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

Yogesh K. Chutake, Christina C. Lam, Whitney N. Costello, Michael P. Anderson and Sanjay I. Bidichandani; Nucl. Acids Res. (2016) doi: 10.1093/nar/gkw107 First published online: February 20, 2016

OPEN

We conclude that repeat-mediated epigenetic promoter silencing in FRDA is mediated by class I HDACs, and it is reversible via treatment with specific inhibitors. It is noteworthy that the correction of both the structural and functional defects of the FXN promoter in FRDA, albeit partial, occurs in its natural genomic context, i.e. while in continued physical proximity to the cis-acting expanded GAA-TR sequence. These features bode well for the development of class I HDAC inhibitors as a rational therapeutic modality for FRDA.

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

Startups, Biotech, By Meghana Keshavan http://medcitynews.com.

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.

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

February 18, 2016,  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).

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

Joseph F. Nabhan, Kristy M. Wood, Varada P. Rao, Jeffrey Morin, Surya Bhamidipaty, Timothy P. LaBranche, Renea L. Gooch, Fazli Bozal, Christine E. Bulawa & Braydon C. Guild; Nature, Scientific Reports 6, Article number: 20019 (2016) doi:10.1038/srep20019

OPEN

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.
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.

Understanding the Role of Mitochondrial Pathophysiology in Friedreich's Ataxia

Rosella Abeti, Michael H. Parkinson, Iain P. Hargreaves, Mark A. Pook, Andrey Y. Abramov, Paola Giunti, Biophysical Journal, Volume 110, Issue 3, Supplement 1, 16 February 2016, Page 474a, ISSN 0006-3495, doi:10.1016/j.bpj.2015.11.2534.

By using functional microscopy and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the FRDA mouse models.

Scientists find potential treatment for Friedreich’s ataxia

UT Southwestern, Newsroom. 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.

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

David Dávila, Silvia Fernández and Ignacio Torres-Alemán; The Journal of Biological Chemistry, 291, 2510-2523. doi: 10.1074/jbc.M115.695478

These results point out the importance of AKT activation for astrocyte survival during oxidative stress and reinforce the idea that modulation of astrocytes by IGF-I forms part of the brain responses to oxidative damage.

Energy metabolism in neuronal/glial induction and iPSC-based modeling of brain disorders

Barbara Mlody, Carmen Lorenz, Gizem Inak, Alessandro Prigione; Seminars in Cell & Developmental Biology, Available online 11 February 2016, ISSN 1084-9521, doi: 10.1016/j.semcdb.2016.02.018.

Neurons derived from FRDAiPSCs recapitulated the characteristic features of the disease terms of GAA expansion as well as FRDA instability. Importantly, impaired mitochondrial function could be observed in derived neuronal cells, including decreased mitochondrial membrane potential and progressive mitochondrial degeneration. Hence, the iPSC system may represent a promising tool for advancing the understanding of the mechanisms of action and brain targeting of mitochondrial disorders due to both nuclear and mitochondrial mutations.

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; Archives of Cardiovascular Diseases Supplements, Volume 8, Issue 1, January 2016, Page 25, ISSN 1878-6480, doi: 10.1016/S1878-6480(16)30075-1.

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.

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

Santiago E. Faraj, Rodolfo M. González-Lebrero, Ernesto A. Roman & Javier Santos; (Nature) Scientific Reports 6, Article number: 20782 (2016) doi:10.1038/srep20782

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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.