http://www.bioportfolio.com/news/article/2883537/Launches-of-First-Therapies-Approved-for-Spinal-Muscular-Atrophy-and-Friedreichs-Ataxia.html
Launches of First Therapies Approved for Spinal Muscular Atrophy and Friedreich’s Ataxia Will Revolutionize Treatment and Drive Growth of These Rare Disease Markets
BURLINGTON, Mass., Oct. 25, 2016 /PRNewswire/ — Decision Resources Group finds that the anticipated launches of the first therapies for the treatment of spinal muscular atrophy (SMA) or Friedreich’s ataxia (FA) will transform treatment of these diseases and lead to their markets expanding dramatically. Medical practice in SMA and FA is currently dominated by supportive care or symptomatic treatment. However, the complete lack of efficacious treatment options translates into high unmet need and represents an as-yet untapped and lucrative market opportunity for drug developers.
Related Biotechnology, Pharmaceutical and Healthcare News
·        Success for Biogen, Ionis as spinal muscular atrophy drug performs in Phase III
·        Trial offers hope of a treatment for spinal muscular atrophy
·        First treatment for spinal muscular atrophy to be submitted for FDA approval based on positive results in clinical trial
·        Scientists locate possible therapy target for spinal muscular atrophy
·        Promising new therapeutic target could lead to better prognosis of spinal muscular atrophy
Ionis/Biogen’s antisense oligonucleotide nusinersen, which targets the underlying cause of SMA, will be the first agent ever approved for this disease. Based on efficacy data fromclinical trials, interviewed pediatric neurologists expect rapid and widespread use of nusinersen. Assuming high-premium pricing, the launch of nusinersen, expected in 2017, will be a key driver of market expansion.
Following the anticipated label expansion of Horizon Pharma’s Actimmune (interferon gamma-1b), the FA market is forecasted to grow significantly over the next ten years. However, interviewed neurologists’ perceived limitations of Actimmune, including its unclear mechanism of action, variable effect on frataxin protein levels, and modest preservation of neurological function, could constrain its uptake and allow competitors to challenge Actimmune’s position.
Other key findings from the Niche & Rare Disease Landscape & Forecast reports entitled Spinal Muscular Atrophy and Friedreich’s Ataxia:
·        In both SMA and FA, first-to-market therapies will likely benefit patients, but commercial opportunity remains for novel therapies that can offer improvements in efficacy, safety, and delivery. Further, physicians expect new therapies with different targets and mechanisms of action would be used in combination with existing agents.
·        During the second half of the 2015-2025 study period, nusinersen may face competition from AveXis’s investigational gene therapy AVXS-101, which has shown tremendous promise in an ongoing clinical trial. AVXS-101 could potentially be delivered in a single intravenous administration, in contrast to nusinersen’s triannual intrathecal administration, and may be curative.
·        According to interviewed experts, gene therapy will also transform the FA treatment landscape, possibly negating the need for drug treatment. However, gene therapies being developed by Agilis Biotherapeutics, Pfizer, and RaNA Therapeutics are in preclinical testing and unlikely to launch during the study period.
Comments from Decision Resources Group Analysts, Ian Love, Ph.D., and Tara M. Stewart, M.A., Ph.D., respectively:
·        “SMA is a serious and often fatal rare disease usually afflicting children, and there are no useful therapies available to treat this devastating condition. Thanks to the continued commercial interest in developing treatments for severe rare diseases, SMA patients may soon have access to effective therapies. Nusinersen and AVXS-101 have the potential to revolutionize care for SMA patients.”
·        “Despite the lack of competing brands entering the market in the near term, Actimmune’s high U.S. cost may be an obstacle for its rapid adoption among patients with FA. If Actimmune can show that it delays disease progression or improves neurological function over a year or more, prescribers, patients, and payers are likely to accept its very high price.”
For more information on purchasing these reports, please email questions@dresourcesgroup.com.
About Decision Resources GroupDecision Resources Group offers best-in-class, high-value data,


http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165788
Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting
·        Helen Bergquist,
·        Cristina S. J. Rocha,
·        Rubén Álvarez-Asencio,
·        Chi-Hung Nguyen,
·        Mark. W. Rutland,
·        C. I. Edvard Smith,
·        Liam Good,
·        Peter E. Nielsen,
·        Rula Zain
Abstract
Expansion of (GAA)n repeats in the first intron of the Frataxin gene is associated with reduced mRNA and protein levels and the development of Friedreich’s ataxia. (GAA)n expansions form non-canonical structures, including intramolecular triplex (H-DNA), and R-loops and are associated with epigenetic modifications. With the aim of interfering with higher order H-DNA (like) DNA structures within pathological (GAA)n expansions, we examined sequence-specific interaction of peptide nucleic acid (PNA) with (GAA)n repeats of different lengths (short: n=9, medium: n=75 or long: n=115) by chemical probing of triple helical and single stranded regions. We found that a triplex structure (H-DNA) forms at GAA repeats of different lengths; however, single stranded regions were not detected within the medium size pathological repeat, suggesting the presence of a more complex structure. Furthermore, (GAA)4-PNA binding of the repeat abolished all detectable triplex DNA structures, whereas (CTT)5-PNA did not. We present evidence that (GAA)4-PNA can invade the DNA at the repeat region by binding the DNA CTT strand, thereby preventing non-canonical-DNA formation, and that triplex invasion complexes by (CTT)5-PNA form at the GAA repeats. Locked nucleic acid (LNA) oligonucleotides also inhibited triplex formation at GAA repeat expansions, and atomic force microscopy analysis showed significant relaxation of plasmid morphology in the presence of GAA-LNA. Thus, by inhibiting disease related higher order DNA structures in the Frataxingene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression.


http://www.sciencedirect.com/science/article/pii/S1935861X16302996
Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia
·        Alberto Benussia,
·        Valentina Dell’Eraa,
·        Maria Sofia Cotellib,
·        Marinella Turlab,
·        Carlo Casalic,
·        Alessandro Padovania,
·        Barbara Borronia, ,
Abstract
Background
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.
Objective
The present study investigated whether a two-weeks’ treatment with cerebellar anodal tDCS could improve symptoms in patients with neurodegenerative cerebellar ataxia and could modulate cerebello-motor connectivity, at short and long term.
Methods
We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia. Each patient underwent a clinical evaluation pre- and post-anodal tDCS or sham stimulation. A follow-up evaluation was performed at one and three months. Cerebello-motor connectivity was evaluated using transcranial magnetic stimulation (TMS) at baseline and at follow-up.
Results
Patients who underwent anodal tDCS showed a significant improvement in all performance scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale, 9-hole peg test, 8-m walking time) and in cerebellar brain inhibition compared to patients who underwent sham stimulation.
Conclusions
A two-weeks’ treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia.


http://jamanetwork.com/journals/jamaneurology/article-abstract/2578327
Doubts About Therapy for Neurological Diseases With Antisense Oligonucleotides
Satyakam Bhagavati, MD1
To the Editor The review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on which ASO-based treatment is based is promising, a review of the literature, however, reveals critical lacunae in the data that have been used to claim efficacy.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497958/
Friedreich’s Ataxia Causes Redistribution of Iron, Copper, and Zinc in the Dentate Nucleus
Arnulf H. Koeppen, 1,2,3 R. Liane Ramirez,1 Devin Yu,1 Sarah E. Collins,1 Jiang Qian,3 Patrick J. Parsons,4,5 Karl X. Yang,4,5 Zewu Chen,6 Joseph E. Mazurkiewicz,7 and Paul J. Feustel7
Go to:
Abstract
Friedreich’s ataxia (FRDA) causes selective atrophy of the large neurons of the dentate nucleus (DN). High iron (Fe) concentration and failure to clear the metal from the affected brain tissue are potential risk factors in the progression of the lesion. The DN also contains relatively high amounts of copper (Cu) and zinc (Zn), but the importance of these metals in FRDA has not been established. This report describes nondestructive quantitative X-ray fluorescence (XRF) and “mapping” of Fe, Cu, and Zn in polyethylene glycol–dimethylsulfoxide (PEG/DMSO)-embedded DN of 10 FRDA patients and 13 controls. Fe fluorescence arose predominantly from the hilar white matter, whereas Cu and Zn were present at peak levels in DN gray matter. Despite collapse of the DN in FRDA, the location of the peak Fe signal did not change. In contrast, the Cu and Zn regions broadened and overlapped extensively with the Fe-rich region. Maximal metal concentrations did not differ from normal (in micrograms per milliliter of solid PEG/DMSO as means ± S.D.): Fe normal, 364 ± 117, FRDA, 344 ± 159; Cu normal, 33 ± 13, FRDA, 33 ± 18; and Zn normal, 32 ± 16, FRDA, 33 ± 19. Tissues were recovered from PEG/DMSO and transferred into paraffin for matching with immunohistochemistry of neuron-specific enolase (NSE), glutamic acid decarboxylase (GAD), and ferritin. NSE and GAD reaction products confirmed neuronal atrophy and grumose degeneration that coincided with abnormally diffuse Cu and Zn zones. Ferritin immunohistochemistry matched Fe XRF maps, revealing the most abundant reaction product in oligodendroglia of the DN hilus. In FRDA, these cells were smaller and more numerous than normal. In the atrophic DN gray matter of FRDA, anti-ferritin labeled mostly hypertrophic microglia. Immunohistochemistry and immunofluorescence of the Cu-responsive proteins Cu,Zn-superoxide dismutase and Cu++-transporting ATPase α-peptide did not detect specific responses to Cu redistribution in FRDA. In contrast, metallothionein (MT)-positive processes were more abundant than normal and contributed to the gliosis of the DN. The isoforms of MT, MT-1/2, and brain-specific MT-3 displayed only limited co-localization with glial fibrillary acidic protein. The results suggest that MT can provide effective protection against endogenous Cu and Zn toxicity in FRDA, similar to the neuroprotective sequestration of Fe in holoferritin.
Friedreich’s ataxia (FRDA) causes selective atrophy of the large neurons of the dentate nucleus (DN). High iron (Fe) concentration and failure to clear the metal from the affected brain tissue are potential risk factors in the progression of the lesion. The DN also contains relatively high amounts of copper (Cu) and zinc (Zn), but the importance of these metals in FRDA has not been established. This report describes nondestructive quantitative X-ray fluorescence (XRF) and “mapping” of Fe, Cu, and Zn in polyethylene glycol–dimethylsulfoxide (PEG/DMSO)-embedded DN of 10 FRDA patients and 13 controls. Fe fluorescence arose predominantly from the hilar white matter, whereas Cu and Zn were present at peak levels in DN gray matter. Despite collapse of the DN in FRDA, the location of the peak Fe signal did not change. In contrast, the Cu and Zn regions broadened and overlapped extensively with the Fe-rich region. Maximal metal concentrations did not differ from normal (in micrograms per milliliter of solid PEG/DMSO as means ± S.D.): Fe normal, 364 ± 117, FRDA, 344 ± 159; Cu normal, 33 ± 13, FRDA, 33 ± 18; and Zn normal, 32 ± 16, FRDA, 33 ± 19. Tissues were recovered from PEG/DMSO and transferred into paraffin for matching with immunohistochemistry of neuron-specific enolase (NSE), glutamic acid decarboxylase (GAD), and ferritin. NSE and GAD reaction products confirmed neuronal atrophy and grumose degeneration that coincided with abnormally diffuse Cu and Zn zones. Ferritin immunohistochemistry matched Fe XRF maps, revealing the most abundant reaction product in oligodendroglia of the DN hilus. In FRDA, these cells were smaller and more numerous than normal. In the atrophic DN gray matter of FRDA, anti-ferritin labeled mostly hypertrophic microglia. Immunohistochemistry and immunofluorescence of the Cu-responsive proteins Cu,Zn-superoxide dismutase and Cu++-transporting ATPase α-peptide did not detect specific responses to Cu redistribution in FRDA. In contrast, metallothionein (MT)-positive processes were more abundant than normal and contributed to the gliosis of the DN. The isoforms of MT, MT-1/2, and brain-specific MT-3 displayed only limited co-localization with glial fibrillary acidic protein. The results suggest that MT can provide effective protection against endogenous Cu and Zn toxicity in FRDA, similar to the neuroprotective sequestration of Fe in holoferritin.


http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30287-3/abstract?cc=y=
Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study
Kathrin Reetz, MD
,
Imis Dogan, PhD
,
Prof Ralf-Dieter Hilgers, PhD
,
Paola Giunti, MD
,
Caterina Mariotti, MD
,
Alexandra Durr, MD
,
Sylvia Boesch, MD
,
Thomas Klopstock, MD
,
Francisco Javier Rodriguez de Rivera, MD
,
Prof Ludger Schöls, MD
,
Prof Thomas Klockgether, MD
,
Katrin Bürk, MD
,
Myriam Rai, PhD
,
Prof Massimo Pandolfo, MD
,
Prof Jörg B Schulz, MD Press enter key for correspondence information Press enter key to Email the author
for the EFACTS Study Group†
Summary
Background
The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich’s ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials.
Methods
We enrolled patients with genetically confirmed Friedreich’s ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing.
Findings
Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich’s ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial.
Interpretation
Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich’s ataxia.
Funding
European Commission.


http://www.newswise.com/articles/northwestern-medicine-scientists-use-advanced-technology-to-better-understand-a-devastating-neurodegenerative-disorder
Northwestern Medicine Scientists Use Advanced Technology To Better Understand A Devastating Neurodegenerative Disorder
150 years of research paves the way for patients suffering from ataxia
·
DNA strain of cerebellar ataxia
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CITATIONS
JAMA Neurol. Oct-2016
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Mental HealthNeuroTechnologyJAMALocal – IllinoisAll Journal News
Newswise — CHICAGO – According to a recent study published in JAMA Neurology, Northwestern Medicine scientists have examined more than a century of data of the genetic makeup of ataxias, a neurodegenerative disorder, to better understand the different forms of this devastating disease and how it affects patients. This research has the potential for scientists to have a better understanding on how to diagnose and treat the disease, which has no known cure for patients suffering from the condition.
“More than 150,000 Americans suffer from hereditary or sporadic ataxia in the United States and being able to better understand the genetic diversity allows us to gain insight on a system level into genes and cellular pathways that result in neurodegeneration,” said Puneet Opal, MD, PhD, neurologist at Northwestern Memorial Hospital.
Ataxia often occurs when parts of the nervous system that control movement are damaged. People with ataxia experience a failure of muscle control in their arms and legs, resulting in a lack of balance and coordination or a disturbance of gait, according to the National Institute of Neurological Disorders and Stroke.
To better diagnose and treat patients with ataxia, co-authors Opal and former Northwestern Medicine researcher and current University of California San Francisco School of Medicine adjunct professor Alessandro Didonna, PhD, reviewed the genetic makeup of ataxias syndrome and the use of genetic sequencing and computer driven bioinformatics over the last 150 years.
With the major advances in gene sequencing, a clearer understanding of ataxias through The Human Genome Project, the first successful undertaking to precisely sequence the human genetic code by solving the 3 billion “letters” in human DNA, and next generation sequencing (NGS), first commercially available sequencing technology that helps to identify genes with underlying genetic syndromes, helps provided additional insight on ataxia.
The Human Genome Project was launched in 1998 to be able to read nature’s complete genetic blueprint for building a human being. The ability to catalog the first full human DNA sequence inspired another approach for genome analysis called NGS which became available to researchers in 2007. This technology allowed scientists to make large scale whole genome sequencing through a computerized system that is faster, more in-depth and cost-effective.
The co-authors also discovered that cellular pathways and protein networks in ataxias exist in the genes. This discovery helped to better understand how aging plays a role in the risk for neurogenerative diseases like ataxia. In addition, scientists compared ataxia with other diseases and found a link with Alzheimer, Parkinson, and Huntington disease. Scientists now know that ataxias can be inherited by all modes of Mendelian inheritance with mutations in more than 70 genes responsible for autosomal recessive ataxias, approximately 40 autosomal dominant ataxias, 6 X-linked genes, and 3 mitochondrial – all of which are subtypes of hereditary ataxias.

“This number is likely to increase,” said Opal. “However, we are quickly closing the gap in understanding the cause of neurodegeneration. Moreover, we know that genetically different ataxia syndromes converge to cellular pathways that we hope will help generate rationale drugs that can attack these pathways and eventually provide personalized medicine for patients diagnosed with this disease.”
As part of the ongoing efforts, the co-authors of the study will be examining the complexities of the genetic mutation in ataxias syndrome hoping to discover more types of ataxias that are still uncharacterized.
The study was funded by the National Institutes of Health and the Opal Laboratory grants 1R01NS062051 and 1R01NS082351.
About Northwestern Medicine
To learn more about Northwestern Medicine, please visit: http://news.nm.org/about-northwestern-medicine.html.


https://www.eurekalert.org/pub_releases/2016-11/r-nim102716.php
New iPS-cell model system helps develop treatments for spinocerebellar ataxia
RIKEN

IMAGE: HIGH MAGNIFICATION IMAGES OF L7+ PURKINJE CELLS (GREEN) DERIVED FROM CONTROL (TOP), SCA6 HETEROZYGOUS (MIDDLE) AND SCA6 HOMOZYGOUS (BOTTOM) IPSCS ON CULTURE DAY 75 ARE SHOWN. NOTE THE DENDRITIC DEGRADATION… view more 
CREDIT: RIKEN
Researchers at the RIKEN Center for Developmental Biology have succeeded in creating a new model system that can be used to develop drug therapies for genetic disorders like spinocerebellar ataxia type 6 (SCA6). Published in Cell Reports, the study shows how stem cells from patients with SCA6 can be transformed into mature Purkinje cells — the same type of neuron that starts dying when people develop SCA6 later in life. With this setup, the team discovered that mature Purkinje cells with the SCA6 mutation became vulnerable when deprived of thyroid hormone.
SCA6 is a movement disorder characterized by death of Purkinje cells in the cerebellum, a brain region that controls our ability to produce smooth movements. No effective treatment or cure exists for this neurodegenerative disorder, and animal models have proved inconclusive. As an alternative, the team led by Keiko Muguruma focused their efforts on making a disease model based on human Purkinje cells grown in culture.
As Muguruma explains, “we succeeded in generating Purkinje cells with full sets of SCA6 patient genes. Unlike animal models, these patient-derived Purkinje cells will be extremely useful for investigating disease mechanisms and for developing effective drug therapies.”
The disease manifests in middle age and results from mutations that increase the number of times a particular section of the CACNA1A gene are repeated. The researchers first induced skin or blood cells from patients and control participants to become pluripotent stem cells. Then they used techniques recently developed in their lab to create self-organizing cerebellar tissue and Purkinje cells.
When tested, the team found that while both types of mature Purkinje cells seemed outwardly similar, they differed in how much the CACNA1A gene was expressed. The patient-derived cells contained more of the protein encoded by the CACNA1A gene than the normal cells. When immature cells were tested, protein expression levels were similar, regardless of their origins.
The part of the CACNA1A protein that contains the excessively repeated section is called α1ACT. When researchers compared expression of this fragment between normal and patient-derived cells, they found that it was expressed much less in the SCA6 Purkinje cells. Because α1ACT normally binds to DNA in the nucleus and triggers the expression of other proteins that are important for normal Purkinje-cell development, these proteins were also expressed much less in the cells that contained the mutation. Again, when the team looked at immature Purkinje cells, α1ACT expression was similar for all groups.
“This new system is particularly useful for drug discovery,” notes Muguruma. “Using it, we were able to demonstrate that patient-derived Purkinje cells show a vulnerability to nutrient depletion and that this vulnerability can be suppressed by several compounds.”
Knowing that thyroid hormone is important for proper maturation and maintenance of Purkinje cells, the researchers deprived mature neurons of the hormone and found that many of the patient-derived cells died, while those that survived showed physical abnormalities. Purkinje cells without the mutation were unaffected. Further testing showed that even when deprived of thyroid hormone, negative changes in SCA6 Purkinje cells could be prevented using thyroid releasing hormone. Similar results occurred with Riluzole, a drug often used to treat another neuromuscular disorder called ALS — also known as Lou Gehrig’s disease.
Decreased thyroid gland activity, a condition known as hypothyroidism, also occurs with age, and might be linked to SCA6 onset. Muguruma cautions, “there are some reports that hypothyroidism is related to cerebellar ataxia and cerebellar atrophy, but we do not yet know whether the SCA6 disease phenotypes are causally linked to decreased thyroid hormone.”
Now that they have proved the usefulness of this model system, Muguruma and her colleagues can continue to investigate how thyroid releasing hormone was able to protect the cells, and ultimately find a cure for this type of spinocerebellar ataxia.
###
Reference:
Ishida Y, Kawakami H, Kitajima H, Nishiyama A, Sasai Y, Inoue H, Muguruma K (2016). Vulnerability of Purkinje cells generated from spinocerebellar ataxia type 6 patient-derived iPS cells. Cell Reports. doi: 10.1016/j.celrep.2016.10.026.


http://www.jbc.org/content/275/21/16023.short
Transcription Factor Nrf2 Coordinately Regulates a Group of Oxidative Stress-inducible Genes in Macrophages*
1.  Tetsuro Ishii,
2.  Ken Itoh§,
3.  Satoru Takahashi,
4.  Hideyo Sato,
5.  Toru Yanagawa,
6.  Yasutake Katoh,
7.  Shiro Bannai and
8.  Masayuki Yamamoto
+Author Affiliations
1.  From the Institute of Basic Medical Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan
Abstract
Electrophiles and reactive oxygen species have been implicated in the pathogenesis of many diseases. Transcription factor Nrf2 was recently identified as a general regulator of one defense mechanism against such havoc. Nrf2 regulates the inducible expression of a group of detoxication enzymes, such as glutathione S-transferase and NAD(P)H:quinone oxidoreductase, via antioxidant response elements. Using peritoneal macrophages from Nrf2-deficient mice, we show here that Nrf2 also controls the expression of a group of electrophile- and oxidative stress-inducible proteins and activities, which includes heme oxygenase-1, A170, peroxiredoxin MSP23, and cystine membrane transport (system xc −) activity. The response to electrophilic and reactive oxygen species-producing agents was profoundly impaired in Nrf2-deficient cells. The lack of induction of system xc − activity resulted in the minimum level of intracellular glutathione, and Nrf2-deficient cells were more sensitive to toxic electrophiles. Several stress agents induced the DNA binding activity of Nrf2 in the nucleus without increasing its mRNA level. Thus Nrf2 regulates a wide-ranging metabolic response to oxidative stress.


http://www.curefa.org/active-clinical-trials/reata-phase-2-trial-for-rta-408

Active Clinical Trials
Reata Phase 2 Trial for RTA 408
Written by Jen Farmer

Category: Active Clinical Trials
Published: Saturday, February 14, 2015
Phase 2 Trial with Reata Pharmaceutical’s RTA 408
Ages: 18-40 at CHOP; 16-40 at Emory, Ohio State University, University of Florida, University of South Florida
Locations: Children’s Hospital of Philadephia (CHOP), Emory, Ohio State University, University of Florida, University of South Florida
Details: RTA 408 is one of a class of drugs that Reata developed to target the activation of a transcriptional factor Nrf2, a therapeutic target in FA. Increasing Nrf2 could improve mitochondrial function by reducing oxidative stress. The ability of RTA 408 to activate Nrf2 and induce antioxidant target genes is hypothesized to be therapeutic in patients with Friedreich’s ataxia. Participation in the study is for up to 5 months, including 12 weeks of treatment.

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