Brady Huggett, Nature Biotechnology 35, 301 (2017) doi:10.1038/nbt0417-301 Published online 11 April 2017
n January Kaiser Health News published a data-rich report focusing on the increase in approvals of orphan disease drugs, detailing how even high-volume products have reaped the tax breaks and market exclusivity that come with orphan drug status.
For each approval, drugmakers receive government incentives plus seven years exclusivity for that rare disease. Orphan status became a commercial opportunity.
Orphan drug rules “appear to be stretched beyond their original intent,” which may be helping to stoke drug prices for commonly used drugs.
Wednesday, April 12, 2017
Tuesday, April 11, 2017
Biogen Accused Of Stifling Neurological Drug Competition
Law360, Los Angeles (April 4, 2017, 7:05 PM EDT) -- Biogen Inc. is facing an antitrust suit in California federal court filed Tuesday by Ixchel Pharma LLC alleging it attempted to hold a monopoly on drug treatments containing dimethyl fumarate, preventing Ixchel from creating a drug for a degenerative neurological disease.
The complaint claims Biogen specifically stopped a partnership between Ixchel and a competitor to develop a new treatment for Friedreich’s ataxia, a debilitating neuro-degenerative disorder. The condition doesn’t have an FDA-approved treatment, the complaint says, but Ixchel since 2012 has been working to develop one....
The complaint claims Biogen specifically stopped a partnership between Ixchel and a competitor to develop a new treatment for Friedreich’s ataxia, a debilitating neuro-degenerative disorder. The condition doesn’t have an FDA-approved treatment, the complaint says, but Ixchel since 2012 has been working to develop one....
Saturday, April 8, 2017
SNPs in microRNA target sites and their potential role in human disease
Adrianna Moszyńska, Magdalena Gebert, James F. Collawn, Rafał Bartoszewski; Open Biology, The Royal Society Publishing, Published 5 April 2017.DOI: 10.1098/rsob.170019
FXN | miR-124-3p: Reduced expression of the mitochondrial frataxin (FXN) protein has been postulated to play a role in Friedreich's ataxia (FRDA), an inherited neurodegenerative disease. Lower levels of frataxin are due to GAA repeat expansion in the FXN gene. Additionally, Bandiera et al. have suggested that miR-124-3p regulates FXN expression in vivo only in FRDA patients. They identified seven SNPs in the 3′-UTR of FXN in children and adults diagnosed with FRDA. One of them, rs11145043 (G>T), permits miR-124-3p binding only when the T allele is present. Although miR-124-3p is highly expressed in the nervous system, it is overexpressed in FRDA patients, suggesting its role in FRDA. However, its influence on FXN needs further clarification.
FXN | miR-124-3p: Reduced expression of the mitochondrial frataxin (FXN) protein has been postulated to play a role in Friedreich's ataxia (FRDA), an inherited neurodegenerative disease. Lower levels of frataxin are due to GAA repeat expansion in the FXN gene. Additionally, Bandiera et al. have suggested that miR-124-3p regulates FXN expression in vivo only in FRDA patients. They identified seven SNPs in the 3′-UTR of FXN in children and adults diagnosed with FRDA. One of them, rs11145043 (G>T), permits miR-124-3p binding only when the T allele is present. Although miR-124-3p is highly expressed in the nervous system, it is overexpressed in FRDA patients, suggesting its role in FRDA. However, its influence on FXN needs further clarification.
Wednesday, April 5, 2017
New research front to tackle Friedreich’s Ataxia
IRB Barcelona, 14 Mar 2017. IRB Barcelona starts a project with the long-term goal to achieve an injectable frataxin treatment able to reach the brain. The project specifically aims to complete a step necessary in order to move towards a future frataxin replacement therapy for the brain, where the reduction of this protein causes the most damage in patients with Friedreich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.
The study is headed by Ernest Giralt, head of the Peptides and Proteins Lab, who has many years of experience and is a recognised expert in peptide chemistry and new systems of through which to delivery drugs to the brain, such as peptide shuttles—molecules that have the capacity to carry the drug across the barrier that surrounds and protects the brain. Since the lab started its relation with these patients’ associations in 2013*, it has been developing another two projects into Friedrich’s Ataxia.
Monday, April 3, 2017
Reata Pharmaceuticals, Inc. Secures $35 Million Term Loan Facility
IRVING, Texas, April 03, 2017 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced that it entered into a $35 million loan and security agreement with Oxford Finance LLC and Silicon Valley Bank. Proceeds from the loan will be utilized primarily to support Reata’s multiple Phase 2 and 3 clinical trial programs for bardoxolone methyl and omavaloxolone.
The loan proceeds are available to Reata in two tranches. The first $20 million tranche was funded on Friday, March 31st. The additional $15 million tranche will be available to Reata from July 1, 2017 to March 31, 2018, and after Reata enrolls the first patient in either (a) the Phase 3 portion of the ongoing Phase 2/3 clinical trial of bardoxolone methyl in chronic kidney disease caused by Alport syndrome or (b) Part 2 of the ongoing two-part clinical trial, or a separate Phase 3 clinical trial, of omavaloxolone in Friedreich’s ataxia.
The loan proceeds are available to Reata in two tranches. The first $20 million tranche was funded on Friday, March 31st. The additional $15 million tranche will be available to Reata from July 1, 2017 to March 31, 2018, and after Reata enrolls the first patient in either (a) the Phase 3 portion of the ongoing Phase 2/3 clinical trial of bardoxolone methyl in chronic kidney disease caused by Alport syndrome or (b) Part 2 of the ongoing two-part clinical trial, or a separate Phase 3 clinical trial, of omavaloxolone in Friedreich’s ataxia.
Sunday, April 2, 2017
Characteristics of Friedreich’s Ataxia and Autosomal Dominant Spinocerebellar Ataxia Types 1, 2, 3, and 6
Pınar Bengi Boz, Filiz Koç, Sabriye Kocatürk Sel, Ali İrfan Güzel, Halil Kasap, Arch Neuropsychiatry 2016; 53: 115-119, DOI:10.5152/npa.2015.9925
This study aimed to analyze the genotypic characteristics of Friedreich’s ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings.
In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA.
This study aimed to analyze the genotypic characteristics of Friedreich’s ataxia (FA) and autosomal dominant ataxias [such as spinocerebellar ataxia (SCA) types 1, 2, 3, and 6] using molecular and biological methods in hereditary cerebellar ataxia considering both clinical and electrophysiological findings.
In our study, 47.2% of patients with FA had developed hereditary cerebellar ataxia. Ground and autosomal dominant-linked SCA1 and SCA6 were each detected in one family. These data suggest that patients with cerebellar ataxia of hereditary origin should be primarily examined for FA.
Friday, March 31, 2017
Longitudinal Gait and Balance Decline in Friedreich’s Ataxia: A Pilot Study
Theresa A. Zesiewicz, Jeannie B. Stephenson, Seok Hun Kim, Kelly L. Sullivan, Israt Jahan, Yangxin Huang, Jason L. Salemi, Lynn Wecker, Jessica D. Shaw, Clifton L. Gooch, Gait & Posture, Available online 30 March 2017, ISSN 0966-6362, doi:10.1016/j.gaitpost.2017.03.019.
In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores.
The GAITRite and Biodex systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA.
In the FA group, comfortable and fast gait velocity declined 8.0% and 13.9% after 12 months and 24.1% and 30.3% after 24 months, respectively. Postural stability indices increased in FA subjects an average of 41% from baseline to 24 months, representing a decline in balance. Subjects with FA also demonstrated a 17.7% increase in FARS neurological exam scores over 24 months. There were no changes in gait or balance variables in controls. In the FA group, multiple gait and balance measures correlated significantly with FARS neurological exam scores.
The GAITRite and Biodex systems provided objective and clinically relevant measures of functional decline in subjects with FA that correlated significantly with performance measures in the FARS. Gait velocity may be an important objective measure to identify disease progression in adults with FA.
Thursday, March 30, 2017
Ferroptosis Inhibition: Mechanisms and Opportunities
Jose Pedro Friedmann Angeli, Ron Shah, Derek A. Pratt, Marcus Conrad, Trends in Pharmacological Sciences, Available online 28 March 2017, ISSN 0165-6147, doi:10.1016/j.tips.2017.02.005.
The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies.
Supplementation of cell media with deuterated linoleic acid (LA) was investigated, and has proven beneficial in several cell models of lipid peroxidation-related neurological disease including PD and Friedreich’s ataxia. In addition,it was also recently shown that cells exposed to deuterated LA presented a marked resistance to ferroptosis.
Ever since therecognition of the privileged position of a-tocopherol as Nature’s premier lipid-soluble Radical-Trapping Antioxidants, researchers have developed with success synthetic compounds with increased reactivity towards peroxyl radicals.
The past decade has yielded tremendous insights into how cells die. This has come with our understanding that several distinct forms of cell death are encompassed under the umbrella term necrosis. Among these distinct forms of regulated necrotic cell death, ferroptosis has attracted considerable attention owing to its putative involvement in diverse pathophysiological processes. A key feature of the ferroptosis process is the requirement of phospholipid peroxidation, a process that has been linked with several human pathologies. Now with the establishment of a connection between lipid peroxidation and a distinctive cell death pathway, the search for new small molecules able to suppress lipid peroxidation has gained momentum and may yield novel cytoprotective strategies. We review here advances in our understanding of the ferroptotic process and summarize the development of lipid peroxidation inhibitors with the ultimate goal of suppressing ferroptosis-relevant cell death and related pathologies.
Supplementation of cell media with deuterated linoleic acid (LA) was investigated, and has proven beneficial in several cell models of lipid peroxidation-related neurological disease including PD and Friedreich’s ataxia. In addition,it was also recently shown that cells exposed to deuterated LA presented a marked resistance to ferroptosis.
Ever since therecognition of the privileged position of a-tocopherol as Nature’s premier lipid-soluble Radical-Trapping Antioxidants, researchers have developed with success synthetic compounds with increased reactivity towards peroxyl radicals.
Wednesday, March 29, 2017
Individualized exergame training improves postural control in advanced degenerative spinocerebellar ataxia: A rater-blinded, intra-individually controlled trial
Conny Schatton, Matthis Synofzik, Zofia Fleszar, Martin A. Giese, Ludger Schöls, Winfried Ilg, Parkinsonism & Related Disorders, Available online 28 March 2017, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.03.016.
Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.
The training improvement of 2.5 SARA points indicates a meaningful improvement, given that a reduction of one SARA point is generally considered as clinically relevant. It represents a treatment effect equivalent to gaining back functional performance of 1.5 years of natural disease progression (e.g. progression in Friedreich’s Ataxia: 1.4 point SARA increase/year). Interestingly, the 2.5 SARA point training improvement is in the same range as training via exergames or via physiotherapy in mild-to-moderate degenerative ataxia. Thus, even largely nonambulatory subjects with advanced degenerative ataxia are still capable of training induced improvements, despite far more progressed and multisystemic neurodegeneration.
This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.
Treatment options are rare in degenerative ataxias, especially in advanced, multisystemic disease. Exergame training might offer a novel treatment strategy, but its effectiveness has not been investigated in advanced stages.
The training improvement of 2.5 SARA points indicates a meaningful improvement, given that a reduction of one SARA point is generally considered as clinically relevant. It represents a treatment effect equivalent to gaining back functional performance of 1.5 years of natural disease progression (e.g. progression in Friedreich’s Ataxia: 1.4 point SARA increase/year). Interestingly, the 2.5 SARA point training improvement is in the same range as training via exergames or via physiotherapy in mild-to-moderate degenerative ataxia. Thus, even largely nonambulatory subjects with advanced degenerative ataxia are still capable of training induced improvements, despite far more progressed and multisystemic neurodegeneration.
This study provides first evidence that, even in advanced stages, subjects with degenerative ataxia may benefit from individualized training, with effects translating into daily living and improving underlying control mechanisms. The proposed training strategy can be performed at home, is motivating and facilitates patient self-empowerment.
Tuesday, March 28, 2017
Nonreplicative genomic HSV-1 derived vectors for dorsal root ganglion gene therapy of Friedreich´s ataxia
María Ventosa Rosales, Directores de la Tesis: Filip Lim (dir. tes.) Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016. Idioma: inglés
Our approach has consisted on the construction and preliminary characterization of a high capacity nonreplicative genomic HSV-1 vector carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1. We show that the nonreplicative HSV-1 genomic vector deleted for 23 kb maintains its growth capacity and the FXN transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression.
Transduction of cultured fetal rat DRG neurons with the 27_4_Or2_β22 FXNinlZ vector results in sustained expression of human FXN transcripts and FXN protein. Rat footpad inoculation with the 27_4_Or2_β22 FXNinlZ vector results in human FXN transgene delivery to the DRG, with expression persisting for at least 1 month.
Our results support the feasibility of using this vector for sustained neuronal expression of human FXN for future FRDA gene therapy.
Our approach has consisted on the construction and preliminary characterization of a high capacity nonreplicative genomic HSV-1 vector carrying a reduced version of the human FXN genomic locus, comprising the 5 kb promoter and the FXN cDNA with the inclusion of intron 1. We show that the nonreplicative HSV-1 genomic vector deleted for 23 kb maintains its growth capacity and the FXN transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression.
Transduction of cultured fetal rat DRG neurons with the 27_4_Or2_β22 FXNinlZ vector results in sustained expression of human FXN transcripts and FXN protein. Rat footpad inoculation with the 27_4_Or2_β22 FXNinlZ vector results in human FXN transgene delivery to the DRG, with expression persisting for at least 1 month.
Our results support the feasibility of using this vector for sustained neuronal expression of human FXN for future FRDA gene therapy.
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