Referencias científicas


Artículos copiados de diversas fuentes 

Scientists find potential treatment for Friedreich’s ataxia

Feb 16, 2016

DALLAS – Feb. 16, 2016 – Researchers at UT Southwestern Medical Center have identified synthetic RNA and DNA that reverses the protein deficiency causing Friedreich’s ataxia, a neurological disease for which there is currently no cure.

Friedreich’s ataxia results from modifications to DNA sequences that prevent cells from producing enough of a needed protein called frataxin. The lack of frataxin can result in a variety of problems that include loss of muscle control, fatigue, vision or hearing impairment, slurred speech, and serious heart conditions.

Dr. David Corey

Dr. David Corey, Professor of Pharmacology and Biochemistry

Using synthetic RNA or DNA, researchers have identified a way to allow normal frataxin production to resume.

“The synthetic DNA or RNA prevents the mutant sequence from bending back and blocking the frataxin gene. This action activates the frataxin gene, which then makes frataxin RNA and protein at normal levels,” saidDr. David Corey, Professor of Pharmacology and Biochemistry. “In addition, our approach is selective for targeting the frataxin geneFXN and does not affect other genes.”

In contrast to the CRISPR genomic editing technique, which requires modifications to genes, the molecules in this study are synthetic. The DNA and RNA belong to classes of molecules that already are being used clinically, making development of a new therapy more straightforward, said Dr. Corey, who holds the Rusty Kelley Professorship in Medical Science.

For use in Friedreich’s ataxia, the remaining challenge will be to adequately deliver the synthetic molecules to tissues that are affected by the disease, but those challenges are being addressed by existing clinical programs targeting Huntington’s disease and spinal muscular atrophy, Dr. Corey said.

About one in 50,000 people have Friedreich’s ataxia, and typical onset is between 5 and 18 years of age, according to the National Institute of Neurological Disorders and Stroke. The disease is caused by cells making too little of the protein frataxin, although the proteins that are made are considered normal.

“The problem arises because of a mutation within the frataxin gene FXNthat does not code for protein. In this case, the mutation causes the synthesis of a longer piece of RNA. This longer sequence binds the DNA and gums up the works, blocking RNA production needed to produce the frataxin protein,” Dr. Corey said.

The findings appear in the journal Nature Communications.

Other UT Southwestern authors include Dr. Masayuki Matsui, Assistant Instructor of Pharmacology, and Liande Li, research scientist in Pharmacology. 

Support for the research came from RaNA Pharmaceuticals, the Robert A. Welch Foundation, the Friedreich’s Ataxia Research Alliance and the National Institute of General Medical Sciences. 

UT Southwestern has established the Peter O’Donnell Jr. Brain Institute, a comprehensive initiative dedicated to better understanding the basic molecular workings of the brain and applying these discoveries to the prevention and treatment of brain diseases and injuries. 

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has included six who have been awarded Nobel Prizes since 1985. The faculty of almost 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in about 80 specialties to more than 100,000 hospitalized patients and oversee approximately 2.2 million outpatient visits a year.

Media Contact: Gregg Shields


Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling

·        Dorota Hoffman-Zacharska 

·        , Tomasz Mazurczak

·        , Tomasz Zajkowski

·        , Renata Tataj

·        ,Paulina Górka-Skoczylas

·        , Katarzyna Połatyńska

·        , Łukasz Kępczyński

·        , Mariusz Stasiołek

·        , Jerzy Bal



Friedreich ataxia (FRDA) is the most common hereditary ataxia. It is an autosomal recessive disorder caused by mutations of the FXN gene, mainly the biallelic expansion of the (GAA)n repeats in its first intron. Heterozygous expansion/point mutations or deletions are rare; no patients with two point mutations or a point mutation/deletion have been described, suggesting that loss of the FXNgene product, frataxin, is lethal. This is why routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of the parent’s carrier status, together with diagnostic tests, are performed in rare cases, and, because of that, we may underestimate the frequency of deletions. Even though FXN deletions are characterised as ‘exquisitely rare,’ we were able to identify one case (2.4 %) of a (GAA)n expansion/exonic deletion in a group of 41 probands. This was a patient with very early onset of disease with rapid progression of gait instability and hypertrophic cardiomyopathy. We compared the patient’s clinical data to expansion/deletion carriers available in the literature and suggest that, in clinical practice, the FXN deletion test should be taken into account in patients with early-onset, rapid progressive ataxia and severe scoliosis.


Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia

·        Laura Ludovica Gramegna

·        , Caterina Tonon 

·        , David Neil Manners

·        , Antonella Pini

·        , Rita Rinaldi

·        ,Stefano Zanigni

·        , Claudio Bianchini

·        , Stefania Evangelisti

·        , Filippo Fortuna

·         and 3 more

Principio del formulario


Friedreich’s ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (1H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and 1H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) values were calculated for the same 1H-MRS VOI. Clinical severity was evaluated using the International Cooperative Ataxia Rating Scale (ICARS). FRDA patients showed a significant reduction of N-acetyl-aspartate (NAA), a neuroaxonal marker, and choline (Cho), a membrane marker, both expressed relatively to creatine (Cr), and increased MD values. In FRDA patients NAA/Cr negatively correlated with MD values (r = −0.396, p = 0.037) and with ICARS score (r = −0.669, p < 0.001). Age-normalized NAA/Cr loss correlated with the GAA expansion (r = −0.492,p = 0.008). The reduced cerebellar NAA/Cr in FRDA suggests that neuroaxonal loss is related to the microstructural changes determining higher MD values. The correlation between NAA/Cr and the severity of disability suggests that this biochemical in vivo MR parameter might be a useful biomarker to evaluate therapeutic interventions.



CNS Drug Delivery: Beyond the Spinal Cord

Recently the intrathecal administration has been proposed as part of a hopeful therapy for FA (Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia). This paper shows (in laboratory animals) the feasibility of the use of intrathecal administration to reach efficiently the dorsal root ganglia.

This presentation explains the current state of the art in other neurological diseases in which it is required reach the CNS.

Mission: Improve outcomes for epileptic patients who don’t respond to conventional treatments by administering reformulated, micro-doses of anti-epileptic drugs directly to the brain.

 CNS Drug Delivery: Beyond the Spinal Cord.pptx (5 MB, 3 downloads so far)





Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia

1.   Francesco Saccà MD1,*

2.   Giorgia Puorro MBiol1

3.   Angela Marsili MBiol1

4.   Antonella Antenora MD1

5.   Chiara Pane MD1

6.   Carlo Casali MD2

7.   Christian Marcotulli MD2,

8.   Giovanni Defazio MD3

9.   Daniele Liuzzi MD3,

10.               Chiara Tatillo MD1

11.               Donata Maria Cambriglia MD1

12.               Giuseppe Schiano di Cola MD1

13.               Luigi Giuliani MD1

14.               Vincenzo Guardasole MD, PhD4

15.               Andrea Salzano MD4

16.               Antonio Ruvolo MD, PhD4

17.               Anna De Rosa MD, PhD1

18.               Antonio Cittadini MD, PhD4

19.               Giuseppe De Michele MD1and

20.               Alessandro Filla MD1



Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown.


We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks.


A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO2 max was not modified after treatment (0.01 [−0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (−17.24 sec. [−31.5 to −3.0]; P = .018). The treatment was safe and well tolerated.


Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO2 max in patients with Friedreich ataxia  

Intrathecal delivery of frataxin mRNA encapsulated in lipid nanoparticles to dorsal root ganglia as a potential therapeutic for Friedreich’s ataxia


In Friedreich’s ataxia (FRDA) patients, diminished frataxin (FXN) in sensory neurons is thought to yield the predominant pathology associated with disease. In this study, we demonstrate successful usage of RNA transcript therapy (RTT) as an exogenous human FXN supplementation strategy in vitro and in vivo, specifically to dorsal root ganglia (DRG). Initially, 293 T cells were transfected with codon optimized human FXN mRNA, which was translated to yield FXN protein. Importantly, FXN was rapidly processed into the mature functional form of FXN (mFXN). Next, FXN mRNA, in the form of lipid nanoparticles (LNPs), was administered intravenously in adult mice. Examination of liver homogenates demonstrated efficient FXN LNP uptake in hepatocytes and revealed that the mitochondrial maturation machinery had efficiently processed all FXN protein to mFXN in ~24 h in vivo. Remarkably, greater than 50% mFXN protein derived from LNPs was detected seven days after intravenous administration of FXN LNPs, suggesting that the half-life of mFXN in vivo exceeds one week. Moreover, when FXN LNPs were delivered by intrathecal administration, we detected recombinant human FXN protein in DRG. These observations provide the first demonstration that RTT can be used for the delivery of therapeutic mRNA to DRG.


Understanding the Role of Mitochondrial Pathophysiology in Friedreich's Ataxia

·        Rosella Abeti1

·        Michael H. Parkinson1

·        Iain P. Hargreaves2

·        Mark A. Pook3

·        Andrey Y. Abramov1

·        Paola Giunti1

·        1 Molecular Neuroscience, UCL, London, United Kingdom

·        2 Neurometabolic Unit, National Hospital, London, United Kingdom

·        3 3Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health & Li, Brunel University, Uxbridge, United Kingdom



Agilis Biotherapeutics and Waisman Biomanufacturing Enter Into Exclusive Manufacturing Agreement for Friedreich’s Ataxia Gene Therapy

Waisman to provide global supply of Agilis’ novel AGIL-FA gene therapy

February 18, 2016 07:30 AM Eastern Standard Time

CAMBRIDGE, Mass. & MADISON, Wis.--(BUSINESS WIRE)--Agilis Biotherapeutics, LLC (Agilis), a biotechnology company advancing innovative gene therapies for rare genetic diseases that affect the central nervous system (CNS), and Waisman Biomanufacturing, a non-profit gene and cell therapy development and manufacturing group located at the UW-Madison Waisman Center, (Waisman) announced today that the companies have entered into an exclusive partnership agreement for the production of Agilis’ novel gene therapy product, AGIL-FA, for the treatment of Friedreich’s ataxia (FA). FA is a debilitating multi-system disease arising from mutation of the FXN gene. It is the most common inherited ataxia, with 1 in every 100 people being carriers of a mutated FXN gene. FA typically arises between the ages of 5 and 15 and manifests as difficulty with balance and coordination. Over time, the disease progresses to an array of neurological symptoms and life-altering changes in mobility, energy, speech, hearing, and other body systems including the cardiovascular system, which collectively reduce longevity in many cases.

“Our partnership with Waisman is an important step in advancing our AGIL-FA gene therapy for the potential treatment of the neurological symptoms in Friedreich’s ataxia patients”

Tweet this

Following the completed evaluation and selection of the lead therapeutic candidate for FA, AGIL-FA, Agilis has completed molecular characterization and initial proof-of-concept and biodistribution studies of AGLIL-FA in advance of submission of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration. The FXN gene construct used in AGIL-FA was optimized and developed in partnership with Intrexon Corporation (NYSE: XON).

Under the terms of the agreement, Waisman will utilize its personnel, facilities and proprietary processes to manufacture GLP material for non-clinical studies, cGMP material for non-clinical and clinical studies, and potential future commercial supply should AGIL-FA be successfully developed and approved. Agilis and Waisman will each provide team experts to contribute to the overall execution of the full range of manufacturing, quality and regulatory activities.

“Our partnership with Waisman is an important step in advancing our AGIL-FA gene therapy for the potential treatment of the neurological symptoms in Friedreich’s ataxia patients,” said Dr. Mark Pykett, Agilis President and CEO. “Waisman is a leading manufacturer of biological products, with extensive experience and a strong track record in the production of innovative medical products. In partnering with Waisman to leverage their proprietary systems, organizational expertise, and extensive infrastructure, Agilis has solidified a key strategic component in the near-term and long-term development and commercialization of AGIL-FA. We are pleased to partner with such a reputable organization as Waisman to ensure high quality, scalable manufacturing of the product.”

Founded in 2001, Waisman Biomanufacturing, a non-profit entity of the Waisman Center and the University of Wisconsin, currently operates a 15,000 square foot biologics manufacturing facility with eight cGMP compliant cleanroom areas to accommodate clinical production of mammalian and microbial therapies and aseptic filling of final products. The Waisman Quality System and cleanroom facility are designed to maximize regulatory compliance and environmental quality.

Dr. Derek Hei, Director of Waisman, commented, “Our partnership with Agilis is reflective of Waisman’s mission to provide high quality cGMP biologic products to our partners and to assist with the advancement of innovative medicines to enhance the treatment of human diseases. We are pleased to collaborate with Agilis on its exciting gene therapy product for Friedreich’s ataxia and to facilitate supply of the product for the sequence of development stages required for its approval and ultimate commercialization.”

About Friedreich’s Ataxia

Friedreich’s ataxia (FA) is an inherited neuromuscular disorder most commonly caused by a single genetic defect in the FXN gene that leads to reduced production of frataxin, a mitochondrial protein that is important for iron metabolism. FA results in a physically debilitating, life-shortening condition and is the most common hereditary ataxia, with an estimated 5,000 to 10,000 patients in the U.S. (i.e., one in every 50,000 people). Both male and female children can inherit the disorder. Symptoms of FA include progressive loss of coordination and muscle strength, which lead to the full-time use of a wheelchair; scoliosis (which often requires surgical intervention); diabetes mellitus; hearing and vision impairment; serious heart conditions; and premature death. Current FA therapies are primarily focused on symptomatic relief, and there are no FDA-approved drugs to treat the cause of FA.

About Agilis Biotherapeutics

Agilis is advancing innovative gene therapies designed to provide long-term efficacy for patients with debilitating, often fatal, rare genetic diseases that affect the central nervous system. Agilis' therapies are engineered to impart sustainable clinical benefits, and potentially a functional cure, by inducing persistent expression of a therapeutic gene. The Company’s technology is aimed at the precise targeting and restoration of a lost gene function, while avoiding unintended off-target effects. Agilis' integrated strategy increases the efficiency of developing DNA therapeutics into safe, targeted gene therapies that achieve long-term efficacy and enable patients to remain asymptomatic without continuous invasive treatment. Agilis’ rare disease programs are focused on gene therapy for AADC Deficiency, Friedreich’s ataxia, Angelman syndrome, and Fragile X syndrome, rare genetic diseases that include severe neurological deficits and result in physically debilitating conditions.


UNC gene therapy spinout Bamboo Therapeutics raises $49.5M Series A


 Post a comment / 






 / Feb 11, 2016 at 12:28 PM

dna genomics researchNorth Carolina gene therapy startupBamboo Therapeutics has raised a stunning $49.5 million, according to an SEC filing. The startup is focused on advancing the work of Dr. Richard Jude Samulski, director of the gene therapy center at the University of North Carolina, into the clinic to treat rare neurologic diseases like Duchenne’s muscular dystrophy.

Bamboo says that Samulski was the first person to use adeno-associated viruses to replace defective genes with healthy ones; as a result, the company holds more than 20 patents in using AAV for therapeutic applications.

This looks to be a Series A, as it’s Bamboo’s only fundraise on the regulatory books. Six investors participated in the round. We’re waiting to hear back from CEO Sheila Mikhailto confirm, and learn more about the company’s use for this funding round. Bamboo did raise an undisclosed amount of funding from CureDuchenne Ventures on January 10.

The startup’s developing gene therapies for rare neurologic diseases, which include Giant axonal neuropathy (GAN), Canavan disease, Friedreich’s ataxia as well as Duchenne muscular dystrophy. Bamboo’s most advanced program is its therapeutic for GAN, which is currently in Phase 1/2 trials. CBS News ran a piece on Bamboo’s approach to GAN in October.

Just last month, Bamboo acquired a UNC’s viral vector core gene therapy manufacturing facility, Friedrich’s Ataxia News reports.

“We believe that having a leading manufacturing facility fully integrated into our business provides flexibility and a competitive advantage,” Samulski said in a release. “We anticipate rapidly moving our programs forward, including our DMD program, which is expected to enter the clinic in early 2017.”




Reversal of epigenetic promoter silencing in Friedreich ataxia by a class I histone deacetylase inhibitor

1.  Yogesh K. Chutake1

2.  Christina C. Lam1

3.  Whitney N. Costello1

4.  Michael P. Anderson2 and

5.  Sanjay I. Bidichandani1,3,*

+Author Affiliations

1.   1Department of Pediatrics, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USA

2.   2Department of Biostatistics & Epidemiology, University of Oklahoma College of Public Health, Oklahoma City, OK 73104, USA

3.   3Department of Biochemistry & Molecular Biology, University of Oklahoma College of Medicine, Oklahoma City, OK 73104, USAAbstract

Friedreich ataxia, the most prevalent inherited ataxia, is caused by an expanded GAA triplet-repeat sequence in intron 1 of the FXN gene. Repressive chromatin spreads from the expanded GAA triplet-repeat sequence to cause epigenetic silencing of the FXN promoter via altered nucleosomal positioning and reduced chromatin accessibility. Indeed, deficient transcriptional initiation is the predominant cause of transcriptional deficiency in Friedreich ataxia. Treatment with 109, a class I histone deacetylase (HDAC) inhibitor, resulted in increased level of FXNtranscript both upstream and downstream of the expanded GAA triplet-repeat sequence, without any change in transcript stability, suggesting that it acts via improvement of transcriptional initiation. Quantitative analysis of transcriptional initiation via metabolic labeling of nascent transcripts in patient-derived cells revealed a >3-fold increase (P < 0.05) in FXN promoter function. A concomitant 3-fold improvement (P < 0.001) in FXN promoter structure and chromatin accessibility was observed via Nucleosome Occupancy and Methylome Sequencing, a high-resolution in vivo footprint assay for detecting nucleosome occupancy in individual chromatin fibers. No such improvement in FXN promoter function or structure was observed upon treatment with a chemically-related inactive compound (966). Thus epigenetic promoter silencing in Friedreich ataxia is reversible, and the results implicate class I HDACs in repeat-mediated promoter silencing.

Moving beyond DNA: A brief history of epigenetics

Posted February 18, 2016 in Episona Blog Mike Karsian 


Although a relatively new field in its modern form, epigenetics has a long and storied history dating back to the mid 18th century.

Early Ideas

Like many principles in science, epigenetics started with the recognition of an inexplicable phenomenon – that is, how are traits propagated between generations? The first seeds of epigenetics were arguably planted by Charles Darwin, the 19th century biologist and father of evolutionary theory. Darwin argued for a mechanism of heredity termed pangenesis. In this model, indeterminate molecules referred to as “gemmules” were released from cells and transported via the bloodstream to one’s germ cells. These proposed hereditary units were thought to possess plasticity in the sense that different kinds of gemmules would be produced depending on environmental conditions. Darwin’s idea formalized a notion, often misattributed to Jean-Baptiste Lamarck, that organism’s can pass on traits that develop as a product of their lifestyle. (The origin of this concept – “inheritance of acquired characteristics” – is beyond the scope of this review). A commonly cited example is that of the humble giraffe. Since giraffes extend their necks up to high trees in search for food, Lamarck proposed that successive generations which reached for higher and higher trees would pass on increasingly elaborate necks.

History and examples of epigenetics

A Lamarckian idea that the act of stretching one’s neck could lead to change in phenotype across generations.

Until the mid-twentieth century, it remained unclear how the fertilized egg develops into a fully functional human with processes compartmentalized into distinct organs. However, it was known that, in general, all cells in the body contained the same genome. That is to say, the sequence of A’s, T’s, C’s, and G’s were no different in one’s neurons than in one’s muscles. The question was: how can cells function so differently with the same genetic code? A series of informative experiments shed light on this mystery.

examples of epigenetics and male fertility test

Although cells throughout the human body have identical DNA, they may have very different form and function between types. This is due to differences in epigenetics.

By transplanting nuclei from xenopus (frog) somatic cells into empty egg cells, Nobel Laureate John Gurdon paved the way for our understanding of how cell types are determined. This work definitively demonstrated the plasticity of cell identity. The embryos developed into adult frogs that were fertile and able to reproduce. Thus, the full set of processes necessary for embryogenesis were recapitulated in the egg cell that received the transplanted nucleus. This implied that the factors influencing cell fate decisions are localized to the nucleus. Given the supposed genetic homogeneity of these cells, it was clear that some other factor within the nucleus was at play.

History and examples of epigenetics

The term epigenetics is literally translated as being above or upon genetics, which is befitting given that it is an extra layer of biological information overlaid on the genome. In practice, epigenetics is defined as changes to DNA excluding those which alter the actual nucleotide sequence. However, a great irony arose in 1953 when the double-helical structure of DNA was elucidated by James Watson and Francis Crick; The composition of DNA was characterized well after its chemical modifications (epigenetics) were. Indeed, and chromatin-mediated silencing of gene expression as outlined by Edgar Stedman preceded the DNA structure by 3 years. Histones were documented as far back as 1884 by Albrecht Kossel.

Conrad Waddington coined the term, “epigenetic lasndscape” and is thought of by many to be the father of epigenetics. Waddington’s landscape concept was a pivotal concept in developmental biology as it attempted to explain how a static set of DNA sequences could dynamically give rise to a complex organism. Pioneering work by Waddington also demonstrated compelling evidence for inheritance of a seemingly acquired characteristic in drosophila fruit flies.

Modern Epigenetics

Modern day epigenetics is comprised of methylation, histones and their modifications, and non-coding RNAs. Acting in concert, these features coordinate intricate regulatory mechanisms that tightly control the expression of the genome. The propensity of the environment for perturbing these epigenetic pathways has become increasingly evident. Contemporary scientists are therefore taking a fresh look at Lamarckian inheritance with the idea that epigenetics may be a validating manifestation of this phenomenon.

DNA Methylation

A tangible example of methylation is the inactivation of the second X chromosome in females which is systematically “shut down” during development. It wasn’t until 1975 that a mechanistic understanding of methylation began to take shape. In that year, using the X chromosome as an extreme example of epigenetic repression, Arthur Riggs proposed a silencing role for methylation which functioned to prevent the binding of proteins involved in gene regulation. This paradigm has since been refined, and already ten years later Adrian Bird made it known that methyl groups tend to preferentially inhabit CpG islands.

Histones and Histone Modification

Chromatin are the complex coiled structures formed through the interaction of DNA with associated histone proteins. These histones can undergo modification via acetylation, citrullination, methylation and phosphorylation of their amino residues. It is commonly accepted that loosening or tightening of the chromatin into euchromatin and heterochromatin respectively serves to modulate gene expression. This became clear with a landmark paper in 1964 by Alfrey, Faulkner and Mirsky that tied chromatin modifications to transcriptional regulation.

Non-Coding RNA

The term non-coding RNA and all of its subclasses refers to RNA that does not encode proteins. Unlike methylation, non-coding RNA is not a direct modification of DNA however, it merits falling under the category of epigenetics because it can regulate gene expression in the absence of a changing DNA sequence. RNA interference, a prominent subgroup of RNA interaction, was discovered by Andrew Fire and Craig Mello in 1998. They reasoned that these interfering RNAs could bind to messenger RNAs and neutralize them, thereby preventing translation into protein. To this day new types of non-coding RNA continue to be discovered with large intergenic non coding RNA (lincRNA) having only been discovered at the turn of the century.

The ability of the environment to establish epigenetic annotations has been extensively documented in recent years. In parallel, Lamarckian ideas have undergone a revival with a greater focus on rigorous mechanistic interrogation. As an illustrative example from 2014, prediabetes can change the sperm epigenome and predispose children to full-blown diabetes. This represents a clear link between lifestyle-induced non-genetic changes that end up reaching the offspring and dictating their health in a measurable way.

Disease as Viewed Through an Epigenetic Lens

Epigenetics has been implicated in the pathogenesis of diseases as diverse as cancer, neurodevelopmental disorders, autism, and fragile X. Once the role of epigenetics in normal biological processes became established, groups around the world began exploring its contribution to the etiology of disease. Cancer epigenetics, for example, has exploded with the recognition that methylation of promoter regions has a silencing effect on tumor suppressor genes which normally function to protect cells from turning cancerous. In 1983, Andrew Feinberg and Bert Vogelstein set the field ablaze when they began comparing the methylation profiles of known cancer genes between normal and malignant human tissue. In the case of cancer, these epigenetic changes are thought to arise within the lifespan of an organism. However, in other diseases, like Angelman syndrome, the abnormal epigenetic pattern is established before the child is born. Such a disorder is referred to as an imprinting disorder because the methylation occurs in the parents’ gametes and are passed on to their offspring. Angelman syndrome and the related Prader-Willi syndrome were the first disorders discovered to have an imprinting defect. It wasn’t until decades after the syndromes were first observed clinically that the associated chromosome 15 abnormalities were uncovered. Today, transgenerational inheritance of epigenetic disease states is an active area of research which has yielded surprising results. Thus far one thing is clear: there are an abundance of abnormal epigenetic changes which have the capacity to drive diverse pathological processes

Male Factor Infertility: A Case Study for Epigenetic Diagnostics

Epigenetics has had a storied past in the scientific community, but its utility in the clinical realm is becoming ever more apparent. One disease application that looks particularly promising is that of male infertility diagnosis. Current male fertility tests are limited in the scope of parameters they can test leaving many cases of sub-fertility unexplained. There also exists an imbalance between the number of tests available for females versus males despite the fact that male factors comprise up to 50% of the couples infertility.Interestingly, a recent paper has suggested that there aremethylation signatures of infertility in the sperm epigenome. Therefore, male infertility testing represents an important unmet clinical need.

male fertility test

In some cases of infertility, sperm DNA methylation may be altered. Thus, it is possible that DNA methylation may serve as a unique biomarker for male infertility. 

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity
J. Biol. Chem. 2016 291: 2510-2523.First Published on December 2, 2015,




Targeted RNA or BDNF gene transfer protects against frataxin deficiency

Friedreich ataxia is a genetic disorder caused by a GAA expansion in intron 1 of the FXN gene, which encodes frataxin. In two recently published studies, the pathological consequences of thisFXN mutation have been successfully counteracted in in vitro and in vivo models with the use of different approaches,…

Gene transfer of brain derived neurotrophic factor (BDNF) prevents neurodegeneration triggered by frataxin deficiency

Y Katsu-Jiménez1,2, F Loria1,2, JC Corona1,2, and J Diaz-Nido1,2

1.   1.Centro de Biología Molecular Severo Ochoa (UAM-CSIC) and Departamento de Biología Molecular. Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain.

2.   2.Instituto de Investigaciones Sanitarias Hospital Puerta de Hierro-Majadahonda (IDIPHIM), 28222, Madrid, Spain

Correspondence: Javier Díaz-Nido, Centro de Biología Molecular Severo Ochoa. Universidad Autónoma de Madrid (UAM). Spain Telephone: +34 91 196 4562 E-mail:

Present address: Hospital Infantil de México “Federico Gómez”, 06720, México, D.F., México.

The work was done: Madrid, Spain.

Received 11 September 2015; Accepted 21 January 2016
Accepted article preview online 5 February 2016



Friedreich's ataxia (FRDA) is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin. Here we have used a herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) to drive its overexpression in neuronal cells and test for its effect on frataxin-deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of frataxin gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for a frataxin-specific shRNA into the mouse cerebellar cortex triggers a frataxin deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These pathological changes are accompanied by a loss of motor coordination of mice as assayed by the rota-rod test. Co-injection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect frataxin-deficient neurons from degeneration. 

Ferroptosis: process and function

Y Xie1,2, W Hou1, X Song1, Y Yu1, J Huang2, X Sun3, R Kang1 and D Tang1,3

1.   1Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

2.   2Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China

3.   3Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

Correspondence: R Kang or D Tang, Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, G.27C Hillman Cancer Center, 5157 Center Ave, Pittsburgh, PA 15213, USA. Tel: +1 412 6231211; Fax: +1 412 6231212; E-mail: or


Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.


Pluripotent stem cells in disease modelling and drug discovery

·        Yishai Avior,

·        Ido Sagi

·        & Nissim Benvenisty


Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening.



·        Share/bookmark

Activating frataxin expression by repeat-targeted nucleic acids

·        Liande Li,

·        Masayuki Matsui

·        & David R. Corey


Friedreich’s ataxia is an incurable genetic disorder caused by a mutant expansion of the trinucleotide GAA within an intronic FXN RNA. This expansion leads to reduced expression of frataxin (FXN) protein and evidence suggests that transcriptional repression is caused by an R-loop that forms between the expanded repeat RNA and complementary genomic DNA. Synthetic agents that increase levels of FXN protein might alleviate the disease. We demonstrate that introducing anti-GAA duplex RNAs or single-stranded locked nucleic acids into patient-derived cells increases FXN protein expression to levels similar to analogous wild-type cells. Our data are significant because synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels. More broadly, our results demonstrate that interfering with R-loop formation can trigger gene activation and reveal a new strategy for upregulating gene expression.

Human Frataxin Folds Via an Intermediate State. Role of the C-Terminal Region

The aim of this study is to investigate the folding reaction of human frataxin, whose deficiency causes the neurodegenerative disease Friedreich’s Ataxia (FRDA). The characterization of different conformational states would provide knowledge about how frataxin can be stabilized without altering its functionality. Wild-type human frataxin and a set of mutants, including two highly destabilized FRDA-associated variants were studied by urea-induced folding/unfolding in a rapid mixing device and followed by circular dichroism. The analysis clearly indicates the existence of an intermediate state (I) in the folding route with significant secondary structure content but relatively low compactness, compared with the native ensemble. However, at high NaCl concentrations I-state gains substantial compaction, and the unfolding barrier is strongly affected, revealing the importance of electrostatics in the folding mechanism. The role of the C-terminal region (CTR), the key determinant of frataxin stability, was also studied. Simulations consistently with experiments revealed that this stretch is essentially unstructured, in the most compact transition state ensemble (TSE2). The complete truncation of the CTR drastically destabilizes the native state without altering TSE2. Results presented here shed light on the folding mechanism of frataxin, opening the possibility of mutating it to generate hyperstable variants without altering their folding kinetics.


0161: Usefulness of plasma high sensitive troponin t and Nt-proBNP in the diagnosis of cardiopathy in Friedreich ataxia

·        Lise Legrand, , 

·        Carole Maupain, 

·        Marie Lorraine Monin, 

·        Alina Tataru, 

·        Alexandra Durr, 

·        Françoise Pousset, 

·        Richard Isnard

Friedreich ataxia, due to mitochondrial dysfunction, is the most common genetic sensory ataxia. It’s due to lack of frataxin. Hypertrophic cardiomyopathy is associated with Friedreich ataxia and is the major cause of death, (80%).

This study concerned the role of plasma biomarkers, high sensitive troponin and Nt-proBNP, in the diagnostic of cardiopathy in Friedreich ataxia.

From December 2012 to January 2015, we included 76 genetically confirmed Friedreich’s ataxia patients in Pitié-Salpêtrière Hospital. Clinical examination, ECG, echocardiography and blood samples were obtained.

Patients were aged of 38±12 years, (mean±sd), 50% were male. 4 patients had palpitations, 2 dyspnea and no patients had chest pain. 89% had negative T waves on the ECG. 49% had echographic cardiac hypertrophy according to Henry’s nomogram. Patients with hypertrophy were younger: 34±10 years versus 42±14 years, age at onset of the disease was earlier: 15±6 years versus 21±15 years. Interventricular septal wall thickness was 12,9±1,7mm versus 10±1,2mm, and posterior wall thickness was 11,3±1,5mm versus 9,4±1mm. Left ventricle ejection fraction was similar (64%). For patients with hyper-trophy, troponin was higher: 22±21 ng/L versus 10±7 ng/L. Plasma NtproBNP was the same between the 2 groups 104±170 ng/L versus 64±122 ng/ L. 5 patients had plasma Nt-proBNP ≥300 ng/L, they all had had atrial fibrillation or heart failure.

Plasma High sensitive troponin is a diagnostic marker of hypertrophic cardiomyopathy in Friedreich ataxia’s patients, whereas plasma Nt-proBNP is associated with cardiac events and could be a prognostic marker in these patients.


Energy metabolism in neuronal/glial induction and in iPSC models of brain disorders

·        Barbara Mlody, 

·        Carmen Lorenz, 

·        Gizem Inak, 

·        Alessandro Prigione, 


The metabolic switch associated with the reprogramming of somatic cells to pluripotency has received increasing attention in recent years. However, the impact of mitochondrial and metabolic modulation on stem cell differentiation into neuronal/glial cells and related brain disease modeling still remains to be fully addressed. Here, we seek to focus on this aspect by first addressing brain energy metabolism and its inter-cellular metabolic compartmentalization. We then review the findings related to the mitochondrial and metabolic reconfiguration occurring upon neuronal/glial specification from pluripotent stem cells (PSCs). Finally, we provide an update of the PSC-based models of mitochondria-related brain disorders and discuss the challenges and opportunities that may exist on the road to develop a new era of brain disease modeling and therapy.



The present invention relates to a method for preventing or treating cardiomyopathy due to energy failure in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vector which comprises a nucleic acid sequence of a gene that can restore energy failure. More particularly, the invention relates to a method for preventing or treating a cardiomyopathy associated with Friedreich ataxia in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a vector which comprises a frataxin (FXN) encoding nucleic acid.

Cth2 Protein Mediates Early Adaptation of Yeast Cells to Oxidative Stress Conditions

·        Laia Castells-Roca ,

·        Jordi Pijuan ,

·        Francisco Ferrezuelo,

·        Gemma Bellí,

·        Enrique Herrero 


Cth2 is an mRNA-binding protein that participates in remodeling yeast cell metabolism in iron starvation conditions by promoting decay of the targeted molecules, in order to avoid excess iron consumption. This study shows that in the absence of Cth2 immediate upregulation of expression of several of the iron regulon genes (involved in high affinity iron uptake and intracellular iron redistribution) upon oxidative stress by hydroperoxide is more intense than in wild type conditions where Cth2 is present. The oxidative stress provokes a temporary increase in the levels of Cth2 (itself a member of the iron regulon). In such conditions Cth2 molecules accumulate at P bodies-like structures when the constitutive mRNA decay machinery is compromised. In addition, a null Δcth2 mutant shows defects, in comparison toCTH2 wild type cells, in exit from α factor-induced arrest at the G1 stage of the cell cycle when hydroperoxide treatment is applied. The cell cycle defects are rescued in conditions that compromise uptake of external iron into the cytosol. The observations support a role of Cth2 in modulating expression of diverse iron regulon genes, excluding those specifically involved in the reductive branch of the high-affinity transport. This would result in immediate adaptation of the yeast cells to an oxidative stress, by controlling uptake of oxidant-promoting iron cations.


Annapurna Therapeutics to Collaborate with Weill Cornell Medicine on Gene-Therapy Portfolio

Collaboration To Yield Market-Leading R&D Pipeline




Volver a la Portada