identifier: NCT02705547 First received: March 5, 2016
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States, 19103
Principal Investigator: David Lynch, MD PhD
This is an open-label study of Rosuvastatin (Crestor) in patients with FRDA. Study subjects will receive 10 mg of Rosuvastatin daily for 3 months.Daily administration of oral tablets of Rosuvastatin, 10 mg.
Context: Friedreich ataxia (FRDA) is a progressive neurodegenerative disease of children and adults for which there is presently no therapy. It has previously been reported that patients with FRDA have lower than expected HDL levels, and recent work by Dr. Blair at the University of Pennsylvania has found that serum ApoA-1 levels in FRDA patients are lower than those in controls. ApoA-1 levels are controlled by HMG-CoA activity, which is elevated in FRDA, and we hope to examine whether HMG-CoA levels can be inhibited by giving statins to patients with FRDA. Inhibition of this pathway has been proposed as a treatment for a variety of neurodegenerative disorders, and we will examine if FRDA may be one of them by looking at various biomarkers in the disease.
Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States, 19103
Principal Investigator: David Lynch, MD PhD
This is an open-label study of Rosuvastatin (Crestor) in patients with FRDA. Study subjects will receive 10 mg of Rosuvastatin daily for 3 months.Daily administration of oral tablets of Rosuvastatin, 10 mg.
Context: Friedreich ataxia (FRDA) is a progressive neurodegenerative disease of children and adults for which there is presently no therapy. It has previously been reported that patients with FRDA have lower than expected HDL levels, and recent work by Dr. Blair at the University of Pennsylvania has found that serum ApoA-1 levels in FRDA patients are lower than those in controls. ApoA-1 levels are controlled by HMG-CoA activity, which is elevated in FRDA, and we hope to examine whether HMG-CoA levels can be inhibited by giving statins to patients with FRDA. Inhibition of this pathway has been proposed as a treatment for a variety of neurodegenerative disorders, and we will examine if FRDA may be one of them by looking at various biomarkers in the disease.
Wednesday, March 9, 2016
Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34
Shen Y, McMackin MZ, Shan Y, Raetz A, David S, Cortopassi G. PLoS ONE 11(3): e0151026. doi:10.1371/journal.pone.0151026
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We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1
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We hypothesized that frataxin deficiency increases DNA damage and DNA repair genes specifically in microglia, activating them. siRNA-mediated frataxin knockdown in microglial BV2 cells clearly elevated DNA damage and the expression of DNA repair genes MUTYH and PARP-1
Monday, March 7, 2016
Near-infrared spectroscopy for medical applications: Current status and future perspectives
Akikazu Sakudo, Clinica Chimica Acta, Available online 12 February 2016, ISSN 0009-8981, doi:10.1016/j.cca.2016.02.009.
Chronic obstructive pulmonary disease (COPD), cytochrome c oxidase deficiency, metabolic myopathy, Friedreich's ataxia, mitochondrial myopathy as well as neuromuscular diseases and peripheral artery diseases (PAD) and spinal cord injury can be assessed by NIR spectroscopy to detect abnormal oxygen consumption and vasodilation.
Chronic obstructive pulmonary disease (COPD), cytochrome c oxidase deficiency, metabolic myopathy, Friedreich's ataxia, mitochondrial myopathy as well as neuromuscular diseases and peripheral artery diseases (PAD) and spinal cord injury can be assessed by NIR spectroscopy to detect abnormal oxygen consumption and vasodilation.
Friday, March 4, 2016
An Overview of Direct Somatic Reprogramming: The Ins and Outs of iPSCs (Review )
Siddharth Menon, Siny Shailendra, Andrea Renda, Michael Longaker and Natalina Quarto; Int. J. Mol. Sci. 2016, 17(1), 141; doi:10.3390/ijms17010141 (OPEN ACCESS)
Current techniques produce disease phenotypes, however, the extent of recapitulating all aspects of the disease is still limited. Overall, the vast potential of iPSCs in cell-based therapeutics, drug discovery and disease modeling is clear, though significantly hindered by the lack of understanding of the long-term risks. Until more is understood about the mechanisms of induced pluripotency and differentiation, and the development of extensive screening procedures for genetic aberrations resulting in stable genomes, the use of iPSCs technology remains inadequate for most translational medicine and clinical applications.
Current techniques produce disease phenotypes, however, the extent of recapitulating all aspects of the disease is still limited. Overall, the vast potential of iPSCs in cell-based therapeutics, drug discovery and disease modeling is clear, though significantly hindered by the lack of understanding of the long-term risks. Until more is understood about the mechanisms of induced pluripotency and differentiation, and the development of extensive screening procedures for genetic aberrations resulting in stable genomes, the use of iPSCs technology remains inadequate for most translational medicine and clinical applications.
Wednesday, March 2, 2016
The medical experience of a patient with a rare disease and her family
Roberta Garau. Orphanet Journal of Rare Diseases201611:19. DOI: 10.1186/s13023-016-0401-7
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This letter considers the main challenges that people with rare diseases and their families face: delay in diagnosis, lack of appropriate support and information, and impaired access to treatment.
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This letter considers the main challenges that people with rare diseases and their families face: delay in diagnosis, lack of appropriate support and information, and impaired access to treatment.
Sunday, February 28, 2016
Moving beyond DNA: A brief history of epigenetics
Posted February 18, 2016 in Episona Blog by Mike Karsian
The search for new therapies for Friedreich's Ataxia based on epigenetics is more and more relevant , but, what does epigenetics mean?. In this post we can find a brief informative explanation in layman words about epigenetics, and the chronology of discoveries in which current knowledge is based.
The search for new therapies for Friedreich's Ataxia based on epigenetics is more and more relevant , but, what does epigenetics mean?. In this post we can find a brief informative explanation in layman words about epigenetics, and the chronology of discoveries in which current knowledge is based.
Friday, February 26, 2016
Targeted RNA or BDNF gene transfer protects against frataxin deficiency
Ian Fyfe, Research Highlight: Nature Reviews Neurology (2016), doi:10.1038/nrneurol.2016.19, Published online 26 February 2016
In two recently published studies, the pathological consequences of this FXN mutation have been successfully counteracted in in vitro and in vivo models with the use of different approaches, each with therapeutical potential.
-In the first study, David Corey and colleagues introduced synthetic anti‑GAA duplex RNA molecules into patient-derived cells that had the FXN mutation, this increased expression of frataxin by up to sixfold. They believe that their findings are a starting point for the development of RNA-based drugs, and are looking to take the next step.
-The second study, led by Javier Diaz-Nido, did not involve targeting the FXN gene, but aimed to block the apoptosis. Neurotrophic factors are potent suppressors of neuronal apoptosis, they were able to protect neurons from death triggered by frataxin gene silencing”. Now, they plan to test whether there is a synergy between two gene therapy strategies: one based on frataxin gene replacement and the other based on neurotrophic factor gene delivery
ORIGINAL ARTICLES:
-Katsu-Jiménez, Y. et al. Gene transfer of brain derived neurotrophic factor (BDNF) prevents neurodegeneration triggered by frataxin deficiency. Mol. Ther.
-Li, L. et al. Activating frataxin expression by repeat-targeted nucleic acids. Nat. Comm.
In two recently published studies, the pathological consequences of this FXN mutation have been successfully counteracted in in vitro and in vivo models with the use of different approaches, each with therapeutical potential.
-In the first study, David Corey and colleagues introduced synthetic anti‑GAA duplex RNA molecules into patient-derived cells that had the FXN mutation, this increased expression of frataxin by up to sixfold. They believe that their findings are a starting point for the development of RNA-based drugs, and are looking to take the next step.
-The second study, led by Javier Diaz-Nido, did not involve targeting the FXN gene, but aimed to block the apoptosis. Neurotrophic factors are potent suppressors of neuronal apoptosis, they were able to protect neurons from death triggered by frataxin gene silencing”. Now, they plan to test whether there is a synergy between two gene therapy strategies: one based on frataxin gene replacement and the other based on neurotrophic factor gene delivery
ORIGINAL ARTICLES:
-Katsu-Jiménez, Y. et al. Gene transfer of brain derived neurotrophic factor (BDNF) prevents neurodegeneration triggered by frataxin deficiency. Mol. Ther.
-Li, L. et al. Activating frataxin expression by repeat-targeted nucleic acids. Nat. Comm.
Thursday, February 25, 2016
Genotoxicity in Mice Following AAV Gene Delivery: A Safety Concern for Human Gene Therapy?
Randy J Chandler, Matthew C LaFave, Gaurav K Varshney, Shawn M Burgess and Charles P Venditti; (Nature) Molecular Therapy 24, 198-201 (February 2016) | doi:10.1038/mt.2016.17
Given the lack of therapies for the many diseases that rAAV gene therapy promises to treat, such as lethal inborn errors of metabolism, the risk of toxicity imposed by rAAV exposure will need to be balanced against the significant benefits offered by effective gene therapy, which for some patients could be lifesaving.
Although the lack of natural pathogenicity and the capacity for effective gene delivery coupled with stable, long-term gene expression have supported the advancement of rAAV as an optimal vector for human clinical trials, recent studies in mice have challenged the belief that rAAV is an innocuous gene therapy vector.
Given the lack of therapies for the many diseases that rAAV gene therapy promises to treat, such as lethal inborn errors of metabolism, the risk of toxicity imposed by rAAV exposure will need to be balanced against the significant benefits offered by effective gene therapy, which for some patients could be lifesaving.
Although the lack of natural pathogenicity and the capacity for effective gene delivery coupled with stable, long-term gene expression have supported the advancement of rAAV as an optimal vector for human clinical trials, recent studies in mice have challenged the belief that rAAV is an innocuous gene therapy vector.
MicroRNAs Form Triplexes with Double Stranded DNA at Sequence-Specific Binding Sites; a Eukaryotic Mechanism via which microRNAs Could Directly Alter Gene Expression
Paugh SW, Coss DR, Bao J, Laudermilk LT, Grace CR, Ferreira AM, M. Brett Waddell, Granger Ridout, Deanna Naeve, Michael Leuze, Philip F. LoCascio, John C. Panetta, Mark R. Wilkinson, Ching-Hon Pui, Clayton W. Naeve, Edward C. Uberbacher, Erik J. Bonten, William E. Evans (2016); PLoS Comput Biol 12(2): e1004744. doi:10.1371/journal.pcbi.1004744
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Friedreichs ataxia, the most common form of ataxia in humans, is caused by the expansion of a (GAA)n repeat in intron 1 of the Frataxin gene, which in turn results in transcriptional silencing, presumably because of the triplex-forming potential of the (GAA)n repeat. This suggests that, not only may the formation of DNA triplexes be a well-conserved and essential mechanism to regulate gene transcription, but that stable or prolonged triplex formation may have undesirable consequences.
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Friedreichs ataxia, the most common form of ataxia in humans, is caused by the expansion of a (GAA)n repeat in intron 1 of the Frataxin gene, which in turn results in transcriptional silencing, presumably because of the triplex-forming potential of the (GAA)n repeat. This suggests that, not only may the formation of DNA triplexes be a well-conserved and essential mechanism to regulate gene transcription, but that stable or prolonged triplex formation may have undesirable consequences.
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