Primary Cultures of Pure Embryonic Dorsal Root Ganglia Sensory Neurons as a New Cellular Model for Friedreich’s Ataxia

Griso O., Puccio H. (2020). In: Richard GF. (eds) Trinucleotide Repeats. Methods in Molecular Biology, vol 2056. Humana, New York, NY. doi:10.1007/978-1-4939-9784-8_15

We have established a model of primary cultures of DRG sensory neurons in which we induce the loss of the frataxin protein. With such a model we can alleviate the issues related to the complexity of DRG tissues and low amount of sensory neuron material in adult mouse. Hereby, we provide a protocol of detailed and optimized methods to obtain high yield of healthy mouse DRG sensory neuron in culture.

SINEUP non-coding RNAs rescue defective frataxin expression and activity in a cellular model of Friedreich's Ataxia

Carlotta Bon, Riccardo Luffarelli, Roberta Russo, Silvia Fortuni, Bianca Pierattini, Chiara Santulli, Cristina Fimiani, Francesca Persichetti, Diego Cotella, Antonello Mallamaci, Claudio Santoro, Piero Carninci, Stefano Espinoza, Roberto Testi, Silvia Zucchelli, Ivano Condò, Stefano Gustincich; Nucleic Acids Research, , gkz798, doi:10.1093/nar/gkz798

We have previously described SINEUPs, natural and synthetic antisense long non-coding RNAs, which promote translation of partially overlapping mRNAs through the activity of an embedded SINEB2 domain. Here, by in vitro screening, we have identified a number of SINEUPs targeting human FXN mRNA and capable to up-regulate frataxin protein to physiological amounts acting at the post-transcriptional level. Furthermore, FXN-specific SINEUPs promote the recovery of disease-associated mitochondrial aconitase defects in FRDA-derived cells. In summary, we provide evidence that SINEUPs may be the first gene-specific therapeutic approach to activate FXN translation in FRDA and, more broadly, a novel scalable platform to develop new RNA-based therapies for haploinsufficient diseases.

A case of Friedreich ataxia in an adolescent with 16p11.2 microdeletion syndrome

Valentina Pelliccia, Silvia Ferranti, Rosa Mostardini, Salvatore Grosso; Neurol Sci (2019). doi:10.1007/s10072-019-04075-z

A completely different genetic mechanism is the one responsible for Friedreich ataxia; the disorder is provoked by an unstable expansion of the GAA triplet located in the frataxin gene [4]. Friedreich ataxia is the most common type of inherited ataxia; onset of symptoms usually occurs during adolescence, and clinical course is slowly progressive. The main clinical signs include gait imbalance, abnormal eye movements, scoliosis, feet deformities, urinary dysfunction, and cardiac involvement.

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.