Health-related quality of life and depressive symptoms in Friedreich ataxia

Javier Pérez-Flores, Atteneri Hernández-Torres, Fernando Montón, Antonieta Nieto; Qual Life Res. 2019 Sep 28. doi: 10.1007/s11136-019-02311-9.

Friedreich ataxia (FRDA) is a chronic, progressive and highly disabling cerebellar degenerative disease. Despite this, little attention has been paid to the health-related quality of life (HRQOL) in this disease. The aim of the present study was to assess FRDA patients’ perception of HRQOL and to determine the influence of depression, and demographic and clinical variables.
Our study demonstrates the high impact of Friedreich ataxia on quality of life. This impact does not only occur in those aspects most related to motor disability but it is also present in non-motor dimensions. Depressive symptomatology is the most relevant variable for predicting quality of life.

Physicochemical Characterization and Antioxidant Activity Evaluation of Idebenone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex

Venuti, V.; Crupi, V.; Fazio, B.; Majolino, D.; Acri, G.; Testagrossa, B.; Stancanelli, R.; De Gaetano, F.; Gagliardi, A.; Paolino, D.; Floresta, G.; Pistarà, V.; Rescifina, A.; Ventura, C.A. Biomolecules 2019, 9, 531. DOI:10.3390/biom9100531

Idebenone (IDE) is an antioxidant drug active at the level of the central nervous system (CNS), whose poor water solubility limits its clinical application. An IDE/2-hydroxypropyl-β-cyclodextrin (IDE/HP-β-CD) inclusion complex was investigated by combining experimental methods and theoretical approaches. Furthermore, biological in vitro/ex vivo assays were performed. Phase solubility studies showed an AL type diagram, suggesting the presence of a 1:1 complex with high solubility. Scanning electron microscopy (SEM) allowed us to detect the morphological changes upon complexation. The intermolecular interactions stabilizing the inclusion complex were experimentally characterized by exploring the complementarity of Fourier-transform infrared spectroscopy in attenuated total reflectance geometry (FTIR-ATR) with mid-infrared light, Fourier-transform near-infrared (FT-NIR) spectroscopy, and Raman spectroscopy. From the temperature evolution of the O–H stretching band of the complex, the average enthalpy ΔHHB of the hydrogen bond scheme upon inclusion was obtained. Two-dimensional (2D) rotating frame Overhauser effect spectroscopy (ROESY) analysis and computational studies involving molecular modeling and molecular dynamics (MD) simulation demonstrated the inclusion of the quinone ring of IDE inside the CD ring. In vitro/ex vivo studies evidenced that complexation produces a protective effect of IDE against the H2O2-induced damage on human glioblastoma astrocytoma (U373) cells and increases IDE permeation through the excised bovine nasal mucosa.

A Randomized, Double-Blind, Controlled, Phase 2/3 Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04102501, September 25, 2019.

Retrotope, Inc, drug RT001 (9-cis, 12-cis-11,11-D2-linoleic acid ethyl ester), Phase 3
Ages Eligible for Study: 12 Years to 50 Years (Child, Adult).

Locations, United States: Collaborative Neuroscience Network, LLC (Long Beach, California), UCLA (Los Angeles, California), USF Ataxia Research Center (Tampa, Florida), University of Iowa Stead Family Children's Hospital (Iowa City, Iowa) and Children's Hospital of Philadelphia (Philadelphia, Pennsylvania)

This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability, in subjects with FRDA following the oral administration of study drug (active or placebo capsules). Sixty eligible patients will undergo various assessments at different time points during the the study. The study duration is 13 months which includes screening, treatment and washout period.

Targeting BDNF signaling by natural products: novel synaptic repair therapeutics for neurodegeneration and behavior disorders

Sweta Bawari, Devesh Tewari, Sandro Argüelles, Archana N. Sah, Seyed Fazel Nabavi, Suowen Xu, Rosa Anna Vacca, Seyed Mohammad Nabavi, Samira Shirooie, Pharmacological Research, 2019, 104458, doi:10.1016/j.phrs.2019.104458.

Neurodegenerative disorders like Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, spinocerebellar ataxias, amyotrophic lateral sclerosis, frontotemporal dementia to prion diseases, Friedreich’s ataxia, hereditary spastic paraplegia and optic atrophy type 1, and behavior disorders like neuropsychiatric, hyperactivity and autism spectrum disorders are closely associated with neurobiological deficits. Brain derived neurotrophic factor (BDNF) is an extensively studied neurotrophin. BDNF is essential for neuronal genesis, differentiation, survival, growth, plasticity, synaptic viability and transmission. BDNF has emerged as a promising target for regulating synaptic activity and plasticity. An overview of effects and mechanisms of the natural products targeting BDNF is described. This review is an attempt to enumerate the effects of various natural products on BDNF as a novel therapeutic approach for neurodegenerative and neuropsychiatric disorders.

The CureFA Foundation, Rye, NY, USA, has joined the ownership of Fratagene Therapeutics

Fratagene Therapeutics. September 2019. The CureFA Foundation, Rye, NY, USA, has joined the ownership of Fratagene Therapeutics. The CureFA foundation funds scientific projects and industry partnership that leverage new technologies for the treatment and cure of Friedreich ataxia. Its assets in Fratagene will help support the first clinical trial aimed at assessing the safety and efficacy of etravirine in FA patients.

Mechanism of activation of the human cysteine desulfurase complex by frataxin

Shachin Patra and David P. Barondeau; PNAS first published September 11, 2019 doi:10.1073/pnas.1909535116

Our results support key roles for this essential cysteine residue in substrate binding, as a general acid to advance the Cys-quinonoid PLP intermediate, as a nucleophile to form an NFS1 persulfide, and as a sulfur delivery agent to generate a persulfide species on the Fe-S scaffold protein ISCU2. FXN specifically accelerates each of these individual steps in the mechanism. Our resulting architectural switch model explains why the human Fe-S assembly system has low inherent activity and requires activation, the connection between the functional mobile S-transfer loop cysteine and FXN binding, and why the prokaryotic system does not require a similar FXN-based activation. Together, these results provide mechanistic insights into the allosteric-activator role of FXN and suggest new strategies to replace FXN function in the treatment of FRDA.

Two new Pfizer-coauthored studies validate Novoheart’s pioneering human bioengineered heart tissues and chambers for improving drug development

Novoheart Holdings Inc.; September 09, 2019.

Novoheart seeks to revolutionize human heart tissue engineering for disease modeling and drug discovery.
Peer-reviewed publications feature results from the completion of two research contracts between Novoheart and Pfizer.

In the second study, published in the July 2019 issue of Stem Cell Research and Therapy2, Novoheart developed the world’s first customized, 3D engineered, human cardiac tissue models of Friedreich’s ataxia (FRDA), a rare neuromuscular degenerative disease that affects over 1 in 50,000 people worldwide. FRDA patients have a defective Frataxin gene, which often leads to lethal heart complications. This new disease model, based on MyHeartTM assays, was created using genetically modified as well as FRDA patient-derived cells, capturing both electrical and mechanical defects of the heart observed in FRDA patients.

This new approach marks an important step away from using animals as traditional testing models – they have limited predictive ability for drug discovery due to dramatic differences from human physiology. Novoheart’s FRDA models, on the other hand, offer an innovative and powerful human-based platform to develop new therapies for FRDA’s cardiac symptoms, for which no effective treatments are currently available.

With sole ownership of the intellectual property rights, Novoheart is now commercializing the FRDA disease model and has subsequently confirmed commercial contracts with multiple drug developers.

Changes detected in swallowing function in Friedreich ataxia over 12 months

Megan Keage, Martin B. Delatycki, Jessamy Dyer, Louise A. Corben, Adam P. Vogel, Neuromuscular Disorders, 2019, doi:10.1016/j.nmd.2019.08.013

A decline in function was observed at three anatomical sites considered important for safe and effective swallowing (tongue, pharyngeal, cricopharyngeal). However, these deficits did not translate into any meaningful functional decline in swallowing related health over 12 months for individuals with FRDA.

Scoliosis in Patients With Friedreich Ataxia: Results of a Consecutive Prospective Series

Anne Laure Simon, Jean Meyblum, Bastien Roche, Christophe Vidal, Keyvan Mazda, Isabelle Husson, Brice Ilharrebord; Spine Deformity,
Volume 7, Issue 5, 2019, Pages 812-821, doi:10.1016/j.jspd.2019.02.005.

The prevalence of scoliosis in FA was high (71%), and thoracic hyperkyphosis, with anterior misalignment, was frequently observed, which might be related to the anterior imbalance frequently encountered in patients with an ataxia. Posterior fusion including sacral instrumentation was only performed in nonambulatory patients, and the loss of ambulation was not associated with spinal surgery.

Biohackers are pirating a cheap version of a million-dollar gene therapy

MIT Technology Review magazine, Aug 30, 2019. by Alex Pearlman

A group of independent biologists say they plan to copy a costly gene therapy. Are they medicine’s Robin Hood or a threat to safety?

The drug being copied is Glybera, a gene therapy that was the world’s most expensive drug when it came on the market in Europe in 2015 with a price tag of $1 million per treatment. Glybera was the first gene therapy ever approved to treat an inherited disease.

The gene therapy that the biohackers say they are copying, Glybera, was approved for people with an ultra-rare blood disease called lipoprotein lipase deficiency. But it didn’t prove cost-effective and was pulled from the market in 2017 by its manufacturer, UniQure. To date, only one insurer, in Germany, is known to have paid for the treatment.

“This was developed in a shed in Mississippi, a warehouse in Florida, a bedroom in Indiana, and on a computer in Austria,” says Gabriel Licina, a biohacker based in South Bend, Indiana. He says the prototype gene therapy cost less than $7,000 to create.

This year the Swiss pharmaceutical firm Novartis introduced another gene therapy, Zolgesma, for spinal muscular atrophy, with a price of $2.1 million. Because of the cost, some parents have struggled to obtain it for their children and the treatment is unlikely to be made available in most of the world.

“It’s a fairly big deal to see biohackers turning their focus to gene therapies because the potential consequences can be quite large,” said Rachel Sachs, an associate professor of law at Washington University in St. Louis and an expert on drug pricing. “They may see themselves as serving the interests of the patient community.”

Newly Funded FARA Grants, July 2019

Newly Funded FARA Grants, July 2019

FARA's most recent grant round was of very high quality, and included some very innovative research. After much work by the applicants, reviewers and Scientific Review Committee, the following grants will be funded:

Benoit D’Autreaux, Paris-Saclay University: “Cell-free high throughput screening assays for the discovery of compounds replacing frataxin in FA”

Hélène Puccio, the Institut de Génétique et de Biologie Moléculaire et Cellulaire: “Characterization of new humanized mouse model (TG(FXN)YG8Pook/800J) carrying 650-800 GAA repeats”

Mirella Dottori, University of Wollongong: “Nanoparticle-mediated gene delivery of frataxin to neurons”

Massimo Pandolfo, Université Libre de Bruxelles (ULB), Hôpital Erasme:“Induced pluripotent stem cells-derived neurons for translational research in Friedreich ataxia"

Muscular Dystrophy Association Awards 25 Grants Totaling More Than $6.6 Million for Neuromuscular Disease Research

NEW YORK, Sept. 5, 2019 /PRNewswire. NEWS PROVIDED BY: Muscular Dystrophy Association, Sep 05, 2019.

Critical funding provided by MDA will support studies to further understand disease mechanisms, optimize and build upon existing therapies, and advance drug target identification, especially toward gene-targeted therapies -- research that will have translational and clinical application across many neuromuscular diseases

Jordi Magrane, PhD
Weill Cornell Medical College
Research grant, $300,000
Cell and non-cell autonomous effects of frataxin deficiency in FA pathophysiology

Friedreich ataxia- pathogenesis and implications for therapies

Martin B. Delatycki, Sanjay I. Bidichandani, Neurobiology of Disease, 2019, 104606, doi: 10.1016/j.nbd.2019.104606.

Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.

An Affordable Method for Evaluation of Ataxic Disorders Based on Electrooculography

Alberto López, Francisco Ferrero, Octavian Postolache; Sensors 2019, 19(17), 3756; doi:10.3390/s19173756

This paper reports an affordable ataxic disorders evaluation method based on the processing of EOG, which could be used to replace the traditional naked-eye method. The EOG, combined with a computer application, may be a useful for testing a patient’s eye coordination and identifying whether the subject might have some type of ataxia. The results obtained show the feasibility of the proposed method as a promising clinical assessment modality for performing an objective evaluation. However, signal processing and parameter setting improvements are necessary.

Hepcidin and its therapeutic potential in neurodegenerative disorders

Qian, Z‐M, Ke, Y.; Med Res Rev. 2019; 1‐ 21. Doi:10.1002/med.21631

Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron‐related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood‐brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron‐associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.

Multifunctional radical quenchers as potential therapeutic agents for the treatment of mitochondrial dysfunction

Xun Ji, Omar M Khdour & Sidney M Hecht; FUTURE MEDICINAL CHEMISTRYVOL. 11, NO. 13; Published Online:30 Aug 2019 doi:10.4155/fmc-2018-0481

Mitochondrial dysfunction is associated with a wide range of human diseases, including neurodegenerative diseases, and is believed to cause or contribute to the etiology of these diseases. These disorders are frequently associated with increased levels of reactive oxygen species. One of the design strategies for therapeutic intervention involves the development of novel small molecules containing redox cores, which can scavenge reactive oxygen radicals and selectively block oxidative damage to the mitochondria. Presently, we describe recent research dealing with multifunctional radical quenchers as antioxidants able to scavenge reactive oxygen radicals. The review encompasses ubiquinone and tocopherol analogs, as well as novel pyri(mi)dinol derivatives, and their ability to function as protective agents in cellular models of mitochondrial diseases.

The Working Life of People with Degenerative Cerebellar Ataxia

A. Ranavolo, M. Serrao, T. Varrecchia, C. Casali, A. Filla, A. Roca, A. Silvetti, C. Marcotulli, B. M. Rondinone, S. Iavicoli, F. Draicchio; Cerebellum (2019). doi:10.1007/s12311-019-01065-x

Supporting patients with ataxia to find an appropriate job is an important priority because about 78% of non-workers search for a job and workers and non-workers have the same potential work abilities (no relevant differences were found in terms of disease characteristics, gender, and work resilience). In this view, introducing non-workers to work-life may have a potential rehabilitative aspect. Findings of this study highlight that equal job opportunities for subjects affected by cerebellar ataxia are recommended.