Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich Ataxia. D L Ouellet, K Cherif, J Rousseau and J-P Tremblay; Gene Therapy, accepted article preview 26 December 2016; doi: 10.1038/gt.2016.89.
Short title: Correction of the frataxin gene using CRISPR
Here, we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo.
All experiments present in this article help to identify the most suitable mouse model for gene editing in vivo, hoping this will quickly lead to human clinical trials in Friedreich ataxia patients. However, as any kind of therapy, the side effects of a treatment must be clearly defined and known before going further with the massive treatment of patients.
Wednesday, December 28, 2016
Tuesday, December 27, 2016
DNA repair in the trinucleotide repeat disorders
Lesley Jones, Henry Houlden, Sarah J Tabrizi; The Lancet Neurology, Volume 16, Issue 1, January 2017, Pages 88-96, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30350-7
Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich’s ataxia. Mechanisms related to DNA repair have been implicated as modulators of somatic expansion of the disease-associated repeated sequences in mouse modelsof Huntington’s disease, myotonic dystrophy, fragile X syndrome, and Friedreich’s ataxia.
Where next?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.
Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich’s ataxia. Mechanisms related to DNA repair have been implicated as modulators of somatic expansion of the disease-associated repeated sequences in mouse modelsof Huntington’s disease, myotonic dystrophy, fragile X syndrome, and Friedreich’s ataxia.
Where next?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.
Monday, December 26, 2016
Mitochondrial capacity, muscle endurance & low energy in friedreich ataxia
Hannah. M. Bossie M.S., T. Bradley. Willingham M.S., Robbi. A. Van Schoick M.S., Patrick. J. O'Connor Ph.D. andKevin. K. McCully Ph.D., Muscle & Nerve (Accepted Article) DOI: 10.1002/mus.25524
RESULTS: Groups did not differ in mitochondrial capacity (FRDA and AB: 1.8 ± 0.3 1/min). The difference in muscle endurance at 6 Hz was lower by 19.2% in the FRDA (group affect: P < 0.001). Feelings of physical energy were 34% lower in FRDA. In FDRA muscle, endurance was positively related to mitochondrial capacity (r=0.59, P=0.03), and disease severity was negatively related to mitochondrial capacity (r=-0.55, P=0.04) and muscle endurance (r=-0.60, P=0.01). DISCUSSION: Non-invasive measures of skeletal muscle mitochondrial capacity and muscle specific endurance are useful in monitoring FRDA.
RESULTS: Groups did not differ in mitochondrial capacity (FRDA and AB: 1.8 ± 0.3 1/min). The difference in muscle endurance at 6 Hz was lower by 19.2% in the FRDA (group affect: P < 0.001). Feelings of physical energy were 34% lower in FRDA. In FDRA muscle, endurance was positively related to mitochondrial capacity (r=0.59, P=0.03), and disease severity was negatively related to mitochondrial capacity (r=-0.55, P=0.04) and muscle endurance (r=-0.60, P=0.01). DISCUSSION: Non-invasive measures of skeletal muscle mitochondrial capacity and muscle specific endurance are useful in monitoring FRDA.
Sunday, December 25, 2016
Cytokine therapy-mediated neuroprotection in a Friedreich's ataxia mouse model
Kevin C Kemp MSc, PhD, Nadia Cerminara BSc, PhD, Kelly Hares BSc, PhD, Juliana Redondo BSc, PhD, Amelia J Cook, Harry R Haynes BSc, MBChB, Bronwen R Burton BSc, PhD, Mark Pook BSc, PhD, Richard Apps PhD, Neil J Scolding FRCP, PhD and Alastair Wilkins FRCP, PhD; Annals of Neurology, Accepted Article DOI: 10.1002/ana.24846
Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological and behavioural deficits associated with Friedreich's ataxia. These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying and neuroprotective treatment for Friedreich's ataxia.
Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological and behavioural deficits associated with Friedreich's ataxia. These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying and neuroprotective treatment for Friedreich's ataxia.
Saturday, December 24, 2016
Profitability and Market Value of Orphan Drug Companies: A Retrospective, Propensity-Matched Case-Control Study
Hughes DA, Poletti-Hughes J (2016), PLoS ONE 11(10): e0164681. doi:10.1371/journal.pone.0164681
OPEN ACCESS
The small markets associated with rare diseases, however, necessitate high prices for returns to be made on investments, and orphan drugs are generally more expensive than non-orphan drugs. Each one of the world’s 10 most expensive drugs is an orphan, with alipogene tiparvovec (gene therapy approved in Europe for inherited lipoprotein lipase deficiency) ranked highest at about US$1.4m per patient over a year. The revenue-generating potential of orphan drugs is consequently as great as for non-orphan drugs with almost a third being US$1bn blockbuster products in terms of global annual sales.
Orphan drugs also command a higher profit margin, owing to shorter clinical development time, incentives related to research and development, reduced marketing costs and premium pricing. However, it is unclear whether this necessarily translates to higher company profits. One cross-sectional analysis of a small sample of specialised orphan drug companies concluded that they had not performed as strongly as other companies. This observation is not supported by the evidence of the rapid and extensive diversification into the orphan drugs market by large pharmaceutical companies, some of which have established dedicated rare disease units, and acquired or partnered biotech companies already in the rare disease sector.
Concerns have been expressed meanwhile that orphan drug policies are being exploited by companies as treatments initially approved for rare diseases are later used more broadly. Rituximab, as one example, was initially approved as an orphan drug by the FDA for the treatment of follicular non-Hodgkin’s lymphoma. It is now used to treat a wide variety of conditions making it the fourth best-selling drug in the world in 2014.
We hypothesise that companies with orphan drug market authorization are more profitable and are more attractive investment opportunities than non-orphan drug companies. We aimed to test whether the financial performance of publicly listed European and US orphan drug companies is better than matched non-orphan drug companies in terms of their market value and profitability.
OPEN ACCESS
The small markets associated with rare diseases, however, necessitate high prices for returns to be made on investments, and orphan drugs are generally more expensive than non-orphan drugs. Each one of the world’s 10 most expensive drugs is an orphan, with alipogene tiparvovec (gene therapy approved in Europe for inherited lipoprotein lipase deficiency) ranked highest at about US$1.4m per patient over a year. The revenue-generating potential of orphan drugs is consequently as great as for non-orphan drugs with almost a third being US$1bn blockbuster products in terms of global annual sales.
Orphan drugs also command a higher profit margin, owing to shorter clinical development time, incentives related to research and development, reduced marketing costs and premium pricing. However, it is unclear whether this necessarily translates to higher company profits. One cross-sectional analysis of a small sample of specialised orphan drug companies concluded that they had not performed as strongly as other companies. This observation is not supported by the evidence of the rapid and extensive diversification into the orphan drugs market by large pharmaceutical companies, some of which have established dedicated rare disease units, and acquired or partnered biotech companies already in the rare disease sector.
Concerns have been expressed meanwhile that orphan drug policies are being exploited by companies as treatments initially approved for rare diseases are later used more broadly. Rituximab, as one example, was initially approved as an orphan drug by the FDA for the treatment of follicular non-Hodgkin’s lymphoma. It is now used to treat a wide variety of conditions making it the fourth best-selling drug in the world in 2014.
We hypothesise that companies with orphan drug market authorization are more profitable and are more attractive investment opportunities than non-orphan drug companies. We aimed to test whether the financial performance of publicly listed European and US orphan drug companies is better than matched non-orphan drug companies in terms of their market value and profitability.
Friday, December 23, 2016
Evaluation of oligonucleotides for therapy of Friedreich ataxia
Brunel University London. 22/12/2016. Principal Investigator: Dr Mark Pook, Funding body: RaNA Therapeutics.
The aim of this project is firstly to characterise a novel transgenic mouse model of the multi-system autosomal inherited genetic disorder, Friedreich ataxia (FRDA). This mouse model, designated YG8LR, contains the human frataxin transgene together with an inserted 410 GAA repeat expansion mutation. Our studies aim to characterise the FRDA mouse model at molecular, biochemical, histopathological and behavioural levels. Once characterised, the FRDA mouse model will then be used in preclinical studies to investigate the potential of specific frataxin oligonucleotides generated by RaNA Therapeutics to stabilize frataxin mRNA and hence increase frataxin expression.
The aim of this project is firstly to characterise a novel transgenic mouse model of the multi-system autosomal inherited genetic disorder, Friedreich ataxia (FRDA). This mouse model, designated YG8LR, contains the human frataxin transgene together with an inserted 410 GAA repeat expansion mutation. Our studies aim to characterise the FRDA mouse model at molecular, biochemical, histopathological and behavioural levels. Once characterised, the FRDA mouse model will then be used in preclinical studies to investigate the potential of specific frataxin oligonucleotides generated by RaNA Therapeutics to stabilize frataxin mRNA and hence increase frataxin expression.
Thursday, December 22, 2016
Using Social Finance to Fund Generic Drug Repurposing for Rare Diseases: A Social Impact Bond Proof of Concept
RS Thompson, J Potter, A Griffiths, S Eljamel, F Raffai, NT Sireau, Value in Health, Volume 19, Issue 7, November 2016, Pages A505-A506, ISSN 1098-3015, doi:10.1016/j.jval.2016.09.923.
Repurposing existing generic pharmaceuticals to treat rare diseases with an unmet medical need has a number of clear benefits; reducing the investment required in drug discovery, and leveraging known information on drug behaviour and safety often in multiple patient populations. Findacure, a charitable organisation, have completed a proof of concept study into the use of social finance to fund generic drug repurposing research. The proof of concept involved the development of health economic models for congenital hyperinsulinism, Wolfram syndrome, and Friedreich’s ataxia. This study has demonstrated that generic drug repurposing has the potential to save the healthcare system quantities of money sufficient to repay investment in a clinical trial, and build an investable and sustainable financial proposition. Crucially this model would deliver much needed new treatments to rare disease patients, treatments which would otherwise be considered financially inviable.
Repurposing existing generic pharmaceuticals to treat rare diseases with an unmet medical need has a number of clear benefits; reducing the investment required in drug discovery, and leveraging known information on drug behaviour and safety often in multiple patient populations. Findacure, a charitable organisation, have completed a proof of concept study into the use of social finance to fund generic drug repurposing research. The proof of concept involved the development of health economic models for congenital hyperinsulinism, Wolfram syndrome, and Friedreich’s ataxia. This study has demonstrated that generic drug repurposing has the potential to save the healthcare system quantities of money sufficient to repay investment in a clinical trial, and build an investable and sustainable financial proposition. Crucially this model would deliver much needed new treatments to rare disease patients, treatments which would otherwise be considered financially inviable.
Wednesday, December 21, 2016
Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders
Md. Torequl Islam, Neurological Research Vol. 0 , Iss. 0,0, Pages 1-10 doi:10.1080/01616412.2016.1251711
Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases.
In Friedreich’s ataxia, iron accumulates in the mitochondria and results mitochondrial Fe–S cluster containing proteins (e.g. aconitase) and abnormality in respiratory chain electron transporters on complex I–III, thereby leading to oxidative stress and free radical accumulation. In addition, to heart, the highest concentration of frataxin is found in the spinal cord (SC) and dorsal root ganglia. The frataxin is evident to regulate iron handling in mitochondria, thus prevents iron-induced oxidative stress. The depletion of frataxin in the mitochondria is a consequence in FRDA.
Oxidative stress has been considered to be linked to the etiology of many diseases, including neurodegenerative diseases (NDDs) such as Alzheimer diseases, Amyotrophic lateral sclerosis, Friedreich’s ataxia, Huntington’s disease, Multiple sclerosis, and Parkinson’s diseases.
In Friedreich’s ataxia, iron accumulates in the mitochondria and results mitochondrial Fe–S cluster containing proteins (e.g. aconitase) and abnormality in respiratory chain electron transporters on complex I–III, thereby leading to oxidative stress and free radical accumulation. In addition, to heart, the highest concentration of frataxin is found in the spinal cord (SC) and dorsal root ganglia. The frataxin is evident to regulate iron handling in mitochondria, thus prevents iron-induced oxidative stress. The depletion of frataxin in the mitochondria is a consequence in FRDA.
Tuesday, December 20, 2016
Iron mediated toxicity and programmed cell death: A review and a re-examination of existing paradigms
Rawan Eid, Nagla T.T. Arab, Michael T. Greenwood, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 2, February 2017, Pages 399-430, ISSN 0167-4889, doi:10.1016/j.bbamcr.2016.12.002.
Friedreich's ataxia is another example of a recessive mutation, the mutation results in a dramatic reduction in the expression of frataxin. Frataxin is thought to store iron and to promote Fe-S cluster assembly. In yeast, the overexpression the iron binding prosurvival ferritin serve to increase the viability of cells lacking frataxin while iron chelators are shown to protect cultured cell and animal models of Friedreich's ataxia. In spite of what appears to be iron overload mediated cell death iron chelator have very little therapeutic value. More likely the lack of frataxin is leading to stress, and increase in redox active iron and the induction of PCD. Thus the overexpression of genes encoding proteins with pro-survival or anti-oxidant functions, including ferritin, as well as anti-oxidants may protect from the decrease in frataxin levels.
Friedreich's ataxia is another example of a recessive mutation, the mutation results in a dramatic reduction in the expression of frataxin. Frataxin is thought to store iron and to promote Fe-S cluster assembly. In yeast, the overexpression the iron binding prosurvival ferritin serve to increase the viability of cells lacking frataxin while iron chelators are shown to protect cultured cell and animal models of Friedreich's ataxia. In spite of what appears to be iron overload mediated cell death iron chelator have very little therapeutic value. More likely the lack of frataxin is leading to stress, and increase in redox active iron and the induction of PCD. Thus the overexpression of genes encoding proteins with pro-survival or anti-oxidant functions, including ferritin, as well as anti-oxidants may protect from the decrease in frataxin levels.
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