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.
Friday, March 4, 2016
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.
Wednesday, February 24, 2016
Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling
Dorota Hoffman-Zacharska , Tomasz Mazurczak, Tomasz Zajkowski, Renata Tataj, Paulina Górka-Skoczylas, Katarzyna Połatyńska, Łukasz Kępczyński, Mariusz Stasiołek, Jerzy Bal; Journal of Applied Genetics
pp 1-7 DOI:10.1007/s13353-015-0331-4 First online: 23 February 2016
Routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of the parent’s carrier status, together with diagnostic tests, are performed in rare cases.
pp 1-7 DOI:10.1007/s13353-015-0331-4 First online: 23 February 2016
Routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of the parent’s carrier status, together with diagnostic tests, are performed in rare cases.
Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia
Laura Ludovica Gramegna, Caterina Tonon , David Neil Manners, Antonella Pini, Rita Rinaldi, Stefano Zanigni, Claudio Bianchini, Stefania Evangelisti, Filippo Fortuna, Valerio Carelli, Claudia Testa, Raffaele Lodi; The Cerebellum pp 1-7, First online: 20 February 2016 DOI: 10.1007/s12311-016-0767-z
The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.
The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.
Tuesday, February 23, 2016
CNS Drug Delivery: Beyond the Spinal Cord
Recently the intrathecal administration has been proposed as part of a hopeful therapy for FA (Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia). This paper shows (in laboratory animals) the feasibility of the use of intrathecal administration to reach efficiently the dorsal root ganglia.
This presentation explains the current state of the art in other neurological diseases in which it is required reach the CNS.
Mission: Improve outcomes for epileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain.
This presentation explains the current state of the art in other neurological diseases in which it is required reach the CNS.
Mission: Improve outcomes for epileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain.
Retrotope Advances RT001 in Clinical Trials to Treat Friedreich's ataxia
(Ref: Marketwired) February 22nd, 2016
LOS ALTOS, CA--(Marketwired) - Retrotope, a privately held clinical stage pharmaceutical company, today announced the successful completion of the first dose cohort and the opening of patient enrollment for the highest dose cohort in its ongoing 28-day study of orally dosed RT001 in Friedreich's ataxia (FA) patients. RT001 was well tolerated and no serious adverse events or dose limiting toxicities were observed.
LOS ALTOS, CA--(Marketwired) - Retrotope, a privately held clinical stage pharmaceutical company, today announced the successful completion of the first dose cohort and the opening of patient enrollment for the highest dose cohort in its ongoing 28-day study of orally dosed RT001 in Friedreich's ataxia (FA) patients. RT001 was well tolerated and no serious adverse events or dose limiting toxicities were observed.
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