Referencias científicas Nº 156

 

Ferroptosis Inhibition: Mechanisms and Opportunities

 

The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies.

Trends

Ferroptosis is a recently recognized form of cell death belonging to the group of regulated necrotic cell death modalities characterized by phospholipid oxidation.

Ferroptosis is suppressed by one member of the glutathione peroxidase family, namely GPX4.

Lipid metabolism determines sensitivity to ferroptosis.

Ferroptosis can be inhibited by small molecules at different molecular steps.

Inhibition of ferroptosis may provide novel therapeutic opportunities for previously untreatable conditions.

Keywords

  • regulated necrosis;
  • cell death;
  • lipid peroxidation;
  • small molecules;
  • glutathione peroxidase;
  • cysteine metabolism


http://www.sciencedirect.com/science/article/pii/S0966636217300929

Longitudinal Gait and Balance Decline in Friedreich’s Ataxia: A Pilot Study

 

Abstract

Introduction

Friedreich’s Ataxia (FA) is a devastating, progressive, neurodegenerative disease. Objective measures that detect small changes in neurological function in FA patients are needed to facilitate therapeutic clinical trials. The purpose of this pilot study was to analyze longitudinal changes in gait and balance in subjects with FA using the GAITRite Walkway System® and Biodex Balance System™, respectively, and to test the ability of these measures to detect change over time compared to the Friedreich’s Ataxia Rating Scale (FARS).

Methods

This was a 24-month longitudinal study comparing ambulatory FA subjects with age- and gender-matched, healthy controls. Eight FA subjects and 8 controls were tested at regular intervals using the GAITRite and Biodex Balance systems and the FARS.

Results

In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores.

Conclusions

The GAITRite and Biodex systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA.

Keywords

  • Friedreich;
  • ’s Ataxia;
  • Gait;
  • Balance;
  • Friedreich’s Ataxia Rating Scale

http://www.sciencedirect.com/science/article/pii/S1353802017301116

Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: A rater-blinded, intra-individually controlled trial

 

 Abstract

Background

Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.

Methods

We examined the effectiveness of a 12-week home-based training with body-controlled videogames in 10 young subjects with advanced degenerative ataxia unable or barely able to stand. Training was structured in two 6-weeks phases, allowing to adapt the training according to individual training progress. Rater-blinded clinical assessment (Scale for the Assessment and Rating of Ataxia; SARA), individual goal-attainment scoring (GAS), and quantitative movement analysis were performed two weeks before training, immediately prior to training, and after training phases 1 and 2 (intra-individual control design). This study is registered with ClinicalTrials.gov, NCT02874911).

Results

After intervention, ataxia symptoms were reduced (SARA -2.5 points, p < 0.01), with benefits correlating to the amount of training (p = 0.04). Goal attainment during daily living was higher than expected (GAS: 0.45). Movement analysis revealed reduced body sway while sitting (p < 0.01), which correlated with improvements in SARA posture and gait (p = 0.005), indicating training-induced improvements in posture control mechanisms.

Conclusion

This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.

Keywords

  • Cerebellum;
  • Ataxia;
  • Neurorehabilitation;
  • Postural control;
  • Exergames;
  • Motor training


http://www.sciencedirect.com/science/article/pii/S1353802017301116

Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: A rater-blinded, intra-individually controlled trial

 

 Abstract

Background

Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.

Methods

We examined the effectiveness of a 12-week home-based training with body-controlled videogames in 10 young subjects with advanced degenerative ataxia unable or barely able to stand. Training was structured in two 6-weeks phases, allowing to adapt the training according to individual training progress. Rater-blinded clinical assessment (Scale for the Assessment and Rating of Ataxia; SARA), individual goal-attainment scoring (GAS), and quantitative movement analysis were performed two weeks before training, immediately prior to training, and after training phases 1 and 2 (intra-individual control design). This study is registered with ClinicalTrials.gov, NCT02874911).

Results

After intervention, ataxia symptoms were reduced (SARA -2.5 points, p < 0.01), with benefits correlating to the amount of training (p = 0.04). Goal attainment during daily living was higher than expected (GAS: 0.45). Movement analysis revealed reduced body sway while sitting (p < 0.01), which correlated with improvements in SARA posture and gait (p = 0.005), indicating training-induced improvements in posture control mechanisms.

Conclusion

This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.

Keywords

  • Cerebellum;
  • Ataxia;
  • Neurorehabilitation;
  • Postural control;
  • Exergames;
  • Motor training

https://repositorio.uam.es/handle/10486/676980

Nonreplicative genomic HSV-1 derived vectors for dorsal root ganglion gene therapy of Friedreich´s ataxia

Título: Nonreplicative genomic HSV-1 derived vectors for dorsal root ganglion gene therapy of Friedreich´s ataxia

Autor (es): Ventosa Rosales, María

Director (es): Lim, Filip (dir.)

Entidad: UAM. Departamento de Biología Molecular

Fecha de edición: 2016-11-18

Materias: Terapia génica – Tesis doctorales; Enfermedades neurodegenerativas – Tesis doctorales; Biología y Biomedicina / Biología

URI: http://hdl.handle.net/10486/676980

Nota: Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 18-11-2016

Resumen:

La ataxia de Friedreich (AF) es una enfermedad neurodegenerativa causada por una mutación en el gen de la frataxina (FXN), que genera una deficiencia de la proteína mitocondrial esencial frataxina (FXN). Esta enfermedad presenta un patrón de herencia autosómica recesiva y en la actualidad no se dispone de ninguna terapia efectiva para su tratamiento o cura. Recientemente, un ensayo clínico para terapia del dolor (Dr Fink, Michigan 2011) demuestra que la administración de vectores genómicos no replicativos derivados del virus del herpes simple tipo 1 (VHS-1) en los ganglios de las raíces dorsales, principal diana para terapia génica de AF, no desencadena ningún efecto adverso. Basándonos en estos resultados y en experimentos previos de nuestro laboratorio que demuestran que mediante el uso del locus genómico de FXN se consigue una expresión sostenida de FXN, nuestro objetivo es el desarrollo de una terapia génica para el tratamiento de la neuropatología de AF. El abordaje de este trabajo ha consistido en la generación y caracterización preliminar de un vector genómico no replicativo y de gran capacidad derivado del VHS-1 (vector 27_4_Or2_β22 FXNinlZ) que contiene una versión reducida del locus genómico humano de FXN: el promotor de 5 kb seguido de la secuencia del ADN complementario manteniendo el intrón 1. En este estudio se observa que: i) tras eliminar 23 kb del vector genómico no replicativo derivado del VHS-1 se mantiene su capacidad de crecimiento; ii) la versión reducida del locus FXN contiene los elementos necesarios para preservar la regulación fisiológica de la expresión de FXN humana en neuronas; iii) tras la transducción in vitro de neuronas de los ganglios de las raíces dorsales de fetos de ratas con el vector 27_4_Or2_β22 FXNinlZ, hay tanto una transcripción como una traducción sostenida de FXN. Finalmente, los experimentos in vivo demuestran que la inoculación intraplantar de nuestro vector en ratas permite la detección de la expresión de FXN humana en los ganglios de la raíces dorsales, la cual se mantiene al menos 1 mes tras la inoculación. Nuestros resultados apoyan la idea del uso de nuestro vector 27_4_Or2_β22 FXNinlZ para la expresión a largo plazo de FXN humana en el desarrollo de una futura terapia génica para el tratamiento de AF.


http://news.stanford.edu/2017/03/20/scientists-find-previously-unknown-role-cerebellum/

Stanford scientists find a previously unknown role for the cerebellum

Researchers long believed that the cerebellum did little more than process our senses and control our muscles. New techniques to study the most densely packed neurons in our brains reveal that it may do much more.

BY NATHAN COLLINS

 

Stanford researchers have found a previously unknown, cognitive role for the cerebellum’s granule cells, which show up as green in this image. (Image credit: Mark Wagner)

Pity the cerebellum, tucked in the back of the brain mostly just keeping our muscles running smoothly. Its larger neighbor, the cerebrum, gets all the attention. It’s the seat of intelligence, the home of thinking and planning. It’s what separates humans from our less quick-witted ancestors. The cerebellum – which literally means “little brain” – is thought to just sit there helping us balance and breathe, like some kind of wee heating and ventilation system.

But maybe not for long. In a series of experiments published March 20 in Nature, Stanford researchers show that neurons within the cerebellum respond to and learn to anticipate rewards, a first step toward a much more exciting future for the cerebrum’s largely overlooked little brother and one that could open up new avenues of research for neuroscientists interested in the roots of cognition.

The conventional thinking: not thinking

Scientists had assumed the cerebellum helped control muscles mostly because of what happened when it got injured. “If you have disruption of the cerebellum, the first thing you see is a motor coordination defect,” said the paper’s senior author, Liqun Luo, an investigator at the Howard Hughes Medical Institute, professor of biology and member of Stanford Bio-X and the Stanford Neurosciences Institute.

Admittedly, there had been some hints of a larger role for the cerebellum, but scientists had a hard time following up on those hints in part because the neurons that make up most of the cerebellum are difficult to study. Those neurons, known as granule cells, account for 80 percent of the neurons in the brain – all packed into the cerebellum – but only about 10 percent of its volume. At that density, conventional techniques for recording cell activity don’t work well, and without an effective way of studying granule cells in real time, scientists were left with an incomplete picture of what the cerebellum was really doing.

A new technology, and a helpful accident waiting to happen

Enter Mark Wagner, a postdoctoral fellow in Luo’s lab who led the research with Tony Kim, a graduate student in the lab of Mark Schnitzer, an investigator at the Howard Hughes Medical Institute and an associate professor of biology and of applied physics. Wagner had not set out to redeem the cerebellum. He simply wanted to study how the cerebellum controls muscles in mice using a new technique that would allow him to record granule cells in real time.

Wagner had earned his PhD working with Schnitzer, who develops pioneering methods for imaging neuronal activity in fruit flies, mice and other living animals. One method, called two-photon calcium imaging, had the resolution Wagner needed to study mouse granule cells in action.

In order to study motor control, the team had to get the mice to move. In this case, mice received sugar water about a second after pushing a little lever. While the mice pushed levers and received their rewards, Wagner recorded activity in each mouse’s granule cells, expecting to find that that activity in those cells would be related to planning and executing arm movements.

And to some extent he was right – some granule cells did fire when the animals moved. But other granule cells fired when the mice were waiting for their sugary rewards. And when Wagner sneakily took away their rewards, still other granule cells fired.

“It was actually a side observation, that, wow, they actually respond to reward,” Luo said.

Putting the brain back together

That discovery is something of a revelation. For 50 years, the assumption was that granule cells – and by extension the cerebellum – performed only the most basic functions. But because no one had the tools to look closely at granule cells in action, “we just didn’t know,” Wagner said.

Now that scientists have a better idea of what’s happening, Wagner’s hope is that it could lead to something much bigger. “Given what a large fraction of neurons reside in the cerebellum, there’s been relatively little progress made in integrating the cerebellum into the bigger picture of how the brain is solving tasks, and a large part of that disconnect has been this assumption that the cerebellum can only be involved in motor tasks,” Wagner said.

“I hope that this allows us to unify it with studies of more popular brain regions like the cerebral cortex, and we can put them together,” Wagner said, to figure out what’s really going on inside our heads.

Luo is also a professor by courtesy of neurobiology and a member of the Stanford Cancer Institute. Schnitzer is a member of Stanford Bio-X and the Stanford Neurosciences Institute. Joan Savall, a senior scientist at the Howard Hughes Medical Institute, is also an author. Wagner was supported by an Epilepsy Training Grant. The research was funded by grants from the National Institutes of Health and a Hughes Collaborative Innovation Award.

Media Contacts

Nathan Collins, Stanford News Service: (650) 725-9364, nac@stanford.edu


http://onlinelibrary.wiley.com/wol1/doi/10.1002/jnr.24042/abstract

Mitochondrial biogenesis in neurodegeneration

  1. Andy Li1,*,
  2. Xiaolin Hou1,2and
  3. Shaocai Hao1,3

 

  1. SIGNIFICANCE Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, cerebral stroke, and others are common neurological disorders that affect millions of people very year. Although there have been advancements in development in the areas of molecular biology, genetics, and pharmaceutical sciences, there are still no effective treatments for these diseases. Activation of mitochondrial biogenesis is a novel therapeutic target that may provide help to inhibit the disease progression or improve the recovery.
  2. Additional funding: XH is supported by National Natural Science Foundation of China (81460182). XH and SH are supported by fellowships from the General Hospital of Ningxia Medical University. BRITE is partially founded by the Golden Leaf Foundation.
  3. Keywords:
  • mitochondrion;
  • mitochondrial biogenesis;
  • neurodegeneration

Mitochondria play a key role in energy production, calcium homeostasis, cell survival, and death. Adverse stimulations including neurodegenerative diseases may result in mitochondrial dynamic imbalance, free radical production, calcium accumulation, intrinsic cell death pathway activation and eventually cell death. Therefore, preserving or promoting mitochondrial function is a potential therapeutic target for the treatment of neurodegenerative disorders. Mitochondrial biogenesis is a process by which new mitochondria are produced from existing mitochondria. This biogenesis process is regulated by Peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator-1alpha (PGC-1α). Once being activated by either phosphorylation or de-acetylation, PGC-1α activates nuclear respiratory factor 1 and 2 (NRF1 and NRF2), and subsequently mitochondrial transcription factor A (Tfam). The activation of this PGC-1α – NRF –Tfam pathway leads to synthesis of mitochondrial DNA and proteins and generation of new mitochondria


https://www.clinicalkey.es/#!/content/playContent/1-s2.0-S088915911730065X?returnurl=http:%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS088915911730065X%3Fshowall%3Dtrue&referrer=http:%2F%2Ffriedreichscientificnews.blogspot.com.es%2F2017%2F03%2Fresveratrol-regulates-microglia-m1m2.html

Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury  RSS

Introduction

Neuroinflammation is a hallmark of neurodegenerative diseases. Therapeutic targeting of inflammation represents an exciting approach for novel neuroprotective strategies ( Baune, 2015; Wang et al., 2015 ). Microglia are the major ce…


https://link.springer.com/article/10.1007%2Fs10072-016-2800-x

A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study

  • Authors
  • Luca Leonardi
  • Maria Gabriella Aceto
  • Christian Marcotulli
  • Giuseppe Arcuria
  • Mariano Serrao
  • Francesco Pierelli
  • Paolo Paone
  • Alessandro Filla
  • Alessandro Roca
  • Carlo CasaliLeonardi, L., Aceto, M.G., Marcotulli

 

Abstract

The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. Eleven adult patients with a confirmed genetic diagnosis of autosomal dominant spinocerebellar ataxia or Friedreich’s ataxia were asked to wear an active device for 3 weeks. Assessments were performed at baseline, after the device use (T1), and 3 weeks after (T2). SARA, 9-HPT, PATA, 6MWT, and spatial and temporal gait parameters, measured with a BTS-G-Walk inertial sensor, were used as study endpoints. As expected, no adverse effects were reported. Statistically significant improvements in SARA, 9HPT dominant hand, PATA test, 6MWT, cadence, length cycle, support right/cycle, support left/cycle, flight right/cycle, flight left/cycle, double support right/cycle, double support left/cycle, single support right/cycle, and single support left/cycle were observed between T0 and T1. All parameters improved at T1 did not show statistically significant differences a T2, with the exception of length of cycle. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.


http://acta.tums.ac.ir/index.php/acta/article/view/5459/0 

Early-Onset Friedreich’s Ataxia With Oculomotor Apraxia

Amene Saghazadeh, Sina Hafizi, Firouzeh Hosseini, Mahmoud Reza Ashrafi, Nima Rezaei

 

ABSTRACT

 

Friedreich’s ataxia (FRDA) is a rare autosomal recessive spinocerebellar ataxia which in the majority of cases is associated with a GAA-trinucleotide repeat expansion in the first intron of Frataxin gene located on chromosome 9. The clinical features include progressive gait and limb ataxia, cerebellar dysarthria, neuropathy, optic atrophy, and loss of vibration and proprioception. Ataxia with ocular motor apraxia type 1 (AOA1) is another autosomal recessive cerebellar ataxia which is associated with oculomotor apraxia, hypoalbuminaemia, and hypercholesterolemia. Here we describe two siblings (13- and 10-year-old) display overlapping clinical features of both early-onset FRDA and AOA1. Almost all of laboratory test (including urinary analysis/culture, biochemistry, peripheral blood smear, C-reactive protein level, erythrocyte sedimentation rate-1h) results were within the normal range for both patients. Due to the normal laboratory test results; we concluded that the diagnosis was more likely to be FRDA than AOA1. Therefore, neurologists should bear in mind that clinical presentations of FRDA may vary widely from the classical phenotype of gait and limb ataxia to atypical manifestations such as oculomotor apraxia.


http://www.sciencedirect.com/science/article/pii/S0891584916308474

Frataxin-Deficiency in the Heart Results in an Impaired Nrf2 Response: A Dual Mechanism Mediated via Up-Regulation of Keap1 and GSK3β Axis

 

Friedreich’s ataxia (FA) is a neuro- and cardio-degenerative disease due to frataxin-deficiency and leads to marked mitochondrial iron loading. The ensuing oxidative stress is likely a key contributor to the pathology. Recent studies in neuronal FA models have reported defective expression of the transcription factor, nuclear factor E2-related factor 2 (Nrf2), which regulates the cellular antioxidant response. However, the mechanism has not been elucidated and no molecular examination of the anti-oxidant response has been conducted in the FA heart where fatal cardiomyopathy develops.

Using the MCK conditional frataxin knockout (KO) mouse, which exhibits a cardiomyopathy that mimics the human disease, we examined the Nrf2 antioxidant response pathway in the frataxin-deficient heart. Our studies demonstrated protein and GSH oxidation in the KO relative to wild-type (WT) littermates. Despite this, we found decreased total and nuclear Nrf2 protein levels and increased Keap1-mediated Nrf2 degradation in the heart. Moreover, we also demonstrated the involvement of Gsk3β-dependent export and degradation of nuclear Nrf2 in the heart, as evident by: (i) increased Gsk3β activation; (ii) increased Fyn phosphorylation, mediating nuclear export; and (iii) increased expression of β-TrCP, a substrate recognition subunit of the E3 ubiqitin ligase complex that is involved in Nrf2 degradation. Furthermore, electrophoretic mobility shift assays demonstrated decreased Nrf2-DNA-binding activity and a general decrease in target gene expression in frataxin KO hearts. These results indicate the blunted anti-oxidant response in the frataxin-deficient heart is, at least in part, due to reduced Nrf2 activity caused by its increased degradation via the Keap1 and Gsk3β pathways.


http://www.sciencedirect.com/science/article/pii/S1044743116301762

A role for astrocytes in cerebellar deficits in frataxin deficiency: Protection by insulin-like growth factor I

 

Abstract

Inherited neurodegenerative diseases such as Friedreich’s ataxia (FRDA), produced by deficiency of the mitochondrial chaperone frataxin (Fxn), shows specific neurological deficits involving different subset of neurons even though deficiency of Fxn is ubiquitous. Because astrocytes are involved in neurodegeneration, we analyzed whether they are also affected by frataxin deficiency and contribute to the disease. We also tested whether insulin-like growth factor I (IGF-I), that has proven effective in increasing frataxin levels both in neurons and in astrocytes, also exerts in vivo protective actions. Using the GFAP promoter expressed by multipotential stem cells during development and mostly by astrocytes in the adult, we ablated Fxn in a time-dependent manner in mice (FGKO mice) and found severe ataxia and early death when Fxn was eliminated during development, but not when deleted in the adult. Analysis of underlying mechanisms revealed that Fxn deficiency elicited growth and survival impairments in developing cerebellar astrocytes, whereas forebrain astrocytes grew normally. A similar time-dependent effect of frataxin deficiency in astrocytes was observed in a fly model. In addition, treatment of FGKO mice with IGF-I improved their motor performance, reduced cerebellar atrophy, and increased survival. These observations indicate that a greater vulnerability of developing cerebellar astrocytes to Fxn deficiency may contribute to cerebellar deficits in this inherited disease. Our data also confirm a therapeutic benefit of IGF-I in early FRDA deficiency.


http://www.fiercepharma.com/pharma/pfizer-looks-at-north-carolina-for-production-facility-for-gene-therapies

Pfizer looks at building major gene therapy manufacturing facility in North Carolina

by Eric Palmer |

Pfizer, which scooped up Bamboo Therapeutics last year in its aim to be a major player in gene therapies, is now looking at building a gene therapy production facility in North Carolina where the biotech is based.

Pfizer spokeswoman Kimberly Becker confirmed a report by the Triangle Business Journal that the company has been exploring the area. The newspaper was told by sources that Pfizer has talked to state and local officials about a potential $100 million expansion project. Bamboo is based in Chapel Hill.

“We recently announced that we’re moving forward with scoping potential sites in Sanford for our new gene therapy site. This work is still in the preliminary stages and we aren’t able to share additional detail at this time,” Becker said in an email.

The sources told the newspaper that Pfizer also is considering putting it in Massachusetts. The drugmaker currently is erecting a $200 million biologics and vaccines production facility at its campus in Andover.

But Bamboo already has an 11,000-square foot, fully staffed and operational manufacturing facility in Sanford it acquired last year from the University of North Carolina about the time that Pfizer made an initial investment in the company. Bamboo has produced phase I and II materials using a in the facility using what Pfizer said was “superior suspension, cell-based production platform that increases scalability, efficiency and purity.”

Pfizer last year bought Bamboo in two-step deal, laying out $193 million to acquire its stock, with a pledge of up to $495 million more in milestones. With gene therapies, genetic material is introduced into a patient’s body to replace gene mutations that cause disease.

The biotech is working on recombinant adeno-associated virus (rAAV)-based gene therapies for rare diseases. It has a pre-clinical asset for Duchenne Muscular Dystrophy (DMD); and three targeted at the central nervous system, with pre-clinical assets for Friedreich’s Ataxia and Canavan disease, and a Phase I asset for Giant Axonal Neuropathy, Pfizer said.

Pfizer first entered the emerging field in 2014 with a deal with Spark Therapeutics in hemophilia. At that time, the company also established a dedicated gene therapy research center in London known as the Genetic Medicines Institute which falls under its Rare Disease Research Unit.

While the field offers the hope of one-time cures by dealing with the genetic root cause of a disease, it offers challenges for insurance coverage and payments. There have been no gene therapies approved yet in the U.S., but Dutch company uniQure developed the first gene therapy approved in Europe, a treatment that has been termed the world’s most expensive drug.

Approved in 2012, Glybera is priced at more than $1.2 million. Only one German doctor has been able to win insurance approval, despite the fact the treatment can cure the ultra-rare disease called lipoprotein lipase deficiency. uniQure is now focused on a hemophilia B program, competing with the gene therapy being developed by Spark Therapeutics with Pfizer. uniQure, which has had to eliminate jobs to cut costs, has a $25 million, 55,000-square-foot gene therapy manufacturing facility in Lexington, Massachusetts.

GlaxoSmithKline has also won approval in Europe for Strimvelis, its gene therapy for “bubble boy” disease. It is offering the one-time treatment at about $665,000, with a money-back guarantee.


http://www.sciencedirect.com/science/article/pii/S0306987716300962

Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events

Abstract

Ferroptosis is a recently discovered form of regulated necrosis that involves iron-dependent lipid peroxidation. How cells die once ferroptosis is triggered remains unclear. Ferroptosis is hypothesized to require three critical events: (1) accumulation of redox-active iron, (2) glutathione depletion, and (3) lipid peroxidation. It is proposed that these three events must unfold simultaneously because stopping any critical event also stops ferroptosis. These events are hypothesized to amplify in severity through positive feedback loops. The cause of death in ferroptosis is therefore the synergistic combination of antioxidant depletion, iron toxicity, and membrane denaturation. The relevance of these feedback loops for cancer and neurodegenerative therapies is discussed.

 


http://www.medical-hypotheses.com/article/S0306-9877(16)30096-2/abstract?cc=y=

Iron accumulation, glutathione depletion, and lipid peroxidation must occur simultaneously during ferroptosis and are mutually amplifying events

Robert L. Bertrand

Department of Chemistry, University of Manitoba, Winnipeg R3T 2N2, Canada

Abstract

Ferroptosis is a recently discovered form of regulated necrosis that involves iron-dependent lipid peroxidation. How cells die once ferroptosis is triggered remains unclear. Ferroptosis is hypothesized to require three critical events: (1) accumulation of redox-active iron, (2) glutathione depletion, and (3) lipid peroxidation. It is proposed that these three events must unfold simultaneously because stopping any critical event also stops ferroptosis. These events are hypothesized to amplify in severity through positive feedback loops. The cause of death in ferroptosis is therefore the synergistic combination of antioxidant depletion, iron toxicity, and membrane denaturation. The relevance of these feedback loops for cancer and neurodegenerative therapies is discussed.

Facebooktwittergoogle_plusmail