Inder Singh, Vishnu Swarup, Sunil Shakya, Vinay Goyal, Mohammed Faruq, Achal Kumar Srivastava, Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders, Journal of the Neurological Sciences, Available online 22 May 2017, ISSN 0022-510X, doi:10.1016/j.jns.2017.05.042.
The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.
Thursday, June 1, 2017
Wednesday, May 31, 2017
Developing gene and cell therapies for rare diseases: an opportunity for synergy between academia and industry
F Mavilio; Gene Therapy , (25 May 2017) doi:10.1038/gt.2017.36
For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.
For the last 20 years, academic research has been the major, and often only, driving force behind the spectacular development of gene transfer technology for the therapy of rare genetic diseases. Investors and industry became eventually interested in gene and cell therapy, due to the success of a series of pioneering clinical trials that proved efficacy and safety of last-generation technology, and to favorable orphan drug legislation in both Europe and the United States. Developing this forms of therapy is however complex and requires skills and knowledge not necessary available to the industry, which is better placed to develop processes and products and put them on the market. Cooperation between academia and industry is an opportunity to de-risk innovative approaches and ensure a faster and more economical development of therapies for diseases with high unmet medical needs and low-profit expectations.
Tuesday, May 30, 2017
Blood–brain barrier peptide shuttles
Macarena Sánchez-Navarro, Ernest Giralt, Meritxell Teixidó, Current Opinion in Chemical Biology, Volume 38, June 2017, Pages 134-140, ISSN 1367-5931, doi:10.1016/j.cbpa.2017.04.019.
Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.
Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.
Brain delivery is hampered by the presence of the blood–brain barrier (BBB), a natural defence of the brain that protects it and allows the entrance of nutrients by several mechanisms. Taking advantage of these mechanisms is an opportunity to treat brain related diseases. Among the different alternatives, BBB peptide shuttles are gaining attention to increase brain delivery of therapeutics.
Peptides shuttles present several advantages over the brain delivery system alternatives. For instance, peptides are amenable for chemical synthesis, and present low toxicity. Some of the challenges of its application are already being solved. The recent development of new and more efficient BBB-shuttles will lead to more pre- clinical studies, and hopefully, to clinical evaluations in the following years.
Monday, May 29, 2017
Cerebral compensation during motor function in Friedreich ataxia: The IMAGE-FRDA study
Harding, I. H., Corben, L. A., Delatycki, M. B., Stagnitti, M. R., Storey, E., Egan, G. F. and Georgiou-Karistianis, N. (2017), Mov. Disord.. doi: 10.1002/mds.27023
Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia.
Contemporary theories, models, and evidence of neural compensation and neural reserve firmly support the notion that neurofunctional changes underlying degenerative diseases are not only detrimental but also may be compensatory. This idea has driven a groundswell of research into novel therapeutic approaches designed to stimulate or maintain these compensatory cerebral processes through, for example, noninvasive brain stimulation, or cognitive therapies. Given the evidence that cerebral compensation may also operate in FRDA, these novel means of intervention represent exciting pathways for future research.
The present study motivates a reconceptualization of cerebral contributions to FRDA. In particular, cerebral alterations are likely not just secondary repercussions of cerebellar and spinal insults. Rather, cerebral changes may represent capacity limited compensatory processes operating at the network level of brain function, which serve to mitigate the behavioral impacts of progressive pathology. Critically, these novel findings inform development of new avenues of clinical intervention for FRDA.
Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity-limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network-level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia.
Contemporary theories, models, and evidence of neural compensation and neural reserve firmly support the notion that neurofunctional changes underlying degenerative diseases are not only detrimental but also may be compensatory. This idea has driven a groundswell of research into novel therapeutic approaches designed to stimulate or maintain these compensatory cerebral processes through, for example, noninvasive brain stimulation, or cognitive therapies. Given the evidence that cerebral compensation may also operate in FRDA, these novel means of intervention represent exciting pathways for future research.
The present study motivates a reconceptualization of cerebral contributions to FRDA. In particular, cerebral alterations are likely not just secondary repercussions of cerebellar and spinal insults. Rather, cerebral changes may represent capacity limited compensatory processes operating at the network level of brain function, which serve to mitigate the behavioral impacts of progressive pathology. Critically, these novel findings inform development of new avenues of clinical intervention for FRDA.
Sunday, May 28, 2017
In Vitro Antioxidant Activity of Idebenone Derivative-Loaded Solid Lipid Nanoparticles
Lucia Montenegro, Maria N. Modica, Loredana Salerno, Anna Maria Panico, Lucia Crascì, Giovanni Puglisi and Giuseppe Romeo; Molecules 2017, 22(6), 887; doi:10.3390/molecules22060887
Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity.
In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.
Idebenone (IDE) has been proposed for the treatment of neurodegenerative diseases involving mitochondria dysfunctions. Unfortunately, to date, IDE therapeutic treatments have not been as successful as expected. To improve IDE efficacy, in this work we describe a two-step approach: (1) synthesis of IDE ester derivatives by covalent linking IDE to other two antioxidants, trolox (IDETRL) and lipoic acid (IDELIP), to obtain a synergic effect; (2) loading of IDE, IDETRL, or IDELIP into solid lipid nanoparticles (SLN) to improve IDE and its esters’ water solubility while increasing and prolonging their antioxidant activity.
In vitro antioxidant activity of these SLN was evaluated in comparison with free drugs by means of oxygen radical absorbance capacity (ORAC) test. IDETRL and IDELIP showed a greater antioxidant activity than IDE and encapsulation of IDE and its derivatives into SLN was able to prolong their antioxidant activity. These results suggest that loading IDETRL and IDELIP into SLN could be a useful strategy to improve IDE efficacy.
Saturday, May 27, 2017
Structural signature of classical versus late-onset friedreich's ataxia by Multimodality brain MRI
Thiago Junqueira R. Rezende, Alberto Rolim M. Martinez, Ingrid Faber, Karen Girotto, José Luiz Pedroso, Orlando G. Barsottini, Iscia Lopes-Cendes, Fernando Cendes, Andreia V. Faria and Marcondes C. França; Hum Brain Mapp. 2017 May 23. doi: 10.1002/hbm.23655. [Epub ahead of print]
The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.
Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).
The cFRDA and LOFA groups have similar, but not identical neuroimaging damage pattern. These structural differences might help to explain the phenotypic variability observed in FRDA.
Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P < 0.001).
Friday, May 26, 2017
Progressive mitochondrial protein lysine acetylation and heart failure in a model of Friedreich’s ataxia cardiomyopathy
Stram AR, Wagner GR, Fogler BD, Pride PM, Hirschey MD, Payne RM (2017). PLoS ONE 12(5): e0178354. doi:10.1371/journal.pone.0178354
Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.
These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.
Acetylation was temporally progressive and paralleled evolution of heart failure in the FXN KO model. Increased acetylation preceded detectable abnormalities in cardiac function and progressed rapidly with age in the FXN KO mouse. Acetylation was also associated with cardiac fibrosis, mitochondrial damage, impaired fat metabolism, and diastolic and systolic dysfunction leading to heart failure. There was a strong inverse correlation between level of protein acetylation and heart function.
These results demonstrate a close relationship between mitochondrial protein acetylation, physiologic dysfunction and metabolic disruption in FRDA hypertrophic cardiomyopathy and suggest that abnormal acetylation contributes to the pathophysiology of heart disease in FRDA. Mitochondrial protein acetylation may represent a therapeutic target for early intervention.
Wednesday, May 24, 2017
Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990–2015: a novel analysis from the Global Burden of Disease Study 2015
GBD 2015 Healthcare Access and Quality Collaborators (Ryan M Barber, Nancy Fullman, Reed J D Sorensen, Thomas Bollyky, Martin McKee, Ellen Nolte, Amanuel Alemu Abajobir, Kalkidan Hassen Abate, Cristiana Abbafati, Kaja M Abbas et al); The Lancet, Volume null, Issue null, DOI:10.1016/S0140-6736(17)30818-8
Funding: Bill & Melinda Gates Foundation.
Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.
National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Funding: Bill & Melinda Gates Foundation.
Unfortunately those affected by a rare disease need a good response from the health system throughout all life, perhaps more than those who are affected by common diseases. Although it is a paper about public health in general it could give us an idea about what we can expect from our national health systems in 195 different countries.
National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.
Tuesday, May 23, 2017
Regulators of frataxin PATENT WO 2017037567 A1
Pfizer Inc., 9 Mar 2017. This invention relates to a method of treating a condition or a disease associated with decreased levels or activity of frataxin, including Friedreich's ataxia, comprising administering to a subject in needthereof a therapeutically effective amount of a BET- family bromodomain inhibitor, or a pharmaceutically acceptable salt thereof. Related methods, pharmaceutical uses and pharmaceutical compositions are disclosed herein.
Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.
Related press releases:
Recent Publication and Patent Application Referencing Apabetalone Support its Continued Development and Success,
CALGARY, May 23, 2017 /CNW/ - Resverlogix Corp. ("Resverlogix" or the "Company") (TSX: RVX) today highlighted two additional works involving its lead drug, apabetalone, one recently published by third party academics and one in the form of a patent application by Pfizer Inc. (Pfizer).
Findings on Frataxin Expression and Friedreich's Ataxia:
Recently, Pfizer applied for a patent titled: "Regulators of Frataxin" (WO 2017/037567 A1), their invention relates to the expression of frataxin by utilizing BET-bromodomain inhibitors. The purpose of the invention is for the potential treatment of a rare disease called Friedreich' ataxia (FA). RVX-208 (apabetalone) was listed as a potentially effective agent against this disease which is present in about 1 in 50,000 people. The ataxia of Friedreich's ataxia occurs from the degeneration of nerve tissue in the spinal cord. Symptoms usually begin between 5 to 15 years of age, leading to wheelchair requirements and can eventually lead to early death often related to cardiovascular disease.
Saturday, May 20, 2017
Nrf2, cellular redox regulation, and neurologic implications
Eduardo E. Benarroch, MD; Neurology May 16, 2017, 88:20 1942-1950; published ahead of print April 19, 2017, 1526-632X
Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.
Nuclear factor erythroid 2 p45-related factor 2 (Nrf2), encoded by the NFE2L2 gene, is a major regulator of cellular homeostasis. Nrf2 is a transcription factor that promotes the production of components of antioxidant systems, including the glutathione and thiol systems, enzymes of pathways that generate nicotinamide adenine dinucleotide phosphate, and proteins involved in iron metabolism, xenobiotic detoxification, proteostasis, and lipogenesis. Nrf2 protects mitochondrial function and promotes clearance of misfolded proteins, and thus prevents initiation of cell death programs. The regulation and effects of Nrf2 signaling have been reviewed recently. Ntf2 activation is neuroprotective in models of neurologic disorders such as Parkinson disease and multiple sclerosis; impaired Nrf2 signaling may contribute to oxidative stress in Friedreich ataxia. Thus, activation of Nrf2 signaling is an attractive pharmacologic target for neuroprotection. This review focuses on some fundamental aspects of Nrf2 effects on redox systems, mitochondrial function, and proteostasis.
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