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.

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.

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.

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

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.

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

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.

Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia (CStDCSAtaxia)

ClinicalTrials.gov Identifier: NCT03120013 First received: April 14, 2017

Neurodegenerative cerebellar ataxias represent a group of disabling disorders for which we currently lack effective therapies. Cerebellar transcranial direct current stimulation (tDCS) is a non-invasive technique, which has been demonstrated to modulate cerebellar excitability and improve symptoms in patients with cerebellar ataxias. In this randomized, double-blind, sham-controlled study, the investigators will evaluate whether a two-weeks' treatment with cerebellar anodal tDCS and spinal cathodal tDCS can improve symptoms in patients with neurodegenerative cerebellar ataxia and can modulate cerebello-motor connectivity, at short and long term.

Condition:
Ataxia, Cerebellar, Cerebellar Ataxia, Spinocerebellar Ataxias, Spinocerebellar Ataxia Type 1, Spinocerebellar Ataxia Type 2, Spinocerebellar Ataxia 3, Spinocerebellar Degenerations, Friedreich Ataxia, Ataxia With Oculomotor Apraxia, Multiple System Atrophy.
Intervention:
Device: Anodal cerebellar and cathodal spinal tDCS, Device: Sham cerebellar and sham spinal tDCS.

Locations:
Italy, AO Spedali Civili, Brescia, BS, Italy, 25100

Contact: Barbara Borroni

Friedreich Ataxia: current status and future prospects

Bürk K; Cerebellum Ataxias. 2017 Apr 7;4:4. doi: 10.1186/s40673-017-0062-x. eCollection 2017.

This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.

Australian children living with rare diseases: experiences of diagnosis and perceived consequences of diagnostic delays

Yvonne Zurynski, Marie Deverell, Troy Dalkeith, Sandra Johnson, John Christodoulou, Helen Leonard, Elizabeth J Elliott and APSU Rare Diseases Impacts on Families Study group; Orphanet Journal of Rare Diseases201712:68 DOI: 10.1186/s13023-017-0622-4; Published: 11 April 2017

Parents of children living with rare chronic and complex diseases have called for better education, resourcing of health professionals to prevent avoidable diagnostic delays, and to facilitate access to early interventions and treatments. Access to psychological support and genetic counselling should be available to all parents receiving a life-changing diagnosis for their child.
The most common perceived reasons for delayed diagnosis reported by parents participating in our study was the lack of knowledge among health professionals.
Receiving a diagnosis of a rare chronic and complex disease for their child is a life-changing event for many families, and most require support at or near the time that diagnosis is made. Almost all parents in our study believed that psychological support should always be offered at the time of diagnosis.
Parents believe that health professionals’ knowledge about rare diseases needs to improve to enable more timely diagnosis, treatment, and provision of accurate information about the implications of the disease to families who are stressed, frustrated and anxious. The integration of genomic medicine into the health system, the establishment of multidisciplinary specialist clinics, and clear referral pathways may improve the timeliness and accuracy of diagnosis for children with rare diseases. The ultimate aim should be to improve patient and family experiences, and it is therefore imperative that patients are involved in development and evaluation of such programs.

No changes in heme synthesis in human Friedreich´s ataxia erythroid progenitor cells

Hannes Steinkellner, Himanshu Narayan Singh, Martina U. Muckenthaler, Hans Goldenberg, Rajeswari R. Moganty, Barbara Scheiber-Mojdehkar, Brigitte Sturm, Gene, Available online 12 April 2017, ISSN 0378-1119, doi:10.1016/j.gene.2017.04.014.

The mystery about the involvement of frataxin on iron metabolism raises the question why frataxin deficiency in primary FRDA cells did not lead to changes in biochemical parameters of heme synthesis. It seems that alternative pathways can circumvent the impact of frataxin deficiency on heme synthesis. We show for the first time in primary FRDA patient cells that reduced frataxin levels are still sufficient for heme synthesis and possibly other mechanisms can overcome reduced frataxin levels in this process. Our data strongly support the fact that so far no anemia in FRDA patients was reported.
FRDA patient cells showed no significant changes in iron levels, hemoglobin synthesis, protoporphyrin IX levels, and ferrochelatase activity. Microarray analysis presented 11 genes that were significantly changed in all patients compared to controls. The genes are especially involved in oxidative stress, iron homeostasis and angiogenesis.

Drugmakers accused of exploiting orphan drug incentives, fueling price problem

Brady Huggett, Nature Biotechnology 35, 301 (2017) doi:10.1038/nbt0417-301 Published online 11 April 2017

n January Kaiser Health News published a data-rich report focusing on the increase in approvals of orphan disease drugs, detailing how even high-volume products have reaped the tax breaks and market exclusivity that come with orphan drug status.
For each approval, drugmakers receive government incentives plus seven years exclusivity for that rare disease. Orphan status became a commercial opportunity.
Orphan drug rules “appear to be stretched beyond their original intent,” which may be helping to stoke drug prices for commonly used drugs.

Biogen Accused Of Stifling Neurological Drug Competition

Law360, Los Angeles (April 4, 2017, 7:05 PM EDT) -- Biogen Inc. is facing an antitrust suit in California federal court filed Tuesday by Ixchel Pharma LLC alleging it attempted to hold a monopoly on drug treatments containing dimethyl fumarate, preventing Ixchel from creating a drug for a degenerative neurological disease.

The complaint claims Biogen specifically stopped a partnership between Ixchel and a competitor to develop a new treatment for Friedreich’s ataxia, a debilitating neuro-degenerative disorder. The condition doesn’t have an FDA-approved treatment, the complaint says, but Ixchel since 2012 has been working to develop one....

SNPs in microRNA target sites and their potential role in human disease

Adrianna Moszyńska, Magdalena Gebert, James F. Collawn, Rafał Bartoszewski; Open Biology, The Royal Society Publishing, Published 5 April 2017.DOI: 10.1098/rsob.170019

FXN | miR-124-3p: Reduced expression of the mitochondrial frataxin (FXN) protein has been postulated to play a role in Friedreich's ataxia (FRDA), an inherited neurodegenerative disease. Lower levels of frataxin are due to GAA repeat expansion in the FXN gene. Additionally, Bandiera et al. have suggested that miR-124-3p regulates FXN expression in vivo only in FRDA patients. They identified seven SNPs in the 3′-UTR of FXN in children and adults diagnosed with FRDA. One of them, rs11145043 (G>T), permits miR-124-3p binding only when the T allele is present. Although miR-124-3p is highly expressed in the nervous system, it is overexpressed in FRDA patients, suggesting its role in FRDA. However, its influence on FXN needs further clarification.

New research front to tackle Friedreich’s Ataxia

IRB Barcelona, 14 Mar 2017. IRB Barcelona starts a project with the long-term goal to achieve an injectable frataxin treatment able to reach the brain. The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.

The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.

Reata Pharmaceuticals, Inc. Secures $35 Million Term Loan Facility

IRVING, Texas, April 03, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced that it entered into a $35 million loan and security agreement with Oxford Finance LLC and Silicon Valley Bank. Proceeds from the loan will be utilized primarily to support Reata’s multiple Phase 2 and 3 clinical trial programs for bardoxolone methyl and omavaloxolone.
The loan proceeds are available to Reata in two tranches. The first $20 million tranche was funded on Friday, March 31st. The additional $15 million tranche will be available to Reata from July 1, 2017 to March 31, 2018, and after Reata enrolls the first patient in either (a) the Phase 3 portion of the ongoing Phase 2/3 clinical trial of bardoxolone methyl in chronic kidney disease caused by Alport syndrome or (b) Part 2 of the ongoing two-part clinical trial, or a separate Phase 3 clinical trial, of omavaloxolone in Friedreich’s ataxia.

Characteristics of Friedreich’s Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6

Pınar Bengi Boz, Filiz Koç, Sabriye Kocatürk Sel, Ali İrfan Güzel, Halil Kasap, Arch Neuropsychiatry 2016; 53: 115-119, DOI:10.5152/npa.2015.9925

This study aimed to analyze the genotypic characteristics of Friedreich’s ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings.
In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA.