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.

Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia

Louise A. Corben, Felicity Klopper, Monique Stagnitti, Nellie Georgiou-KaristianisJohn L. Bradshaw, Gary RanceMartin B. Delatycki; Cerebellum (2017). doi:10.1007/s12311-017-0848-7

There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

Monica Benini, Silvia Fortuni, Ivano Condò, Giulia Alfedi, Florence Malisan, Nicola Toschi, Dario Serio, Damiano Sergio Massaro, Gaetano Arcuri, Roberto Testi, Alessandra Rufini, Cell Reports, Volume 18, Issue 8, 21 February 2017, Pages 2007-2017, ISSN 2211-1247, doi: 10.1016/j.celrep.2017.01.079.

RNF126 depletion results in frataxin accumulation in cells derived from FRDA patients, highlighting the relevance of RNF126 as a new therapeutic target for Friedreich ataxia.
A combined therapy aimed at increasing frataxin levels, either by promoting its gene transcription or through gene therapy or protein replacement, and simultaneously interfering with its RNF126-mediated degradation could be envisioned.

A study of CTI-1601 for the treatment of Friedreich's Ataxia.

Adis International Ltd. Part of Springer Science+Business Media, Trials


Planning
Phase of Trial: Phase I
Latest Information Update: 14 Feb 2017


06 Feb 2017: According to a Chondrial Therapeutics media release, company is planning to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) and after acceptance of the IND, company will initiate this trial.

Health technology assessment of drugs for rare diseases: insights, trends, and reasons for negative recommendations from the CADTH common drug review

Ghayath Janoudi, William Amegatse, Brendan McIntosh, Chander Sehgal, and Trevor Richter; Orphanet J Rare Dis. 2016; 11: 164. doi:10.1186/s13023-016-0539-3

A shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency.
From 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%).
The number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD treatments was high, high cost was a reason for a negative reimbursement recommendation in only two (7.7%) of negative reimbursement recommendations.