Debkumar Pain, Andrew Dancis, Current Opinion in Genetics & Development, Volume 38, June 2016, Pages 45-51, ISSN 0959-437X, doi:10.1016/j.gde.2016.03.006.
Impairment of Fe–S cluster assembly creates diseases in diverse and surprising ways: the loss of function of lipoic acid synthase, the heme biosynthetic pathway in red cell precursors is specifically targeted and tRNA modifications arising from action of the cysteine desulfurase and/or Fe–S cluster proteins are lost. These defects can then result in cancer, neurologic dysfunction or type 2 diabetes.
Monday, April 11, 2016
Sunday, April 10, 2016
The Structure of the Complex Between Yeast Frataxin and Ferrochelatase: Characterization and pre-Steady State Reaction of Ferrous Iron Delivery and Heme Synthesis
Christopher G. Soderberg, Mallory E. Gillam, Eva-Christina Ahlgren, Gregory A. Hunter, Oleksandr Gakh, Grazia Isaya, Gloria C. Ferreira and Salam Al-Karadaghi, The Journal of biological chemistry: 2016 First Published on March 29, 2016, doi: 10.1074/jbc.M115.701128
They support the proposal that frataxin-mediated delivery of this potentially toxic substrate (Fe2+)overcomes formation of reactive oxygen species.
They support the proposal that frataxin-mediated delivery of this potentially toxic substrate (Fe2+)overcomes formation of reactive oxygen species.
Saturday, April 9, 2016
Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia
Charles J. Isaacs BA, Karlla W. Brigatti MS, Olena Kucheruk RN MPH, Sarah Ratcliffe PhD, Tom Sciascia MD, Shana E. McCormack MD, Steven M. Willi MD and David R. Lynch MD PhD, Muscle & Nerve, Accepted manuscript online: 7 APR 2016 DOI: 10.1002/mus.25136
Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient.
Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient.
Friday, April 8, 2016
Accessing the accelerated approval pathway for rare disease therapeutics
Emil D Kakkis, Sara Kowalcyk & Max G Bronstein, Nature Biotechnology 34, 380–383 (2016) doi:10.1038/nbt.3530
Improvements must be made to the qualification process for biomarkers as primary endpoints in pivotal clinical studies of treatments for the rarest of diseases.
Improvements must be made to the qualification process for biomarkers as primary endpoints in pivotal clinical studies of treatments for the rarest of diseases.
Thursday, April 7, 2016
Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie
Abnormal eye movements: Etiologic/topographic diagnostic tool in neurology / Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie
FMC, Volume 7, Issue 1, February 2016, Pages 16-24, ISSN 1878-7762, doi:10.1016/j.praneu.2015.12.003.
Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. We provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.
Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Nous proposons une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.
FMC, Volume 7, Issue 1, February 2016, Pages 16-24, ISSN 1878-7762, doi:10.1016/j.praneu.2015.12.003.
Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. We provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.
Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Nous proposons une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.
Wednesday, April 6, 2016
New tool enables scientists to interpret 'dark matter' DNA
Gladstone Institutes. "New tool enables scientists to interpret 'dark matter' DNA: Breakthrough technology opens the door to identifying new drug targets that could treat many genetic diseases." ScienceDaily. ScienceDaily, 4 April 2016. .
Scientists at the Gladstone Institutes have invented a new way to read and interpret the human genome. The computational method, called TargetFinder, can predict where non-coding DNA--the DNA that does not code for proteins--interacts with genes. This technology helps researchers connect mutations in the so-called genomic "dark matter" with the genes they affect, potentially revealing new therapeutic targets for genetic disorders.
"Our ability to predict the gene targets of enhancers so accurately enables us to link mutations in enhancers to the genes they target," said Pollard. "Having that link is the first step towards using these connections to treat diseases."
Scientists at the Gladstone Institutes have invented a new way to read and interpret the human genome. The computational method, called TargetFinder, can predict where non-coding DNA--the DNA that does not code for proteins--interacts with genes. This technology helps researchers connect mutations in the so-called genomic "dark matter" with the genes they affect, potentially revealing new therapeutic targets for genetic disorders.
"Our ability to predict the gene targets of enhancers so accurately enables us to link mutations in enhancers to the genes they target," said Pollard. "Having that link is the first step towards using these connections to treat diseases."
Tuesday, April 5, 2016
Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease
Ana Dinca, Wei-Ming Chien and Michael T. Chin. Int. J. Mol. Sci. 2016, 17(2), 263; doi:10.3390/ijms17020263
Review
OPEN ACCESS
Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa).
Review
OPEN ACCESS
Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa).
Monday, April 4, 2016
Genome-editing Technologies for Gene and Cell Therapy
Morgan L Maeder and Charles A Gersbach, Molecular Therapy (2016); 24 3, 430–446. doi:10.1038/mt.2016.10
OPEN ACCES (Creative Commons CC-BY license)
Gene therapy has historically been defined as the addition of new genes to human cells. However, the recent advent of genome-editing technologies has enabled a new paradigm in which the sequence of the human genome can be precisely manipulated to achieve a therapeutic effect. This includes the correction of mutations that cause disease, the addition of therapeutic genes to specific sites in the genome, and the removal of deleterious genes or genome sequences. This review presents the mechanisms of different genome-editing strategies and describes each of the common nuclease-based platforms, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, and the CRISPR/Cas9 system. We then summarize the progress made in applying genome editing to various areas of gene and cell therapy, including antiviral strategies, immunotherapies, and the treatment of monogenic hereditary disorders.
OPEN ACCES (Creative Commons CC-BY license)
 |
| Common DNA targeting platforms for genome editing. |
Gene therapy has historically been defined as the addition of new genes to human cells. However, the recent advent of genome-editing technologies has enabled a new paradigm in which the sequence of the human genome can be precisely manipulated to achieve a therapeutic effect. This includes the correction of mutations that cause disease, the addition of therapeutic genes to specific sites in the genome, and the removal of deleterious genes or genome sequences. This review presents the mechanisms of different genome-editing strategies and describes each of the common nuclease-based platforms, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, and the CRISPR/Cas9 system. We then summarize the progress made in applying genome editing to various areas of gene and cell therapy, including antiviral strategies, immunotherapies, and the treatment of monogenic hereditary disorders.
Sunday, April 3, 2016
New developments and controversies in iron metabolism and iron chelation therapy.
Christina N Kontoghiorghe and George J Kontoghiorghes, World J Methodol. 2016 March 26; 6(1): 1–19. Published online 2016 March 26. doi: 10.5662/wjm.v6.i1.1
Open-Access
"Similar issues in relation to chelating drug development were raised with the journal Annals of Neurology regarding the use of (Ferriprox) in Friedreich ataxia patients where the lack of crucial diagnostic and therapeutic outcome procedures in relation to focal iron levels and lack of iron balance studies were questioned. The need for personalised medicine was also raised since there is wide variation in the severity of the disease and level of focal iron deposits in the heart and brain of Friedreich ataxia patients. In this case the editors of the journal referred to “expensive studies to track iron scores” and “the company developing the drug spends millions of dollars”. It should be noted that the original proposal for the use of (Ferriprox) in Friedreich ataxia patients was suggested many years ago and was developed following academic initiatives.
The introduction of Deferiprone (Ferriprox) for the treatment of non iron loaded patients by targeting focal toxic iron deposits, e.g., in Friedreich ataxia and toxic labile iron, e.g., in diabetic and non-diabetic glomerular disease is a reflection of the antioxidant and safety potential of this drug. The safety of (Ferriprox) in many categories of non iron loaded diseases has also been confirmed in clinical trials involving patients with the anaemia of chronic disease, renal dialysis, infections, Parkinson’s and other neurodegenerative diseases, etc. As in many other cases of drug development the introduction prospects of Ferriprox in these diseases is based on commercial and not ethical criteria.
Open-Access
"Similar issues in relation to chelating drug development were raised with the journal Annals of Neurology regarding the use of (Ferriprox) in Friedreich ataxia patients where the lack of crucial diagnostic and therapeutic outcome procedures in relation to focal iron levels and lack of iron balance studies were questioned. The need for personalised medicine was also raised since there is wide variation in the severity of the disease and level of focal iron deposits in the heart and brain of Friedreich ataxia patients. In this case the editors of the journal referred to “expensive studies to track iron scores” and “the company developing the drug spends millions of dollars”. It should be noted that the original proposal for the use of (Ferriprox) in Friedreich ataxia patients was suggested many years ago and was developed following academic initiatives.
The introduction of Deferiprone (Ferriprox) for the treatment of non iron loaded patients by targeting focal toxic iron deposits, e.g., in Friedreich ataxia and toxic labile iron, e.g., in diabetic and non-diabetic glomerular disease is a reflection of the antioxidant and safety potential of this drug. The safety of (Ferriprox) in many categories of non iron loaded diseases has also been confirmed in clinical trials involving patients with the anaemia of chronic disease, renal dialysis, infections, Parkinson’s and other neurodegenerative diseases, etc. As in many other cases of drug development the introduction prospects of Ferriprox in these diseases is based on commercial and not ethical criteria.
Saturday, April 2, 2016
Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.
Elincx-Benizri S, Glik A, Merkel D, Arad M, Freimark D, Kozlova E, Cabantchik I, Hassin-Baer S. J Child Neurol. March 29, 2016, doi: 10.1177/0883073816636087
The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.
The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.
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