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Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
ZOLGENSMA is a gene therapy product that has been developed using an AAV-based vector (AAV9) to treat spinal muscular atrophy in children. In this therapy, a wildtype copy of the survival motor neuron 1 (SMN1) gene is delivered systemically through intravenous injection. It was approved for use in the United States in 2019 (Dunbar et al. 2018; Li and Samulski 2020; Shahryari et al. 2019).
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.
Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Despite these concerns, there have been significant advances in noncancer areas. For example, the gene therapy onasemnogene abeparvovec (ZolgensmaTM) has been approved by the FDA for the treatment of spinal muscular atrophy, a severe neuromuscular disorder caused by a mutation in the SMN1 gene, which significantly reduces the amount of SMN protein necessary for the survival of motor neurons. Approved by the FDA in 2019 for use in children under 2 years, this therapy consists of self-complementary AAV9 virus capsids that contain a SMN1 transgene along with promoters. It is administered intravenously or intrathecally, after which the self-complementary AAV9 viral vector delivers the SMN1 transgene to cell nuclei where the transgene begins encoding SMN protein, thus addressing the root cause of the disease. A single dose of the agent could potentially have a lasting effect throughout the patient’s lifetime, and this is reflected in the current list price of $2.125 million per treatment.
Reflex single-gene non-invasive prenatal testing is associated with markedly better detection of fetuses affected with single-gene recessive disorders at lower cost
Published in Journal of Medical Economics, 2022
Shan Riku, Herman Hedriana, Jacqueline A. Carozza, Jennifer Hoskovec
Early identification of high-risk fetuses allows timely prenatal and neonatal interventions for clinicians and patients (Table 4), which in turn can lead to more effective management and potential cost savings. In particular, SMA has several treatment options, including Zolgensma and Spinraza. These therapies are most effective when delivered neonatally before the onset of symptoms. Moreover, the single-dose gene therapy Zolgensma ($2.1 M per dose) costs less than the lifetime medication Spinraza ($0.75 M for initial dose and $0.46 M per year afterward) (Tables S4, S5). However, Zolgensma must be administered to neonates before two years of age. Since SMA is not included in newborn screening panels in all U.S. states (twelve states do not test for SMA as of June 2021), prenatal SMA diagnosis is essential for affected families to have access to early, clinically effective, and lower-cost treatment options14. The reflex sgNIPT scenario identifies more SMA-affected fetuses than the base scenario, resulting in more newborns eligible for Zolgensma. We estimated the total cost savings associated with more access to Zolgensma in the reflex sgNIPT scenario to be $29.3 M per 100,000 pregnancies (Table 5, Method S4).
Developing DMD therapeutics: a review of the effectiveness of small molecules, stop-codon readthrough, dystrophin gene replacement, and exon-skipping therapies
Published in Expert Opinion on Investigational Drugs, 2021
Currently, steroids and other small molecule drugs, stop codon readthrough, exon-skipping therapies, and gene replacement therapy are among the most promising approaches for the treatment of DMD. Vamorolone represents an advancement of steroids by alleviating DMD symptoms without the majority of difficult adverse effects [38]. While ataluren shows promise in alleviating skeletal muscle deterioration, it has thus far failed to demonstrate dystrophin production. Holistically, gene therapy for neuromuscular disorders has been energized by the approval of zolgensma for treatment of spinal muscular atrophy. At the same time, the field has received a cautionary tale from AT132, the gene therapy for X-linked myotubular myopathy that led to three patient deaths. This presents an alarming scenario for gene therapy. In this context, gene therapy for DMD, in particular, micro-dystrophin gene replacement appears ready to demonstrate effectiveness but must improve safety in parallel. Table 3 summarizes and compares the major therapeutic approaches described in this paper. Through the regulatory approval process, exon-skipping therapies have demonstrated great promise in resisting disease progression.
Is there value in using randomized placebo controlled trials in neuromuscular disease?
Published in Expert Review of Neurotherapeutics, 2021
John R. Bach, Giulio Chiarello, William Weiss, Nizar Souayah
Different NMDs can have very consistent or different disease evolutions. Patients with motor neuron disease (MND) can have extremely variable courses making significant changes in rate of deterioration very difficult to determine by RDBPCTs or observation. While this has been done for Radicava, its 150,000 USD price tag per year for a statistical one-third decrease in rate of functional deterioration, for a condition where spontaneous improvements occur, might make its use difficult to justify [16]. In 1995 Riluzole can onto the market to treat ALS at a 9500 USD annual cost for a statistical prolongation of tracheostomy-free survival of a few months. That seemed expensive at the time. Today there are 500,000 USD annual costs for medications for diabetes mellitus, DMD, Pompe disease, and SMA. Some medications for SMA, like Zolgensma, can cost 2.1 USD to 5.1 USD million for one injection; nusinersen for SMA costs almost 1 USD million the first year then about 400,000 USD annually with many patients showing no benefit from either.