Characterization of human frataxin missense variants in cancer tissues

Maria Petrosino Alessandra Pasquo Leonore Novak Angelo Toto Stefano Gianni Elide Mantuano Liana Veneziano Velia Minicozzi Annalisa Pastore Rita Puglisi Emidio Capriotti Roberta Chiaraluce Valerio Consalvi; Hum Mutat. 2019 May 10. doi: 10.1002/humu.23789.

Defective function of frataxin may cause defects in mitochondria, leading to increased tumorigenesis. Tumour initiating cells show higher iron uptake, a decrease in iron storage and a reduced Fe‐S clusters synthesis and utilization. In this study we selected, from COSMIC database, the somatic human frataxin missense variants found in cancer tissues p.D104G, p.A107V, p.F109L, p.Y123S, p.S161I, p.W173C, p.S181F, and p.S202F to analyze the effect of the single amino acid substitutions on frataxin structure, function and stability. The spectral properties, the thermodynamic and the kinetic stability, as well as the molecular dynamics of the frataxin missense variants found in cancer tissues point to local changes confined to the environment of the mutated residues. The global fold of the variants is not altered by the amino acid substitutions, however some of the variants show a decreased stability and a decreased functional activity in comparison to that of the wild type protein.

Priorities when deciding on participation in early-phase gene therapy trials for Duchenne muscular dystrophy: a best–worst scaling experiment in caregivers and adult patients

Ryan S. Paquin, Ryan Fischer, Carol Mansfield, Brennan Mange, Katherine Beaverson, Annie Ganot, Amy Strong Martin, Carl Morris, Colin Rensch, Valeria Ricotti, Leo J. Russo, Alesia Sadosky, Edward C. Smith and Holly L.; Orphanet Journal of Rare Diseases 2019 14:102 doi:10.1186/s13023-019-1069-6

Several gene therapy trials for Duchenne muscular dystrophy initiated in 2018. Trial decision making is complicated by non-curative, time-limited benefits; the progressive, fatal course; and high unmet needs. Here, caregivers and patients prioritize factors influencing decision making regarding participation in early-phase gene therapy trials.

Objects used to construct choice sets for the best-worst choice experiment

Object	Description
Chance of improved muscle function	Data are positive about the chance of maintaining, and maybe improving, muscle function.
Chance of improved heart function	Data are positive about the chance of maintaining, and maybe improving, heart function.
Chance of improved lung function	Data are positive about the chance of maintaining, and maybe improving, lung function.
Benefit lasts about 10 years	Data suggest that gene therapy will last for 10 years. It may be shorter or longer, but no one knows. It is currently not possible to give a second dose of gene therapy. It may be possible in the future, but no one knows.
Chance of being in placebo group	The trial uses a placebo group, where some participants are randomly assigned to a group that gets an inactive (fake) treatment. People who get placebo during the trial would be eligible for gene therapy in the future.
Lowest dose may be too low for benefit	One of the trial’s goals is to test the right dose of gene therapy. If participants get a dose that is too low to work, they will not get another chance to use gene therapy.
Two muscle biopsies required	Being in the trial requires 2 muscle biopsies (one from the arm and one from the leg) to test for dystrophin production.
Not eligible for future trials	People who get gene therapy will most likely not be eligible for other clinical trials for the rest of their lives. It may someday be possible, but no one knows.
Limits later use of gene therapies or CRISPR	People who get gene therapy may not be able to use some newer types of gene therapy or gene editing (like CRISPR) for the rest of their lives. It may someday be possible, but no one knows.
Chance of long hospitalization	Data suggest a low risk of needing a long hospitalization of 4 weeks or more to recover from serious side effects.
Chance of death (low risk)	Data suggest a very low risk of death soon after using gene therapy. That risk should be even lower than we showed you in the first survey task.

Orphan designation was granted by the European Commission to Takeda Pharma for TAK-831for the treatment of Friedreich’s ataxia

On 1 April 2019, orphan designation (EU/3/19/2148) was granted by the European Commission to Takeda Pharma A/S, Denmark, for 4-hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one (also known as TAK-831) for the treatment of Friedreich’s ataxia.

First published: 07/05/2019
EMADOC-628903358-645

Delivering cellular and gene therapies to patients: solutions for realizing the potential of the next generation of medicine

Kris Elverum & Maria Whitman; Gene Therapy (2019) Doi:10.1038/s41434-019-0074-7

This paper reviews the existing system to deliver cell and gene therapies and outlines the requirements to make them accessible to patients. Informed by interviews with experts, opportunities for improvement are identified along the patient and cell journeys, and a call to action is made for stakeholders to detail and implement change.
Healthcare professionals and patients: fight for progress. With all of the challenges and changes needed in our healthcare system, unfortunately action is not likely unless patients, caregivers, patient organizations, and healthcare professionals fight for progress. With many cell and gene therapies targeting rare diseases, coming together to push for these technologies is even more important to ensure that government, regulatory bodies, and payers have these issues on their priority agenda.

Probing the multifactorial source of hand dysfunction in Friedreich ataxia

Louise A. Corben, Eppie M. Yiu, Geneieve Tai, Sarah C. Milne, Brigitte Lynch, Martin B. Delatycki, J Clin Neurosci. 2019 Apr 22. pii: S0967-5868(18)31910-6. doi: 10.1016/j.jocn.2019.04.009

Friedreich ataxia (FRDA) has a significant effect on hand function which in turn, may compromise independence and quality of life. This study sought to identify the extent of muscle weakness, spasticity and changes in joint range in the hands of individuals with FRDA. We used the Modified Tardieu Scale (MTS), testing of muscle strength and goniometry to examine hand function in 19 individuals with FRDA. Relationships between clinical measures of disease severity, functional independence and measures of hand function were also explored. We found evidence for both upper and lower motor neuron impairment in this population. Thirteen (68.0%) participants had spasticity in the dominant wrist and finger flexors, and seven (36.8%) had contracture in at least one joint of either hand. Sixteen (84.3%) participants demonstrated weakness in the intrinsic musculature of the hands and the majority demonstrated some degree of hyperextension at the metacarpophalangeal joints of either hand. Significant correlations were found between functional independence capacity and clinical parameters, and components of spasticity and weakness in both the dominant and non-dominant hands. Moreover, spasticity and weakness in the dominant hand were shown to be significant predictors of reduced functional independence capacity. This study highlights for the first time the incidence of upper limb spasticity which, in combination with weakness and contracture, suggests a multifactorial source of hand dysfunction in people with FRDA.

Micronised Resveratrol as a Treatment for Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT03933163. May 1, 2019


Phase 2. 40 participants, Double-blind, randomised, placebo-controlled 2-period crossover trial of 2g/day of micronised resveratrol versus placebo. Participants will be randomised in terms of the order in which they received micronised resveratrol and placebo.
The study will be a double-blinded, placebo-controlled randomised 2-period crossover trial of 2g/day of micronised resveratrol in FRDA over 24 weeks. The study will enrol 40 patients with FRDA from 3 sites. The primary outcome measure is the change in modified Friedreich Ataxia Rating Scale (mFARS) score from baseline to 24 weeks.
Sponsors and Collaborators: Murdoch Childrens Research Institute
Locations: Queensland, Victoria, Western Australia (Australia)

Hypoxia Rescues Frataxin Loss by Restoring Iron Sulfur Cluster Biogenesis

Tslil Ast, Joshua D. Meisel, Shachin Patra, Gary Ruvkun, David P. Barondeau, Vamsi K. Mootha; Cell , Volume 0 , Issue 0, Published: April 25, 2019, DOI:10.1016/j.cell.2019.03.045

Fe-S clusters and is considered to be essential for viability. Here we report that when grown in 1% ambient O 2, FXN null yeast, human cells, and nematodes are fully viable. In human cells, hypoxia restores steady-state levels of Fe-S clusters and normalizes ATF4, NRF2, and IRP2 signaling events associated with FRDA. Cellular studies and in vitro reconstitution indicate that hypoxia acts through HIF-independent mechanisms that increase bioavailable iron as well as directly activate Fe-S synthesis. In a mouse model of FRDA, breathing 11% O 2 attenuates the progression of ataxia, whereas breathing 55% O 2 hastens it. Our work identifies oxygen as a key environmental variable in the pathogenesis associated with FXN depletion, with important mechanistic and therapeutic implications.

Brain signals translated into speech using artificial intelligence

Nature news, 24 APRIL 2019 . Giorgia Guglielmi. "Technology could one day be used to help people who can’t talk to communicate".


In an effort to provide a voice for people who can’t speak, neuroscientists have designed a device that can transform brain signals into speech.


Two examples of a participant reading a sentence, followed by the synthesized version of the sentence generated from their brain activity.

Speech synthesis from neural decoding of spoken sentences

Gopala K. Anumanchipalli, Josh Chartier & Edward F. Chang ; Nature volume 568, pages 493–498 (2019) doi:10.1038/s41586-019-1119-1

Technology that translates neural activity into speech would be transformative for people who are unable to communicate as a result of neurological impairments. Decoding speech from neural activity is challenging because speaking requires very precise and rapid multi-dimensional control of vocal tract articulators. Here we designed a neural decoder that explicitly leverages kinematic and sound representations encoded in human cortical activity to synthesize audible speech. Recurrent neural networks first decoded directly recorded cortical activity into representations of articulatory movement, and then transformed these representations into speech acoustics. In closed vocabulary tests, listeners could readily identify and transcribe speech synthesized from cortical activity. Intermediate articulatory dynamics enhanced performance even with limited data. Decoded articulatory representations were highly conserved across speakers, enabling a component of the decoder to be transferrable across participants. Furthermore, the decoder could synthesize speech when a participant silently mimed sentences. These findings advance the clinical viability of using speech neuroprosthetic technology to restore spoken communication.

Erythropoietin and Friedreich Ataxia: Time for a Reappraisal?

Boesch S and Indelicato E (2019); Front. Neurosci. 13:386. doi: 10.3389/fnins.2019.00386

Despite several clinical trials in the past, no treatment is available for the treatment of FRDA. Current lines of research focus on gene therapy, frataxin replacement strategies and on regulation of key metabolic checkpoints such as NrF2. Due to potential crosstalk with all these mechanisms, interventions on the EPO pathway still represent a valuable research field. The recent development of small EPO mimetics which maintain cytoprotective properties without erythropoietic action may open a new era in EPO research for the treatment of FRDA.