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

Theresa A. Zesiewicz, Jeannie B. Stephenson, Seok Hun Kim, Kelly L. Sullivan, Israt Jahan, Yangxin Huang, Jason L. Salemi, Lynn Wecker, Jessica D. Shaw, Clifton L. Gooch, Gait & Posture, Available online 30 March 2017, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.03.019.

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.

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.

Ferroptosis Inhibition: Mechanisms and Opportunities

Jose Pedro Friedmann Angeli, Ron Shah, Derek A. Pratt, Marcus Conrad, Trends in Pharmacological Sciences, Available online 28 March 2017, ISSN 0165-6147, doi:10.1016/j.tips.2017.02.005.

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.

Supplementation of cell media with deuterated linoleic acid (LA) was investigated, and has proven beneficial in several cell models of lipid peroxidation-related neurological disease including PD and Friedreich’s ataxia. In addition,it was also recently shown that cells exposed to deuterated LA presented a marked resistance to ferroptosis.

Ever since therecognition of the privileged position of a-tocopherol as Nature’s premier lipid-soluble Radical-Trapping Antioxidants, researchers have developed with success synthetic compounds with increased reactivity towards peroxyl radicals.

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

Conny Schatton, Matthis Synofzik, Zofia Fleszar, Martin A. Giese, Ludger Schöls, Winfried Ilg, Parkinsonism & Related Disorders, Available online 28 March 2017, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.03.016.

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.
The training improvement of 2.5 SARA points indicates a meaningful improvement, given that a reduction of one SARA point is generally considered as clinically relevant. It represents a treatment effect equivalent to gaining back functional performance of 1.5 years of natural disease progression (e.g. progression in Friedreich’s Ataxia: 1.4 point SARA increase/year). Interestingly, the 2.5 SARA point training improvement is in the same range as training via exergames or via physiotherapy in mild-to-moderate degenerative ataxia. Thus, even largely nonambulatory subjects with advanced degenerative ataxia are still capable of training induced improvements, despite far more progressed and multisystemic neurodegeneration.
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.

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

María Ventosa Rosales, Directores de la Tesis: Filip Lim (dir. tes.) Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016. Idioma: inglés

Our approach has consisted on the construction and preliminary characterization of a high capacity nonreplicative genomic HSV-1 vector carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1. We show that the nonreplicative HSV-1 genomic vector deleted for 23 kb maintains its growth capacity and the FXN transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression.
Transduction of cultured fetal rat DRG neurons with the 27_4_Or2_β22 FXNinlZ vector results in sustained expression of human FXN transcripts and FXN protein. Rat footpad inoculation with the 27_4_Or2_β22 FXNinlZ vector results in human FXN transgene delivery to the DRG, with expression persisting for at least 1 month.
Our results support the feasibility of using this vector for sustained neuronal expression of human FXN for future FRDA gene therapy.

Mitochondrial biogenesis in neurodegeneration

Li, P. A., Hou, X. and Hao, S. (2017), J. Neurosci. Res.. doi: 10.1002/jnr.24042

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.
Under pathological stresses, mitochondria generate extra amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or receive mass influx of calcium. These events trigger the formation of mitochondrial permeability transition pore (MPTP).The MPTP permits proapoptotic molecules to be released from the mitochondria to either the cytosol or nucleus, whereby triggering caspase-dependent and caspase-independent cell death pathways and eventually leading to neurodegeneration. Because of its critical role in mediating neurodegeneration, mitochondrion has been identified as a major target for neuroprotection. Stimulation of mitochondrial biogenesis is a novel approach to preserve mitochondrial function and to improve neuronal cell survival after various injuries.

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

Xiaodong Yang, Shaoqing Xu, Yiwei Qian, Qin Xiao, Brain, Behavior, and Immunity, Available online 6 March 2017, ISSN 0889-1591, doi:10.1016/j.bbi.2017.03.003.

Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases.
We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.

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

Luca Leonardi, Maria Gabriella Aceto, Christian Marcotulli, Giuseppe Arcuria, Mariano Serrao, Francesco Pierelli, Paolo Paone, Alessandro Filla, Alessandro Roca, Carlo Casali; Neurol Sci (2017) 38: 459. doi:10.1007/s10072-016-2800-x

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.
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.

Voyager Therapeutics: Advance multiple preclinical programs towards clinical trials, with the goal of filing three IND applications within the next 24-months VY-FXN01 program

Voyager Therapeutics Reports Fourth Quarter and Full Year 2016 Financial Results and Corporate Highlights. CAMBRIDGE, Mass., March 15, 2017 (GLOBE NEWSWIRE) . Corporate Goals and 2017 Financial Guidance

Voyager remains committed to becoming the leading gene therapy company focused on severe diseases of the CNS with expertise in discovery, development, manufacturing and commercialization of gene therapy products for people living with these devastating diseases. The significant accomplishments achieved during 2016 provide a solid foundation for continued progress during 2017 and beyond, as measured by the planned achievements of the following corporate goals and 2017 financial guidance:

-Advance multiple preclinical programs towards clinical trials, with the goal of filing three IND applications within the next 24-months for the VY-SOD101, VY-HTT01, and VY-FXN01 (for Friedreich’s ataxia) programs.

Affordable orphan drugs: a role for not-for-profit organizations

Davies, E. H., Fulton, E., Brook, D., and Hughes, D. A. (2017). Br J Clin Pharmacol, doi: 10.1111/bcp.13240.

Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.

Early-Onset Friedreich's Ataxia With Oculomotor Apraxia

Amene Saghazadeh, Sina Hafizi, Firouzeh Hosseini, Mahmoud Reza Ashrafi, Nima Rezaei; Acta Medica Iranica 2017. 55(2):128-130.

Here we described two siblings with the concurrence of early onset FRDA and oculomotor apraxia. However, initially, it appeared that AOA1 was more probable than FRDA, as AOA1 is typically diagnosed in young children (mean age at onset=6.8±4.8), while the mean age of onset for FRDA patients is around 10.52 years. Overlapping clinical features between AOA1 and FRDA necessitate laboratory tests and genetic studies for GAAtrinucleotide repeat expansion and Aprataxin gene which are mainly considered to be responsible for FRDA and AOA1, respectively. Due to the normal laboratory test results and given that AOA1 is associated with hypercholesterolemia; the diagnosis was more likely to be FRDA rather than AOA1.
First, those 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. Second, that laboratory test results might provide us with valuable information for differential diagnosis between FRDA and AOA, particularly when genetic analysis cannot be performed. Third, that genetic analysis is presently acknowledged as the most powerful tool for differential diagnosis between inherited ataxias.

Tolérance à l’exercice et capacité physique des patients atteints d’une ataxie de Friedreich tardive

Médéric Descoins, Chantal Verkindt, Bruno Lemarchand, Dalleau Georges, Nicolas Perrot, Claude Mignard, Ariane Choumert, Revue Neurologique, Volume 173, Supplement 2, March 2017, Pages S176-S177, ISSN 0035-3787, doi:10.1016/j.neurol.2017.01.342.

Les capacités maximales aérobies restent satisfaisantes sans augmentation pathologique des marqueurs métaboliques musculaires. La VO2pic est comparable à un français moyen très sédentaire et reste supérieure au seuil définissant le handicap (18 ml/min/kg). L’évaluation des variables relatives aux capacités physiques est relativement faible et oriente les besoins de rééducation vers les fonctions d’équilibre postural et le reconditionnement à l’effort.
Conclusion:
Cette étude a permis de caractériser les capacités physiques et la tolérance à l’effort des patients atteints d’Ataxie de Friedreich tardive pour permettre de proposer des programmes de rééducations adaptés.

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

Amy Anzovino, Shannon Chiang, Bronwyn E Brown, Clare L Hawkins, Des R Richardson, Michael LH Huang, Free Radical Biology and Medicine, Volume 100, Supplement, November 2016, Pages S143-S144, ISSN 0891-5849, doi:10.1016/j.freeradbiomed.2016.10.376.

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: increased Gsk3β activation; increased Fyn phosphorylation, mediating nuclear export; and 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.

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

C Franco, L Genis, JA Navarro, P Perez-Domper, AM Fernandez, S Schneuwly, I Torres Alemán, Molecular and Cellular Neuroscience, Available online 7 March 2017, ISSN 1044-7431, doi:10.1016/j.mcn.2017.02.008.

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. 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. 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.

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

FiercePharma.  Eric Palmer, Mar 8, 2017.
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 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.

Iron Accumulation, Glutathione Depletion, and Lipid Peroxidation Must Occur Simultaneously during Ferroptosis and are Mutually Amplifying Events

Robert L. Bertrand, Medical Hypotheses, Available online 28 February 2017, ISSN 0306-9877, doi:10.1016/j.mehy.2017.02.017.

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.