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.
Monday, May 6, 2019
Friday, May 3, 2019
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.
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.
Thursday, May 2, 2019
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)
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)
Friday, April 26, 2019
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.
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.
Thursday, April 25, 2019
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.
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.
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.
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.
Tuesday, April 23, 2019
A Clinical Study to Evaluate the Effect of MIN-102 on the Progression of Friedreich's Ataxia in Male and Female Patients (FRAMES)
ClinicalTrials.gov Identifier: NCT03917225.
Double-Blind, Placebo-controlled Study on the Effects of MIN-102 on Biochemical, Imaging, Neurophisyiological, and Clinical Markers in Patients With Friedreich's Ataxia.
Sponsor: Minoryx Therapeutics, S.L.
Locations
Belgium
Hôpital Erasme-ULB Not yet recruiting
Brussels, Belgium, B-1070
Contact: Prof. Massimo Pandolfo
France
ICM, Groupe Hospitalier Pitié Salpêtrière Not yet recruiting
Paris, France, 75646
Contact: Prof. Alexandra Durr
Germany
Universitätsklinikum RWTH Not yet recruiting
Aachen, Germany, 52074
Contact: Prof. Jörg B Schulz
Spain
Hospital Sant Joan de Déu Not yet recruiting
Barcelona, Spain
Contact: Dr. Alejandra Darling
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Contact: Dr. Francisco Javier Rodríguez de Rivera
Double-Blind, Placebo-controlled Study on the Effects of MIN-102 on Biochemical, Imaging, Neurophisyiological, and Clinical Markers in Patients With Friedreich's Ataxia.
Sponsor: Minoryx Therapeutics, S.L.
Locations
Belgium
Hôpital Erasme-ULB Not yet recruiting
Brussels, Belgium, B-1070
Contact: Prof. Massimo Pandolfo
France
ICM, Groupe Hospitalier Pitié Salpêtrière Not yet recruiting
Paris, France, 75646
Contact: Prof. Alexandra Durr
Germany
Universitätsklinikum RWTH Not yet recruiting
Aachen, Germany, 52074
Contact: Prof. Jörg B Schulz
Spain
Hospital Sant Joan de Déu Not yet recruiting
Barcelona, Spain
Contact: Dr. Alejandra Darling
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Contact: Dr. Francisco Javier Rodríguez de Rivera
Association between restless legs syndrome and other movement disorders
Hortensia Alonso-Navarro, Elena García-Martín, José A.G. Agúndez, View ORCID ProfileFélix Javier Jiménez-Jiménez; Neurology. 2019 Apr 19. pii: 10.1212/WNL.0000000000007500. doi: 10.1212/WNL.0000000000007500.
Review of PubMed from 1966 to September 2018 and identification of references of interest for the topic. A meta-analysis of eligible studies on the frequency of RLS in patients with PD and controls using Meta-DiSc1.1.1 software and using the PRISMA guidelines was performed.
Several studies have also suggested that RLS could be an early clinical feature of PD. RLS symptoms are frequent in multiple system atrophy, essential tremor, Tourette syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 as well.
Review of PubMed from 1966 to September 2018 and identification of references of interest for the topic. A meta-analysis of eligible studies on the frequency of RLS in patients with PD and controls using Meta-DiSc1.1.1 software and using the PRISMA guidelines was performed.
Several studies have also suggested that RLS could be an early clinical feature of PD. RLS symptoms are frequent in multiple system atrophy, essential tremor, Tourette syndrome, Friedreich ataxia, and spinocerebellar ataxia type 3 as well.
Friday, April 12, 2019
Mechanism of frataxin “bypass” in human iron-sulfur cluster biosynthesis with implications for Friedreich’s ataxia
Deepika Das, Shachin Patra, Jennifer Bridwell-Rabb, and David P. Barondeau; J. Biol. Chem. jbc.RA119.007716. doi:10.1074/jbc.RA119.007716
These results reveal an unexpected mechanism that replaces FXN-based stimulation of the Fe-S cluster biosynthetic pathway and suggest new strategies to overcome the loss of cellular FXN that may be relevant to the development of therapeutics for Friedreich’s ataxia.
These results reveal an unexpected mechanism that replaces FXN-based stimulation of the Fe-S cluster biosynthetic pathway and suggest new strategies to overcome the loss of cellular FXN that may be relevant to the development of therapeutics for Friedreich’s ataxia.
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