BURLINGTON, Mass., Oct. 25, 2016 /PRNewswire/ -- Decision Resources Group finds that the anticipated launches of the first therapies for the treatment of spinal muscular atrophy (SMA) or Friedreich's ataxia (FA) will transform treatment of these diseases and lead to their markets expanding dramatically.
Following the anticipated label expansion of Horizon Pharma's Actimmune (interferon gamma-1b), the FA market is forecasted to grow significantly over the next ten years. However, interviewed neurologists' perceived limitations of Actimmune, including its unclear mechanism of action, variable effect on frataxin protein levels, and modest preservation of neurological function, could constrain its uptake and allow competitors to challenge Actimmune's position.
According to interviewed experts, gene therapy will also transform the FA treatment landscape, possibly negating the need for drug treatment. However, gene therapies being developed by Agilis Biotherapeutics, Pfizer, and RaNA Therapeutics are in preclinical testing and unlikely to launch during the study period.
"Despite the lack of competing brands entering the market in the near term, Actimmune's high U.S. cost may be an obstacle for its rapid adoption among patients with FA. If Actimmune can show that it delays disease progression or improves neurological function over a year or more, prescribers, patients, and payers are likely to accept its very high price."
Wednesday, November 30, 2016
Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA)n Repeats by PNA or LNA Targeting
Helen Bergquist, Cristina S. J. Rocha, Rubén Álvarez-Asencio, Chi-Hung Nguyen, Mark. W. Rutland, C. I. Edvard Smith, Liam Good, Peter E. Nielsen, Rula Zain; PLoS ONE 11(11): e0165788. doi:10.1371/journal.pone.0165788
Chemical and structural probing of GAA repeats provides evidence for pyrimidine triplex (H-DNA) formation and the presence of different structures at the pathological repeats. Furthermore, we find that PNA and LNA sequence-specific targeting of Friedreich’s ataxia GAA repeat expansions can alter and resolve higher order DNA structures. BQQ-OP mediated triplex-specific cleavage of double strand DNA and chloroacetaldehyde chemical modification of single strand DNA regions at (GAA)n repeats demonstrate that GAA-PNA binding result in a duplex invasion complex, that completely dissociates all detectable triplex containing higher order structures at this site, whereas this is not the case for CTT-PNA. Additionally, we obtained a similar pattern using LNA based ONs. Furthermore, a significant change in plasmid morphology in the presence of GAA-LNA was detected using atomic force microscopy. Our results suggest that DNA targeting by modified GAA-oligomers at expanded (GAA)n repeats can be employed to examine the possible role of non-canonical DNA structures in FXN gene silencing and potentially applied to develop new nucleic acids-based therapeutic strategies in Friedreich’s ataxia disease.
Chemical and structural probing of GAA repeats provides evidence for pyrimidine triplex (H-DNA) formation and the presence of different structures at the pathological repeats. Furthermore, we find that PNA and LNA sequence-specific targeting of Friedreich’s ataxia GAA repeat expansions can alter and resolve higher order DNA structures. BQQ-OP mediated triplex-specific cleavage of double strand DNA and chloroacetaldehyde chemical modification of single strand DNA regions at (GAA)n repeats demonstrate that GAA-PNA binding result in a duplex invasion complex, that completely dissociates all detectable triplex containing higher order structures at this site, whereas this is not the case for CTT-PNA. Additionally, we obtained a similar pattern using LNA based ONs. Furthermore, a significant change in plasmid morphology in the presence of GAA-LNA was detected using atomic force microscopy. Our results suggest that DNA targeting by modified GAA-oligomers at expanded (GAA)n repeats can be employed to examine the possible role of non-canonical DNA structures in FXN gene silencing and potentially applied to develop new nucleic acids-based therapeutic strategies in Friedreich’s ataxia disease.
Tuesday, November 29, 2016
Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia
A. Benussi, V. Dell’Era, M.S. Cotelli, M. Turla, C. Casali, A. Padovani, B. Borroni, Brain Stimulation, Available online 3 November 2016, ISSN 1935-861X, doi:10.1016/j.brs.2016.11.001.
We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia (SCA2, SCA38, SCA14, with Friedreich’s ataxia, AOA type 2, MSA-C, FXTAS and SOAO). A two-weeks’ treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia.
We performed a double-blind, randomized, sham controlled trial with cerebellar tDCS (5 days/week for 2 weeks) in twenty patients with ataxia (SCA2, SCA38, SCA14, with Friedreich’s ataxia, AOA type 2, MSA-C, FXTAS and SOAO). A two-weeks’ treatment with anodal cerebellar tDCS improves symptoms in patients with ataxia and restores physiological cerebellar brain inhibition pathways. Cerebellar tDCS might represent a promising future therapeutic and rehabilitative approach in patients with neurodegenerative ataxia.
Monday, November 28, 2016
Doubts About Therapy for Neurological Diseases With Antisense Oligonucleotides
Satyakam Bhagavati, MD, JAMA Neurol. Published online October 31, 2016. doi:10.1001/jamaneurol.2016.4332
The review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on which ASO-based treatment is based is promising, a review of the literature, however, reveals critical lacunae in the data that have been used to claim efficacy.
Related Articles:
Clinical Implications of Basic Neuroscience Research, Synthetic Nucleic Acids and Treatment of Neurological Diseases David R. Corey, PhD
Antisense Oligonucleotides for Treating Neurological Diseases, David R. Corey, PhD
The review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on which ASO-based treatment is based is promising, a review of the literature, however, reveals critical lacunae in the data that have been used to claim efficacy.
Related Articles:
Clinical Implications of Basic Neuroscience Research, Synthetic Nucleic Acids and Treatment of Neurological Diseases David R. Corey, PhD
Antisense Oligonucleotides for Treating Neurological Diseases, David R. Corey, PhD
Sunday, November 27, 2016
Challenges ahead for trials in Friedreich’s ataxia
David R Lynch, Elizabeth Kichula, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1300-1301, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30281-2.
Nevertheless, although natural history studies such as EFACTS identify the problems in progressing with therapeutic trials in Friedreich’s ataxia, they also identify one mechanism for keeping trials small: stratification.
In all of the natural history studies of Friedreich’s ataxia including the EFACTS, individuals with longer GAA repeat lengths had faster progression.
Nevertheless, although natural history studies such as EFACTS identify the problems in progressing with therapeutic trials in Friedreich’s ataxia, they also identify one mechanism for keeping trials small: stratification.
In all of the natural history studies of Friedreich’s ataxia including the EFACTS, individuals with longer GAA repeat lengths had faster progression.
Progression characteristics of the European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS): a 2 year cohort study
Kathrin Reetz, Imis Dogan, Ralf-Dieter Hilgers, Paola Giunti, Caterina Mariotti, Alexandra Durr, Sylvia Boesch, Thomas Klopstock, Francisco Javier Rodriguez de Rivera, Ludger Schöls, Thomas Klockgether, Katrin Bürk, Myriam Rai, Massimo Pandolfo, Jörg B Schulz, The Lancet Neurology, Volume 15, Issue 13, December 2016, Pages 1346-1354, ISSN 1474-4422, http://dx.doi.org/10.1016/S1474-4422(16)30287-3.
"To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial."
In conclusion, our results of the 2 year analysis of the EFACTS cohort allowed substantiation of the suitability of the SARA and ADL as robust outcome measures for future therapeutic trials, which should be designed with an observational period of at least 2 years.
"To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial."
In conclusion, our results of the 2 year analysis of the EFACTS cohort allowed substantiation of the suitability of the SARA and ADL as robust outcome measures for future therapeutic trials, which should be designed with an observational period of at least 2 years.
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