Taking the lottery out of gene therapy

NEW SCIENTIST HEALTH ,Magazine issue 2789

GENE therapy should become a more exact science thanks to the discovery that it is possible to predict where a transferred gene is likely to be inserted into the recipient's DNA.

"Peter Cherepanov at Imperial College London, who was not part of the team, says now that the probability of an undesirable insertion can be estimated, it will become easier to balance the chance of success with the risk of side effects."

ORIGINAL PAPER: Deciphering the Code for Retroviral Integration Target Site Selection

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Catalysis and Mechanistic Insights into Sirtuin Activation.

Chembiochem. 2010 Nov 9. [Epub ahead of print]

 Dittenhafer-Reed KE, Feldman JL, Denu JM.

Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison.

Keywords:  SIRT1, resveratrol,  SRT1720, mechanism by which they activate remains poorly defined,  type II diabetes, neurodegeneration, diseases associated with aging.

Repeat expansion affects both transcription initiation and elongation in friedreich ataxia cells

J Biol Chem. 2010 Dec 2. [Epub ahead of print]

Kumari D, Biacsi RE, Usdin K., NIH, United States.

Keywords: Expansion of a GAA·TTC-repeat, first intron, frataxin (FXN) gene, mRNA deficit, Friedreich ataxia (FRDA), DNA methylation, histone modifications, chromatin immuno-precipitation, chromatin, RNA polymerase II, histone H3 trimethylated on lysine 4, trimethylated H3K36.

Accelerating orphan drug development

Nature Reviews Drug Discovery 9, 901-902 (December 2010) | doi:10.1038/nrd3340

Timothy R. Coté, Kui Xu & Anne R. Pariser

"Given the limited resources available for rare disease R&D, it is imperative that all knowledge gained is used to maximum benefit at each phase.
The FDA is committed to accelerating orphan drug development through a regulatory system built on integrity, consistency and transparency; a system that has delivered benefits to people who desperately need them and promises to deliver much more."

The Neuropathology of Late-Onset Friedreich's Ataxia.

Cerebellum. 2010 Dec 4. [Epub ahead of print]

Koeppen AH, Morral JA, McComb RD, Feustel PJ.
Research Service (151), VA Medical Center, 113 Holland Ave, Albany, NY, 12208, USA.

Keywords: Friedreich's ataxia (FRDA), very young persons, routine laboratory test, cardiomyopathy, late-onset, neurological disability, dorsal root ganglia, atrophy of the dentate nucleus, Frataxin levels.

Mitochondrial Fe-S cluster biogenesis, frataxin and the modulation of susceptibility to drug-induced cardiomyopathy

Aging (Albany NY). 2010 Nov 27.
Michael N. Sack
NHLBI Center for Molecular Medicine, National Institutes of Health, Bethesda, MD 20892, USA
Commentary on: Schulz et al. Activation of mitochondrial energy metabolism protects against cardiac failure. Aging 2010; 2: this issue

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An intriguing new finding, by Shultz et al is published in AGING regarding the induction of frataxin. Mutations in frataxin result in the development of Friedreich's Ataxia, an inherited neurodegenerative disease associated with the development of severe cardiomyopathy. Frataxin, itself is involved in mitochondrial iron-sulphur cluster biogenesis which functions, in part, to incorporate appropriate amounts of iron into mitochondrial proteins including aconitase and succinate dehydrogenase [13]. Whether frataxin functions as an iron-chaperone protein or plays a regulatory role in controlling iron and sulphur flux within mitochondria is not yet completely characterized. Nevertheless, the study by Shultz and colleagues [14] shows that increased cardiac frataxin enhances tricarboxylic acid cycle function resulting in increased cardiac ATP, NADH, NADPH and reduced glutathione levels. This array of features is consistent with an enhanced bioenergetic capacity and increased antioxidant defenses. The authors go on to demonstrate that overexpression of frataxin is cardioprotective against doxorubicin-induced cardiomyopathy. This intriguing study shows that the modulation of the mitochondria at the fundamental level of integrating cofactors required for protein functional integrity have beneficial effects in disease processes that are exacerbated by mitochondrial dysfunction. This study further highlights the complexity of mitochondrial function and adds a new level of regulation operational in the pathophysiology of heart failure that may be amenable to therapeutic modulation.

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The mitochondrial protein frataxin is essential for heme biosynthesis in plants

FEBS Journal, Accepted Article (Accepted, unedited articles published online for future issues)
DOI: 10.1111/j.1742-4658.2010.07968.x

María V. Maliandi1, Maria V. Busi2, Valeria R. Turowski2, Laura Leaden2, Alejandro Araya3, Diego F. Gomez-Casati2.

# 1 Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH) CONICET/UNSAM, Chascomús, Argentina.# 2 Centro de Estudios Fotosintéticos y Bioquímicos (CEFOBI-CONICET), Universidad Nacional de Rosario, Rosario, Argentina. # 3 Microbiologie Cellulaire et Moléculaire et Pathogénicité.Centre National de la Recherche Scientifique and Université Victor Segalen-Bordeaux 2, Bordeaux, France.

Keywords: Frataxin, mitochondrial protein, cellular iron homeostasis, Fe–S cluster, heme biosynthesis, photosynthetic organisms, aconitase, succinate dehydrogenase, AtFH. heme content.

Superior Cerebellar Peduncle Atrophy in Friedreich's Ataxia Correlates with Disease Symptoms.

Cerebellum. 2010 Nov 24.

Akhlaghi H, Corben L, Georgiou-Karistianis N, Bradshaw J, Storey E, Delatycki MB, Egan GF.
Florey Neurosciences Institute, Centre for Neurosciences, University of Melbourne, Parkville, VIC, Australia

KEYWORDS: Friedreich's ataxia (FRDA), cerebellar-sensory ataxia, peripheral sensory loss, loss of lower limb tendon reflexes, hypertrophic cardiomyopathy, superior cerebellar peduncle (SCP), Friedreich's ataxia rating scale score, surrogate marker of disease severity in FRDA.

Feasibility of Implantable Cardioverter Defibrillator Treatment in Five Patients With Familial Friedreich's Ataxia—A Case Series

Artificial Organs, Volume 34, Issue 11, pages 1061–1065, November 2010, DOI: 10.1111/j.1525-1594.2010.01140.x

Keywords: Friedreich's ataxia (FRA), familial cardiomyopathy, the most common cause of death, implantable cardioverter defibrillator (ICD), University Hospital of Goettingen, frataxin locus, electrocardiogram, ventricular dysfunction, ventricular tachyarrhythmias.

"Our experience implies the safe use of ICD in children with FRA"

The future of genetic research on neurodegeneration

Nature Medicine 16, 1215 - 1217 (2010), doi:10.1038/nm.2225


Christine Van Broeckhoven is at the Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerpen, Belgium, and the Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerpen, Belgium.