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Chronic Denervation Myopathy
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
Several different approaches have been utilized to treat SMA. The first is splicing modification of SMN2 in order to improve protein production. Developed by Biogen, Spinraza (nusinersen) is the first Food and Drug Administration (FDA) approved medication for SMA treatment. It is an antisense oligonucleotide targeted to SMN2 pre-messenger RNA (pre-mRNA) that increases the proportion of SMN2 mRNA transcripts that include exon 7. This will let the body produce more SMN proteins. The second approach is the replacement of the SMN1 gene. Gene therapy for SMA is the most advanced medical approach that directly targets the dysfunctional SMN1 gene. Zolgensma (onasemnogene abeparvovec-xioi) is the second FDA approved medication given for children less than 2 years of age with bi-allelic mutations in SMN1 genes. It is an adeno-associated virus vector-based gene therapy.
Issues and Studies in Pharmacoeconomics
Published in Mickey C. Smith, E.M. (Mick) Kolassa, Walter Steven Pray, Government, Big Pharma, and the People, 2020
Mickey C. Smith, E.M. (Mick) Kolassa, Walter Steven Pray
A Wall Street Journal article (May 25, 2019) described the approval of the “Priciest Medicine, Zolgensma, with a ‘sticker price’ of $2,125 million”. That’s well over the Price of its competitor, Spinraza, a bargain at $750,000 for the first year and only $375,000 for following years.
Carriers for Nucleic Acid Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Intracranial injection into the cerebral parenchyma or cerebrospinal fluid (CSF) initially avoids systemic circulation and brings therapeutics close to the target side. Therapeutics injected into the CSF face the much less restrictive single-layer barrier of epithelial cells with gap-junctions between the CSF and the brain tissue [84]. However, the much smaller barrier surface compared to the BBB, constant turnover of CSF into the blood and limited diffusion within the brain parenchyma limit intracranial approaches [85, 86]. Still, the antisense oligonucleotide Nusinersen (Spinraza) gained FDA approval in 2016 for the treatment of spinal muscular atrophy and is administered by intrathecal injection into the CSF for the delivery of a therapeutic gene to neural stem cells [87]. Intraventricularly administered cationic liposomes and organically modified silica nanoparticles were used to successfully deliver siRNA [88] and pDNA [89] to neuronal cells in vivo. Luciferase encoding pDNA encapsulated in liposomes showed luciferase activity throughout the brain after injection in the cisterna magna of rats, but not after direct injection into the parenchyma [90]. Injection of luciferase expressing mRNA incorporated in polyplex nanomicelles into the cisterna magna of mice resulted in protein expression in the CSF for almost a week [91]. Biodegradable arginine ester of PAMAM dendrimers were used to deliver siRNA in the post-ischaemic brain by injection into the cortex of rats [92]. Tf-decorated siRNA-containing liposomes showed extensive local distribution and gene silencing after stereotactic administration into the striatum [93]. Silencing of the transcription factor c-Jun by RNA interference significantly decreased both cell death following glutamate-induced excitotoxic damage in primary neuronal cultures and neuronal death and inflammation following kainic acid-mediated lesions in the mouse hippocampus [94, 95]. Continuous injections of siRNA against toxic Huntingtin protein into the brain parenchyma were performed with osmotic pumps [96] and convection-enhanced delivery [97].
Rare Disease, Advocacy and Justice: Intersecting Disparities in Research and Clinical Care
Published in The American Journal of Bioethics, 2023
Meghan C. Halley, Colin M. E. Halverson, Holly K. Tabor, Aaron J. Goldenberg
Today most payers in the US have coverage policies in place for both Spinraza and Zolgensma. However, due to concerns over the impact on state Medicaid budgets, many state administrators have imposed limitations on eligibility criteria. Recent analyses of Medicaid coverage policies across states found wide variation in coverage for both Spinraza and Zolgensma based on characteristics such as ventilator status, functional status, age, and SMN2 gene count (Ballreich et al. 2022; Berry et al. 2022). States with more restrictive policies also had substantially lower utilization rates for these therapies, suggesting there are patients who would have been able to access these therapies in a different state (Ballreich et al. 2022). A parallel study found similarly high variability among private payers, including eligibility criteria that were significantly more limited than the FDA indication (Margaretos et al. 2022). Surveys of patients and families also report wide variation in the length of time required for insurance approval, which is concerning given the importance of early use for treatment effectiveness (Chen et al. 2021).
Current state of developing advanced therapies for rare diseases in the European Union
Published in Expert Opinion on Orphan Drugs, 2020
Tingting Qiu, Yitong Wang, Monique Dabbous, Eve Hanna, Ru Han, Shuyao Liang, Mondher Toumi
ODs have gained great attention from pharmaceutical companies due to the supportive regulatory environment. More importantly, the high prices of ODs, in order to recover the development investment from small patient pool, also have generate large revenue potential [11,12]. Compared to traditional ODs, ATMPs could result in extra costs driven by the personalized nature of the medicines, meaning that some ATMPs cannot be prepared, tested, and manufactured in bulk and, therefore, involve higher costs for clinical delivery [13]. Furthermore, ATMPs are associated with additional value elements to those of ODs due to its curative potential through the limited-time administration [14]. Undoubtedly, orphan ATMPs hold both pronounced importance for disease treatment and enormous commercialization potential. For example, nusinersen (Spinraza®), the first treatment approved for spinal muscular atrophy (SMA), costs 750,000 USD in the first year and 375,000 USD annually afterward. This placed Spinraza® amongst the priciest drugs in the world post-market launch [15]. However, onasemnogene abeparvovec-xioi (Zolgensma®), as the first gene therapy approved for SMA, was priced at 2.1 USD million per patient for a single injection administration [16], making it the most expensive drug on the global market.
Exploiting differential RNA splicing patterns: a potential new group of therapeutic targets in cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Nidhi Jyotsana, Michael Heuser
Other groups modulated the expression level of SR proteins by morpholinos [114,115]. Morpholino oligos were used to inhibit the silencing of the α exon of FGFR1 resulting in >90% α exon inclusion in glioblastoma cells [116]. RNA interference has also been used in cell culture to suppress protein isoforms [117]. Peptide nucleic acids, locked nucleic acids (LNAs), fully modified oligonucleotides and phosphorodiamidate morpholino oligomer (PMO) based oligomers have shown activity in animal models [118–120]. Administration of LNA-modified SSOe26 reduced tumor growth via splice switching of human epidermal growth factor receptor 4 (HER4) from isoform CYT1 to CYT2 in a MCF7 cell xenograft mouse tumor model [121]. In a melanoma patient-derived xenograft mouse model, ASO-mediated skipping of exon 6 decreased mouse double minute 4 (MDM4) expression levels leading to melanoma growth inhibition and increased sensitivity to MAPK pharmacologic inhibition [122]. Knockdown of SF3B by siRNA inhibited alternative splicing, production of p27, and nuclear retention of most of the non-spliced mRNAs resulting in a comparable phenotype as induced by the SF3B inhibitor Spliceostatin A in treated cells [123]. Though, limited intracellular uptake, toxicity, and plasma stability are the remaining issues that need to be solved for a broad applicability of ASO and siRNA approaches. However, the recent FDA approval of Spinraza™/Nusinersen for the treatment of pediatric and adult spinal muscular atrophy patients provides hope for a broader applicability of this treatment approach.