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.
Friday, April 8, 2016
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.
Friday, April 1, 2016
Assessment and management of cavus foot deformity
J. Grice, H. Willmott, H. Taylor, Orthopaedics and Trauma, Available online 8 March 2016, ISSN 1877-1327, doi:10.1016/j.mporth.2016.02.001.
Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot.
Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot.
Thursday, March 31, 2016
Iron Homeostasis in Health and Disease
Raffaella Gozzelino, and Paolo Arosio; Review: Int. J. Mol. Sci. 2016, 17(1), 130; doi:10.3390/ijms17010130
OPEN ACESS
It is established the involvement of this metal in Friedrich’s ataxia, a disease characterized by progressive degeneration of sensory neurons in the dorsal root ganglia caused by a mutation in the frataxin gene. Frataxin plays an essential role in delivering Fe to mitochondrial pathways involved in ISC biogenesis and when its functionality is reduced below a critical threshold, Fe accumulates in mitochondria. Reduced mitochondrial functioning and impaired electron transport chain results in Fe-mediated ROS, which was shown to positively correlate with the severity of Friedrich’s ataxia.
OPEN ACESS
It is established the involvement of this metal in Friedrich’s ataxia, a disease characterized by progressive degeneration of sensory neurons in the dorsal root ganglia caused by a mutation in the frataxin gene. Frataxin plays an essential role in delivering Fe to mitochondrial pathways involved in ISC biogenesis and when its functionality is reduced below a critical threshold, Fe accumulates in mitochondria. Reduced mitochondrial functioning and impaired electron transport chain results in Fe-mediated ROS, which was shown to positively correlate with the severity of Friedrich’s ataxia.
Wednesday, March 30, 2016
Genome Editing of Structural Variations: Modeling and Gene Correction
Chul-Yong Park, Jin Jea Sung, Dong-Wook Kim, Trends in Biotechnology, Available online 23 March 2016, ISSN 0167-7799, doi:10.1016/j.tibtech.2016.02.011.
Although in vivo gene correction using genetic scissor technology (Meganucleases, ZFNs, TALENs and CRISPR/Cas9) may be available and desirable in the future, effective and cell-specific delivery systems should be developed. These technologies promise to expand our understanding of the mechanism of SVs and our ability to treat SV-related diseases.
For Friedreich's ataxia (FRDA), regions containing GAA repeats from frataxin(FXN) intron 1 were removed by expressing ZFNs targeting 334bp and 896bp upstream of GAA repeats in FRDA fibroblasts and lymphoblasts. The FRDA phenotype was reversed, with increased frataxin expression, when corrected FRDA fibroblasts were converted to iPSCs and differentiated into neurons (Li, Y. et al. (2015)).
Although in vivo gene correction using genetic scissor technology (Meganucleases, ZFNs, TALENs and CRISPR/Cas9) may be available and desirable in the future, effective and cell-specific delivery systems should be developed. These technologies promise to expand our understanding of the mechanism of SVs and our ability to treat SV-related diseases.
For Friedreich's ataxia (FRDA), regions containing GAA repeats from frataxin(FXN) intron 1 were removed by expressing ZFNs targeting 334bp and 896bp upstream of GAA repeats in FRDA fibroblasts and lymphoblasts. The FRDA phenotype was reversed, with increased frataxin expression, when corrected FRDA fibroblasts were converted to iPSCs and differentiated into neurons (Li, Y. et al. (2015)).
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