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

OPEN

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.

Ferroptosis: process and function

Y Xie, W Hou, X Song, Y Yu1, J Huang, X Sun, R Kang and D Tang; Cell Death and Differentiation (2016) 23, 369–379; doi:10.1038/cdd.2015.158; published online 22 January 2016

OPEN

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.

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

Y Katsu-Jiménez, F Loria, JC Corona, and J Diaz-Nido; Molecular Therapy accepted article preview 5 February 2016; doi: 10.1038/mt.2016.32

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.

This work was supported by grants of the Spanish National Research Plan (SAF 2012-38042) and the Autonomous Government of Madrid (S2010/BMD-2331). Research at the authors laboratory is also supported by Friedreich Ataxia Research Alliance (FARA), Ataxia UK, FARA Ireland, Spanish FEDAES, GENEFA, Babel Family, Italian ASIA and Swedich BotaFA.

Activating frataxin expression by repeat-targeted nucleic acids

Liande Li, Masayuki Matsui & David R. Corey; Nature Communications 7, Article number: 10606 doi:10.1038/ncomms10606

Iintroducing 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. Synthetic nucleic acids that target GAA repeats can be lead compounds for restoring curative FXN levels.