Common drug review recommendations for orphan drugs in Canada: basis of recommendations and comparison with similar reviews in Quebec, Australia, Scotland and New Zealand

John I. McCormick, L. Diana Berescu and Nabil Tadros; Orphanet Journal of Rare Diseases201813:27 doi:10.1186/s13023-018-0759-9


The positive recommendation rate for CDR reviews of orphan drugs was highest when both clinical and price parameters formed the basis of the assessment. However, there was a change in CDR review policies in 2016, with a dramatic increase in the number of positive recommendations, the majority of which were conditional on a substantial reduction in drug price. This change in CDR recommendations is reflected in the expanded criteria and conditions of drug reimbursement outlined in CADTH’s March 2016 recommendation framework. However, it remains to be seen if this represents a permanent change in how CDR reviews orphan drugs and if this will result in wider and more timely provincial access for orphan drugs for patients throughout Canada.

Late onset friedreich ataxia presented with spastic paraparesis

G. PSIMMENOS, N. Grigoriadis, D. Parisis, T. Afrantou, P. Ioannidis; Thessaloniki/GR; (Poster POD416) EAN Congress 2017 in Amsterdam

We report two cases , a 56 year old male patient and a 29 year old female patient. In both cases examination revealed typical clinical symptoms of the disease such as gait-limb ataxia , impaired tandem gait, severe swaying on testing for Romberg sign. There was no history of weakness or numbness. The uncommon findings in both of them were the exaggerated deep tendon reflexes and that the symptoms appeared at such an advanced age(>26 years old).That was the reason why both patients initially underwent genetic testing for other genetic disorders(spinocerebellar ataxia SCA). Genetic testing disclosed expanded GAA repeat length of FTX gene confirming a diagnosis of FA.
These cases highlight that the existence of increased tendon reflexes, although unusual is not incompatible with FA and thus should not prevent the clinician to consider it as a possible diagnosis when the rest clinical picture, the personal-family history and the neurological signs are in keeping with diagnosis of FA

Early onset Friedreich Ataxia without cardiomyopathy

O. Rujan, I. BURAGA, A. Enachi, I. Ionescu, C. Baetu; Bucharest/RO; (Poster POD163) EAN Congress 2017 in Amsterdam

There is a very important clinical distinction between classic FA and its variants, which consists in the absence of kyphoscoliosis and heart disease (a frequent component) which gives the latter group a better prognosis. Our case shows that an early onset of FA doesn’t necessarily mean the patient will develop cardiomyopathy.
Our patient is a 25 year old female whose symptoms were onset at the age of 3 years old and consisted of ataxia of gait, difficulties in standing steadily and in running. The clinical features progressed slowly and now she presents: gait and limb ataxia, the lower limb reflexes are preserved, Romberg sign is present, a rhythmic tremor of the head and upper limbs (more visible during emotional stress), horizontal nystagmus, the speech is slow, slurred and explosive, pes cavus and hammertoes.

This case has some particularities: the early onset of the symptoms, a very slow progression, the preserved lower limb reflexes and the absence of cardiomyopathy.

Autosomal-recessive cerebellar ataxias

Brent L. Fogel, Handbook of Clinical Neurology, Elsevier, Volume 147, 2018, Pages 187-209, ISSN 0072-9752, ISBN 9780444632333, Doi:10.1016/B978-0-444-63233-3.00013-0.

The autosomal-recessive cerebellar ataxias comprise more than half of the known genetic forms of ataxia and represent an extensive group of clinically heterogeneous disorders that can occur at any age but whose onset is typically prior to adulthood. In addition to ataxia, patients often present with polyneuropathy and clinical symptoms outside the nervous system. The most common of these diseases is Friedreich ataxia, caused by mutation of the frataxin gene, but recent advances in genetic analysis have greatly broadened the ever-expanding number of causative genes to over 50. In this review, the clinical neurogenetics of the recessive cerebellar ataxias will be discussed, including updates on recently identified novel ataxia genes, advancements in unraveling disease-specific molecular pathogenesis leading to ataxia, potential treatments under development, technologic improvements in diagnostic testing such as clinical exome sequencing, and what the future holds for clinicians and geneticists.

Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases

Susan Stein, Elizabeth Bogard, Nicole Boice, Vivian Fernandez, Tessa Field, Alan Gilstrap, Susan R. Kahn, Jane Larkindale and Toni Mathieson; Orphanet Journal of Rare Diseases 201813:18 doi:10.1186/s13023-018-0761-2

Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Patient advocacy organizations may play a major role by positively influencing research and development, clinical trials, and regulations. Thus, collaboration among patient advocacy organizations and industry is essential to bring new therapeutics to patients.

Activation of Frataxin Protein Expression by Antisense Oligonucleotides Targeting the Mutant Expanded Repeat

Li Liande, Shen Xiulong, Liu Zhongtian, Norrbom Michaela, Prakash Thazha P., O'Reilly Daniel, Sharma Vivek K., Damha Masad J., Watts Jonathan K., Rigo Frank, and Corey David R.. January 2018, ahead of print.doi:10.1089/nat.2017.0703

Agents that increase expression of FXN have the potential to alleviate the disease. We previously reported that duplex RNAs (dsRNAs) and antisense oligonucleotides (ASOs) complementary to the GAA repeat could enhance expression of FXN protein. We now explore the potential of a diverse group of chemically modified dsRNAs and ASOs to define the breadth of repeat-targeted synthetic nucleic acids as a platform for therapeutic development for FA. ASOs and dsRNAs can activate FXN protein expression in FA patient-derived cell lines that possess varied numbers of GAA repeats. Increased FXN protein expression was achieved by ASOs incorporating diverse chemical modifications with low nanomolar potencies, suggesting substantial flexibility in choosing compounds for further chemical optimization and animal studies. Our data encourage further development of ASOs as agents to treat FA.

Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich’s ataxia fibroblasts

De Samber B, Meul E, Laforce B, De Paepe B, Smet J, De Bruyne M, et al. (2018). PLoS ONE 13(1): e0190495. doi:10.1371/journal.pone.0190495

Interestingly, no significant difference in the mean iron concentration was found in the cytoplasm of FRDA fibroblasts, but a significant decrease in zinc concentration. This finding might underscore metal dysregulation, beyond iron, in cells derived from FRDA patients. In conclusion, although currently having slightly increased limits of detection (LODs) compared to non-cryogenic mode, SR based nanoscopic XRF under cryogenic sample conditions largely obliterates the debate on chemical sample preservation and provides a unique tool for trace level elemental imaging in single cells close to their native state with a superior spatial resolution of 20 nm.

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

Jan Ježek, Katrina F. Cooper and Randy Strich; (Review) Antioxidants 2018, 7(1), 13; doi: 10.3390/antiox7010013

Mitochondria are organelles with a highly dynamic ultrastructure maintained by a delicate equilibrium between its fission and fusion rates. Understanding the factors influencing this balance is important as perturbations to mitochondrial dynamics can result in pathological states. As a terminal site of nutrient oxidation for the cell, mitochondrial powerhouses harness energy in the form of ATP in a process driven by the electron transport chain. Contemporaneously, electrons translocated within the electron transport chain undergo spontaneous side reactions with oxygen, giving rise to superoxide and a variety of other downstream reactive oxygen species (ROS). Mitochondrially-derived ROS can mediate redox signaling or, in excess, cause cell injury and even cell death. Recent evidence suggests that mitochondrial ultrastructure is tightly coupled to ROS generation depending on the physiological status of the cell. Yet, the mechanism by which changes in mitochondrial shape modulate mitochondrial function and redox homeostasis is less clear. Aberrant mitochondrial morphology may lead to enhanced ROS formation, which, in turn, may deteriorate mitochondrial health and further exacerbate oxidative stress in a self-perpetuating vicious cycle. Here, we review the latest findings on the intricate relationship between mitochondrial dynamics and ROS production, focusing mainly on its role in malignant disease.

The role of Nrf2 signaling in counteracting neurodegenerative diseases

Dinkova-Kostova, A. T., Kostov, R. V. and Kazantsev, A. G. (), The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J. Accepted Author Manuscript. doi:10.1111/febs.14379

The function of Nrf2 is altered in many neurodegenerative disorders, such as Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Nrf2 activation mitigates multiple pathogenic processes involved in these neurodegenerative disorders through upregulation of antioxidant defenses, inhibition of inflammation, improvement of mitochondrial function, and maintenance of protein homeostasis. Small molecule pharmacological activators of Nrf2 have shown protective effects in numerous animal models of neurodegenerative diseases, and in cultures of human cells expressing mutant proteins. Targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurodegenerative disorders.

Utilidad del tratamiento como uso compasivo de mecasermina (factor de crecimiento insulínico recombinante humano tipo 1) en ataxia de Friedreich

A. García Ron, M. Rodriguez Mesa, Neurología, Available online 12 January 2018, ISSN 0213-4853, doi:10.1016/j.nrl.2017.11.004.

Neuropathische Fußfehlstellungen

Falk Thielemann, Lea Franken, Lars Heubner, Stefan Rammelt, Jens Goronzy, Fuß & Sprunggelenk, Available online 12 January 2018, ISSN 1619-9987, doi:10.1016/j.fuspru.2017.11.007.

Abstract: Zusammenfassung
Ein wesentlicher Fokus der Therapie von Patienten mit neurologischer Erkrankung liegt auf der Förderung, dem Erhalt bzw. der Wiederherstellung von motorischen Funktionen. Muskuläre Tonusstörungen, tarsale Gelenkinstabilitäten und fixierte Fehlstellungen der Füße sind häufig Teilaspekte einer komplexen Störung der gesamten Funktionskette. Ihre Behandlung erfolgt interdisziplinär unter Berücksichtigung assoziierter Komorbiditäten und ist abhängig von der Art und dem Schwergrad der neurologischen Störung, dem Alter des Patienten und der Flexibilität der Deformität. Das Indikationsspektrum zur Stabilisierung oder Korrektur neuropathischen Fußdeformität umfasst unterschiedliche konservative und operative Verfahren.

Summary
Treatment of patients with neurological disorders focuses on the promotion, the maintenance and the restoration of motor function. Muscular dysbalance, tarsal joint instabilities and fixed foot deformities are often partial aspects of a complex dysfunction of the entire functional chain. Their treatment is multidisciplinary, taking into account associated conditions and comorbidities, and is dependent on the nature and severity of the neurological disorder, the age of the patient and the flexibility of the deformity. The treatment options for the stabilisation or correction of neuropathic foot deformities include a variety of conservative and operative procedures.
Schlüsselwörter: üsselwörterPes cavus; Pes equinovarus; Pes planovalgus; infantile Zerebralparese; Instabilität; cavus foot; club foot; flat foot; infantile cerebral palsy; instability

Emotion Recognition and Psychological Comorbidity in Friedreich’s Ataxia

Teresa Costabile, Veronica Capretti, Filomena Abate, Agnese Liguori, Francesca Paciello, Chiara Pane, Anna De Rosa, Silvio Peluso, Giuseppe De Michele, Alessandro Filla, Francesco Saccà; Cerebellum (2018). doi:10.1007/s12311-018-0918-5

Little effort has been made to understand the psychological and emotional burden of the disease. The aim of our study was to measure patients’ ability to recognize emotions using visual and non-verbal auditory hints, and to correlate this ability with psychological, neuropsychological, and neurological variables. FRDA patients have impaired emotion recognition that may be secondary to neuropsychological impairment. Depression and anxiety were not higher in FRDA as compared to HC and should not be considered as part of the disease.

Biophysical characterisation of the recombinant human frataxin precursor

Ignacio Hugo Castro, Alejandro Ferrari, María Georgina Herrera, Martín Ezequiel Noguera, Lorenzo Maso, Monica Benini, Alessandra Rufini, Roberto Testi, Paola Costantini and Javier Santos; FEBS Open Bio (2018). Accepted Article. DOI: 10.1002/2211-5463.12376

We investigated the conformation, stability and function of a recombinant precursor variant (His6-TAT-FXN1-210), which includes a TAT peptide in the N-terminal region to assist with transport across cell membranes. His6-TAT-FXN1-210 was expressed in E. coli and conditions were found for purifying folded protein free of aggregation, oxidation or degradation, even after freezing and thawing.

Copper and Zinc Homeostasis: Lessons from Drosophila melanogaster

Juan A. Navarro and Stephan Schneuwly; Front Genet. 2017; 8: 223. Published online 2017 December 21. doi: 10.3389/fgene.2017.00223

Similar contradictory findings have been recently described in a Drosophila model of Friedreich's ataxia (FRDA). Impairment of transcription of the gene frataxin is the molecular cause underlying the disease. Most of the current evidences support a strong relation between frataxin and iron in several models, including the fly. Moreover, genetic and chemical manipulation of iron biology was found to have a positive impact in FRDA phenotypes. Remarkably, flies displaying reduced levels of frataxin also seemed to have altered levels of other metals such as Zn and Cu. Although the contribution of other metals was already suggested by studies in human samples, this fly work was the first one showing that therapies based on such metals might be beneficial. Indeed, Zn and Cu chelators improved frataxin deficiency without altering iron content. In this line, silencing either dZip42C.1, dZip42C.2 and dZip88E or dZnT35C, dZnT41F and dZnT63C also improved FRDA conditions via reduction of the iron content. All these results raise several interesting questions: Why are Cu and Zn accumulating in FRDA flies? Why does KD of genes with opposite function or acting in different cellular compartments trigger the same effect? Did they also modify the accumulation of Zn in FRDA flies? Is it possible that any of these transporters has also a mitochondrial function?

Quantitative proteomics in Friedreich's ataxia B-lymphocytes: A valuable approach to decipher the biochemical events responsible for pathogenesis

Lorène Télot, Elodie Rousseau, Emmanuel Lesuisse, Camille Garcia, Bastien Morlet, Thibaut Léger, Jean-Michel Camadro, Valérie Serre, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 9 January 2018, ISSN 0925-4439, doi:10.1016/j.bbadis.2018.01.010.


To better understand the biochemical sequelae of frataxin reduction, global protein expression analysis was performed using quantitative proteomic experiments in Friedreich's ataxia patient-derived B-lymphocytes as compared to controls. We were able to confirm a subset of changes in these cells and importantly, we observed previously unreported signatures of protein expression. Among the novel protein signatures that we have identified, the decrease in CHCHD4 might partly explain some aspects of the molecular pathogenesis of FRDA.

The identification of a core set of proteins changing in the FRDA pathogenesis is a useful tool in trying to decipher the function(s) of frataxin in order to clarify the mitochondrial metabolic disease process.

Effect Of Diazoxide on Friedreich Ataxia Models

Antonella Santoro, Sara Anjomani Virmouni, Eleonora Paradies, Valentina L Villalobos Coa, Sahar Al-Mahdawi, Mee Khoo, Vito Porcelli, Angelo Vozza, Mara Perrone, Nunzio Denora, Franco Taroni, Giuseppe Merla, Luigi Palmieri, Mark A Pook, Carlo M T Marobbio, Human Molecular Genetics, ddy016, doi:10.1093/hmg/ddy016

In this study, we tested diazoxide, a drug commonly used as vasodilator in the treatment of acute hypertension, on cellular and animal models of FRDA. We first showed that diazoxide increases frataxin protein levels in FRDA lymphoblastoid cell lines, via the mTOR pathway. We then explored the potential therapeutic effect of diazoxide in frataxin-deficient transgenic YG8sR mice and we found that prolonged oral administration of 3mpk/d diazoxide was found to be safe, but produced variable effects concerning efficacy. YG8sR mice showed improved beam walk coordination abilities and footprint stride patterns, but a generally reduced locomotor activity. Moreover, they showed significantly increased frataxin expression, improved aconitase activity and decreased protein oxidation in cerebellum and brain mitochondrial tissue extracts. Further studies are needed before this drug should be considered for FRDA clinical trials.

Compounded medication for patients with rare diseases

Marc Dooms and Maria Carvalho; Orphanet Journal of Rare Diseases 201813:1 doi:10.1186/s13023-017-0741-y

When there is no authorized on- or in absence even no off-label treatment for patients with rare diseases, pharmacists have to compound medicinal products to meet the patients special needs. However it is important that there is evidence in the medical and/or pharmaceutical literature for such compounded medications.
When there is no on-label or even no off-label treatment for patients with rare diseases pharmacists have to compound the medication. This needs to be done in the best possible conditions by trained compounders following validates procedures.
In this way medicinal products of the best possible quality will be dispensed to our patients with rare diseases. “When it’s not in the book, it’s up to the cook”.

Psychometric properties of outcome measures evaluating decline in gait in cerebellar ataxia: a systematic review

Sarah C. Milne, Anna Murphy, Nellie Georgiou-Kristian’s, Eppie M. Yiu, Martin B. Delatycki, Louise A. Corben; Gait & Posture, Available online 4 January 2018, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.12.031.

Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia.

Pediatric Ataxia: Focus on Chronic Disordersca

David R Lynch, Ashley McCormick, Kimberly Schadt, Elizabeth Kichula, Seminars in Pediatric Neurology, Available online 5 January 2018, ISSN 1071-9091, doi:10.1016/j.spen.2018.01.001.

The differential diagnosis of ataxia remains challenging, and efficiently ascertaining the correct cause difficult. Modern genetic diagnostic techniques have provided many answers, but complete understanding of genetic results still requires basic knowledge of the clinical phenotypes. While few ataxias are treatable, the growth in research and clinical trials for the disorders like FRDA and AT suggest that a new era of treatments may soon be available. This will increase the need for precise yet cost-conscious diagnostic approaches.