Megan J. Keage, Martin B. Delatycki, Isabelle Gupta, Louise A. Corben, Adam P. Vogel; Dysphagia (2017). doi:10.1007/s00455-017-9804-4
Oropharyngeal dysphagia is commonly present in individuals with FRDA and worsens with disease duration and severity. Individuals with FRDA are at risk of aspiration at any stage of the disease and should be reviewed regularly. Instrumental analysis remains the only reliable method to detect aspiration in this population. Dysphagia significantly affects the quality of life of individuals with FRDA. No reliable predictors of penetration or aspiration were identified.
Friday, May 5, 2017
Thursday, May 4, 2017
Glutathione as a Redox Biomarker in Mitochondrial Disease—Implications for Therapy
Gregory M. Enns and Tina M. Cowan; Journal of Clinical Medicine 2017, 6(5), 50; doi:10.3390/jcm6050050
“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function. The lack of validated, widely available, and objective markers of mitochondrial function makes this state-of-the-art of mitochondrial medicine in the 21st century somewhat discouraging.
Dysfunction of the mitochondrial electron transport chain is associated with redox imbalance and abnormally low GSH levels in primary genetic mitochondrial disorders, as well as conditions associated with secondary mitochondrial impairment, such as organic acidemias, Friedreich ataxia, Alzheimer disease, Parkinson disease, amyotropic lateral sclerosis, and Rett syndrome.
Friedreich ataxia patients also have evidence of redox abnormalities and mitochondrial dysfunction. A study of 14 unrelated Friedreich ataxia patients measured total and free GSH concentrations in erythrocytes by HPLC. Patients had a significant reduction of free glutathione levels, although total glutathione levels were comparable to controls. Friedreich ataxia patients were also found to have a significant increase in glutathione bound to hemoglobin in erythrocytes. Glutathione homeostasis was, therefore, considered to be impaired in Friedreich ataxia, raising the possibility that free radicals play a role in disease pathophysiology.
“Do you feel any better?” is a commonly asked question by a physician caring for a patient who has an underlying mitochondrial disorder during a clinic visit, typically after an interval of time following the start of various co-factors, vitamins, or supplements that may have a beneficial effect on mitochondrial function. The lack of validated, widely available, and objective markers of mitochondrial function makes this state-of-the-art of mitochondrial medicine in the 21st century somewhat discouraging.
Dysfunction of the mitochondrial electron transport chain is associated with redox imbalance and abnormally low GSH levels in primary genetic mitochondrial disorders, as well as conditions associated with secondary mitochondrial impairment, such as organic acidemias, Friedreich ataxia, Alzheimer disease, Parkinson disease, amyotropic lateral sclerosis, and Rett syndrome.
Friedreich ataxia patients also have evidence of redox abnormalities and mitochondrial dysfunction. A study of 14 unrelated Friedreich ataxia patients measured total and free GSH concentrations in erythrocytes by HPLC. Patients had a significant reduction of free glutathione levels, although total glutathione levels were comparable to controls. Friedreich ataxia patients were also found to have a significant increase in glutathione bound to hemoglobin in erythrocytes. Glutathione homeostasis was, therefore, considered to be impaired in Friedreich ataxia, raising the possibility that free radicals play a role in disease pathophysiology.
Monday, May 1, 2017
The new top 10 most expensive drugs on the planet
Endpoints News. by John Carroll
April 28, 2017 07:38 AM
¨5. Actimmune $572,292¨
Company: Horizon
Category: Rare disease – orphan drug
(Interferon gamma 1-b)
Approved for severe, malignant osteopetrosis and chronic granulomatous disease, rare genetic diseases, Actimmune noted last last year that the drug failed a Phase III for Friedreich’s ataxia. Horizon obtained a separate orphan drug designation for the drug when it decided to mount the study.
April 28, 2017 07:38 AM
¨5. Actimmune $572,292¨
Company: Horizon
Category: Rare disease – orphan drug
(Interferon gamma 1-b)
Approved for severe, malignant osteopetrosis and chronic granulomatous disease, rare genetic diseases, Actimmune noted last last year that the drug failed a Phase III for Friedreich’s ataxia. Horizon obtained a separate orphan drug designation for the drug when it decided to mount the study.
Sunday, April 30, 2017
Mesenchymal Stem Cell-Derived Factors Restore Function to Human Frataxin-Deficient Cells
Kevin Kemp Rimi Dey, Amelia Cook, Neil Scolding, Alastair Wilkins; Cerebellum (2017). doi:10.1007/s12311-017-0860-y
The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich’s ataxia.
The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich’s ataxia.
Saturday, April 29, 2017
Frataxin Deficiency Impairs Mitochondrial Biogenesis in Cells, Mice and Humans
Mittal J. Jasoliya, Marissa Z. McMackin, Chelsea K. Henderson, Susan L. Perlman, Gino A. Cortopassi; Hum Mol Genet 2017 ddx141. doi: 10.1093/hmg/ddx141
We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency.
We observed decreased mitochondrial copy number in all the three FRDA models tested: cells, mice and patient blood. In addition we observed 40% residual mitochondrial gene expression in FRDA patient blood. These deficiencies of mitochondrial biogenesis in FRDA cells and patient blood are significantly correlated with FXN expression, consistent with the idea that the decreased mitochondrial biogenesis is a consequence of FXN deficiency.
Friday, April 28, 2017
Dimethyl Fumarate Mediates Nrf2-dependent Mitochondrial Biogenesis in Mice and Humans
Genki Hayashi, Mittal Jasoliya, Francesco Saccà, Chiara Pane, Alessandro Filla, Angela Marsili, Giorgia Puorro, Roberta Lanzillo, Vincenzo Brescia Morra, Gino Cortopassi; Hum Mol Genet 2017 ddx167. doi: 10.1093/hmg/ddx167
The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
The induction of mitochondrial gene expression is more dependent on its target Nrf2 than hydroxycarboxylic acid receptor 2 (HCAR2). Thus, DMF induces mitochondrial biogenesis primarily through its action on Nrf2, and is the first drug demonstrated to increase mitochondrial biogenesis with in vivo human dosing. The observation that DMF stimulates mitochondrial biogenesis, gene expression and function suggests that it could be considered for mitochondrial disease therapy and/or therapy in muscle disease in which mitochondrial function is important.
Wednesday, April 26, 2017
Retrotope To Present First Human Data On Safety And Early Efficacy Of RT001 With Neurodegeneration At American Academy of Neurology Meeting
LOS ALTOS, CA, April 21, 2017 – Dr. Theresa Zesiewicz, University of South Florida Movement Disorders Clinic, will give a podium presentation at the American Academy of Neurology annual meeting of clinical trial results of Retrotope’s RT001 in the neuromuscular disease, Friedreich’s ataxia (FA) on April 24, 2017.
The study showed good safety and tolerability of this novel drug class, including early signals of efficacy with regard to disease progression. The trial, a randomized, double--blind, comparator-controlled study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacodynamics (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important disease progression measures showed signals of drug effect in post hoc analysis, unexpected in such a short, small study.
Related news: Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia
The study showed good safety and tolerability of this novel drug class, including early signals of efficacy with regard to disease progression. The trial, a randomized, double--blind, comparator-controlled study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacodynamics (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important disease progression measures showed signals of drug effect in post hoc analysis, unexpected in such a short, small study.
Related news: Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia
Tuesday, April 25, 2017
Determinants of orphan drugs prices in France: a regression analysis
Daria Korchagina, Aurelie Millier, Anne-Lise Vataire, Samuel Aballea, Bruno Falissard and Mondher Toumi; Orphanet Journal of Rare Diseases 201712:75 DOI: 10.1186/s13023-016-0561-5 Published: 21 April 2017
The introduction of the orphan drug legislation led to the increase in the number of available orphan drugs, but the access to them is often limited due to the high price. Social preferences regarding funding orphan drugs as well as the criteria taken into consideration while setting the price remain unclear.
Decisions on orphan drug prices remain non transparent in most of cases. A robust comprehensive framework is needed to assess orphan drugs value. Several methodologies have been proposed mostly based on the multi-criteria decision analysis.
The introduction of the orphan drug legislation led to the increase in the number of available orphan drugs, but the access to them is often limited due to the high price. Social preferences regarding funding orphan drugs as well as the criteria taken into consideration while setting the price remain unclear.
Decisions on orphan drug prices remain non transparent in most of cases. A robust comprehensive framework is needed to assess orphan drugs value. Several methodologies have been proposed mostly based on the multi-criteria decision analysis.
Monday, April 24, 2017
CA Cycle in the Dentate in Friedreich's Ataxia
ClinicalTrials.gov Identifier: NCT03122925 First received: April 18, 2017
OBJECTIVE: To measure the tricarboxylic acid (TCA) cycle rate in the dentate nucleus in a group of control subjects and subjects with Friedreich's Ataxia (FRDA).
HYPOTHESIS: The TCA cycle rate will be lower in FRDA subjects than in controls APPROACH: We will infuse carbon-13 (13C) labeled glucose and measure the rate of 13C label incorporation from glucose to glutamate in the brain using in vivo magnetic resonance spectroscopy.
Detailed Description:
We will measure the TCA cycle rate in the dentate nucleus in a group of FRDA patients and in a group of age-matched healthy controls using 13C MRS in vivo together with systemic i.v. infusion of 13C-labeled glucose.
We aim to obtain adequate data in 16 subjects grouped as follows:
n=4 pilot subjects (healthy subjects) for testing and optimization of the experimental setup.
n=6 healthy controls
n=6 FRDA patients
Locations
United States, Minnesota
CMRR
Minneapolis, Minnesota, United States, 55455
Contact: Diane Hutter, RN 612-625-2350 hutte019@umn.edu
Principal Investigator: Pierre-Gilles Henry, PhD
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
OBJECTIVE: To measure the tricarboxylic acid (TCA) cycle rate in the dentate nucleus in a group of control subjects and subjects with Friedreich's Ataxia (FRDA).
HYPOTHESIS: The TCA cycle rate will be lower in FRDA subjects than in controls APPROACH: We will infuse carbon-13 (13C) labeled glucose and measure the rate of 13C label incorporation from glucose to glutamate in the brain using in vivo magnetic resonance spectroscopy.
Detailed Description:
We will measure the TCA cycle rate in the dentate nucleus in a group of FRDA patients and in a group of age-matched healthy controls using 13C MRS in vivo together with systemic i.v. infusion of 13C-labeled glucose.
We aim to obtain adequate data in 16 subjects grouped as follows:
n=4 pilot subjects (healthy subjects) for testing and optimization of the experimental setup.
n=6 healthy controls
n=6 FRDA patients
Locations
United States, Minnesota
CMRR
Minneapolis, Minnesota, United States, 55455
Contact: Diane Hutter, RN 612-625-2350 hutte019@umn.edu
Principal Investigator: Pierre-Gilles Henry, PhD
Sponsors and Collaborators
University of Minnesota - Clinical and Translational Science Institute
Friday, April 21, 2017
Orphan Drugs: Getting Arms around Rare Diseases
Duygu Koyuncu Irmak; J Comm Pub Health Nurs 2017, 3:2 DOI: 10.4172/2471-9846.1000167
Finding ways to bring new therapies for rare diseases to patients in a timely manner, effectively and affordably is an important public health challenge. The key concern for decision makers in the health authorities for all medicinal products including Orphan Drugs is that the treatment demonstrates efficacy through “substantial evidence” from adequate, well-planned, well-controlled clinical trials.
A successful clinical development programs in rare diseases starts with a tailored approach to ensure the right methodology is employed for the target rare disease therapy. The research methodology needs to be evaluated specifically for each rare disease and the target therapy in the light of all available scientific knowledge by all experts acting in all stakeholders.
Finding ways to bring new therapies for rare diseases to patients in a timely manner, effectively and affordably is an important public health challenge. The key concern for decision makers in the health authorities for all medicinal products including Orphan Drugs is that the treatment demonstrates efficacy through “substantial evidence” from adequate, well-planned, well-controlled clinical trials.
A successful clinical development programs in rare diseases starts with a tailored approach to ensure the right methodology is employed for the target rare disease therapy. The research methodology needs to be evaluated specifically for each rare disease and the target therapy in the light of all available scientific knowledge by all experts acting in all stakeholders.
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