Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective

Aaron Sathyanesan, Vittorio Gallo, Neurobiology of Learning and Memory, Available online 30 April 2018, ISSN 1074-7427, doi:10.1016/j.nlm.2018.04.016.

The fact that clinicians do not wait till the infant or child reaches the adult stage to intervene therapeutically and measure behavioral outcomes should prompt neuroscientists to rethink how behavior is typically analyzed in pre-clinical animal models of neurodevelopmental disorders.
One of the behavioral hallmarks of early cerebellar injury or childhood onset genetic ataxia is abnormal gait and postural control. Children affected with diseases such as Friedreich’s Ataxia and Ataxia Telangiectasia display gait deficits due to inter- and intra-limb miscoordination, highlighting the importance of cerebellar circuitry to gait control during development.
The biggest advantage of using the Erasmus Ladder is the integration of measuring locomotor performance such as gait dynamics and coordination, as well as an associative, adaptive, conditioned learning paradigm to study cerebellar function

Clinical management of Friedreich’s Ataxia: a report of two cases

Yannis Dionyssiotis, Athina Kapsokoulou, Anna Danopoulou, Maria Kokolaki & Athina Vadalouka; Spinal Cord Series and Casesvolume 4, Article number: 38 (2018) doi:10.1038/s41394-018-0071-x

We present two cases, a brother (54 years old) and sister (56 years old), with FDRA that are chronically institutionalized for incomplete quadriplegia without spasticity. Gait and postural ataxia, cerebellar dysarthria, oculomotor dysfunction, musculoskeletal deformities, hearing impairment, hypertrophic cardiomyopathy, and diabetes mellitus are also present. Neurological examination reveals extensor plantar responses and diminished to absent tendon reflexes. Both are wheelchair bound, cannot perform daily tasks and need assistance.
Although there is no cure that can alter the natural course of the disease physiotherapy, management of spasticity and neuropathic pain, symptomatic treatment of heart failure and diabetes and nursing care can grant the patients quality of life.

Increased frataxin expression induced in Friedreich ataxia cells by platinum TALE-VP64s or platinum TALE-SunTag

Khadija Cherif, Catherine Gérard, Joël Rousseau, Dominique L. Ouellet, Pierre Chapdelaine, Jacques P. Tremblay, Molecular Therapy - Nucleic Acids, Available online 27 April 2018, ISSN 2162-2531, doi:10.1016/j.omtn.2018.04.009

Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria’s iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA), such as VP64 or P300, were used to increase the expression of that gene. Many effectors plTALEVP64, plTALEp300 and plTALESunTag targeting 14 sequences of the FXN gene promoter or intron 1 were produced. This permitted to select 3 plTALEVP64s and 2 plTALESunTag that increased FXN gene expression by up to 19 folds in different FRDA primary fibroblasts. Adeno-Associated Viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected plTALEVP64s or plTALESunTag induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10 folds and in skeletal muscles by up to 35 folds. The aconitase activity is positively modulated by the frataxin level in mitochondria and was thus increased in vitro and in vivo by the increased frataxin expression.

BMN 290 for Friedreich's Ataxia

SAN RAFAEL, Calif., April 25, 2018 /PRNewswire

In the fourth quarter of 2017, BioMarin announced that it had selected as its next clinical drug development candidate, BMN 290, a selective chromatin modulation therapy intended for treatment of Friedreich's ataxia. Friedreich's ataxia is a rare autosomal recessive disorder that results in disabling neurologic and cardiac progressive decline associated with a deficiency in frataxin. Prior to the lead compound being acquired by BioMarin from Repligen Corporation (Repligen), it demonstrated increases in frataxin in Friedreich's ataxia patients. On the basis of these results, the Company selected an improved candidate, BMN 290, for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. In preclinical models conducted by BioMarin, BMN 290, a compound derived from the original Repligen compound, increases frataxin message expression in brain tissues more than two-fold. Currently, there are no approved disease modifying therapies for Friedreich's ataxia. The Company expects to submit the IND application for BMN 290 in the second half of 2018.

Reata Announces New Preclinical Data Demonstrating the Potential of Omaveloxolone in the Treatment of Friedreich’s Ataxia and Other Severe Neurological Diseases

IRVING, Texas, April 24, 2018 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (Reata or Company), a clinical-stage biopharmaceutical company, today announced new preclinical data demonstrating that omaveloxolone potently activates the Keap1/Nrf2 pathway, significantly reduces production of reactive oxygen species, and improves mitochondrial function in two different models of severe neurological diseases. These results support the rationale for clinical studies of omaveloxolone in neurodegenerative and neuromuscular disorders, including the ongoing pivotal MOXIe trial in patients with Friedreich’s ataxia.

Patient reported outcome measures in rare diseases: a narrative review

Anita Slade, Fatima Isa, Derek Kyte, Tanya Pankhurst, Larissa Kerecuk, James Ferguson, Graham Lipkin and Melanie Calvert, Orphanet Journal of Rare Diseases 2018 13:61 doi:10.1186/s13023-018-0810-x

Rare diseases can lead to a significant reduction in quality of life for patients and their families. Ensuring the patients voice is central to clinical decision making is key to delivering, evaluating and understanding the efficacy of therapeutic interventions. Patient reported outcome measures (PROMs) are used to capture the patient’s views about their health status and facilitate our understanding of the impact of these diseases and their treatments on patient’s quality of life and symptoms.

Emergence of breath testing as a new non-invasive diagnostic modality for neurodegenerative diseases

N. Siva Subramaniam, C.S. Bawden, H. Waldvogel, R.M.L. Faull, G.S. Howarth, R.G. Snell, , Brain Research, Available online 22 April 2018, ISSN 0006-8993, doi:10.1016/j.brainres.2018.04.017.

Neurodegenerative diseases (NDDs) are incapacitating disorders that result in progressive motor and cognitive impairment. These disease include Alzheimer’s disease the most common cause of dementia, frontotemporal dementia, amyotrophic lateral sclerosis, dementia with Lewy bodies, Parkinson’s, Huntington’s, Friedreich’s ataxia, and prion disease.
The use of breath testing, as a means of monitoring neurodegenerative disease onset and progression, has the potential to have a significant impact on augmenting the diagnosis of NDDs as the approach is non-invasive, relatively cost effective and straight forward to implement. This review highlights key features of current diagnostic methods utilised to identif.

The idebenone metabolite QS10 restores electron transfer in complex I and coenzyme Q defects

Valentina Giorgio, Marco Schiavone, Chiara Galber, Marco Carini, Tatiana Da Ros, Valeria Petronilli, Francesco Argenton, Valerio Carelli, Manuel J. Acosta Lopez, Leonardo Salviati, Maurizio Prato, Paolo Bernardi, Biochimica et Biophysica Acta (BBA) - Bioenergetics, Available online 22 April 2018, ISSN 0005-2728, doi:10.1016/j.bbabio.2018.04.006.

Here we have studied the effects of quinones generated during in vivo metabolism of idebenone with specific emphasis on 6-(9-carboxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (QS10). QS10 partially restored respiration in cells deficient of complex I or of CoQ without inducing the mitochondrial permeability transition, a detrimental effect of idebenone that may offset its potential benefits.

GoFAR reinforces partnership with Powell Gene Therapy Center at University of Florida (UF) to develop a gene therapy for Friedreich’s ataxia

Torino-Italia, April 20-2018. In January, GoFAR awarded an additional grant of $450,000 to Manuela Corti, P.T., Ph.D., assistant professor of Dr. Barry Byrne M.D., Ph.D director of the UF Powell Gene Therapy Center. GoFAR originally began a collaboration with the UF Powell Gene Therapy Center in 2016 to develop AVV-mediated gene therapy for FA awarding a grant of $750,000.The total award of $1.2Ml has been staged to reach milestones toward the clinical implantation of the therapeutic strategy for FA. The most recent award will be used to complete preclinical studies and prepare data for submission to the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Italian regulatory authority, Instituto Superiore della Sanità (ISS). Hopefully trials are expected to begin later this year.

International advocacy group GoFAR funds UF Health research for Friedreich’s ataxia gene therapy program


GoFAR reinforces partnership with Powell Gene Therapy Center at University of Florida (UF) to develop a gene therapy for Friedreich’s ataxia

Retrotope Announces Peer-Reviewed Publication of Positive Phase 1b/2a Findings for RT001 in Friedreich’s Ataxia

Retrotope, April 18, 2018.
Protocol for Pivotal Clinical Trial Has Been Submitted to the US FDA
LOS ALTOS, Calif., April 18, 2018 (GLOBE NEWSWIRE) -- Retrotope announced today peer-reviewed publication of positive Phase 1b/2a trial results for the company's lead candidate, RT001, in patients with Friedreich's ataxia (FA). RT001 is the first in class of a new category of drugs called D-PUFAs (deuterated polyunsaturated fatty acids), which are designed to protect against free radical damage resulting in cell death that is a hallmark of several degenerative diseases, including FA. In an article titled, "Randomized, Clinical Trial of RT001: Early Signals of Efficacy in Friedreich's Ataxia" (DOI:10.1002/mds.27353), appearing online in Movement Disorders, results of the randomized, double-blind, comparator-controlled Phase 1b/2a trial demonstrated early signals of drug effect (including statistically significant improvements in peak exercise workload compared to placebo) and positive safety and tolerability.