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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Onasemnogene abeparvovec is a recombinant adeno-associated viral vector containing complementary DNA encoding the normal human SMN protein. This medication is administered as a one-time intravenous infusion. The ongoing STRIVE trial demonstrated that 62% of treated infants had reached the age of 14 months without the need for permanent ventilation and 48% of infants achieved the ability to sit without support [32].
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.
Onasemnogene abeparvovec for the treatment of spinal muscular atrophy
Published in Expert Opinion on Biological Therapy, 2022
Hugh J. McMillan, Crystal M. Proud, Michelle A. Farrar, Ian E. Alexander, Francesco Muntoni, Laurent Servais
The therapeutic landscape for SMA has changed dramatically over the past few years. Although most cases were essentially untreatable and fatal within the first years of life, disease-modifying treatments, including onasemnogene abeparvovec, are improving survival and permitting many patients to thrive. Prognoses for most patients with SMA are greatly improved, and the importance of ongoing multidisciplinary care remains undiminished. While onasemnogene abeparvovec for SMA represents a significant milestone in human gene therapy, this field is still in its infancy, and challenges and uncertainties, such as patient and disease selection, need to be clarified. The safety and efficacy of gene therapy may be affected by many factors, including patient age, weight, and disease severity, as well as delivery mechanisms and targets of the gene therapy vector.
Therapies in preclinical and clinical development for Angelman syndrome
Published in Expert Opinion on Investigational Drugs, 2021
Theodora Markati, Jessica Duis, Laurent Servais
Major challenges related to host immune response, inflammation, and subsequent cytotoxicity are expected not only in the clinical development of both ASOs and gene replacement therapies. Even though AAVs are considered to have a better immunogenicity profile compared to other viral vectors (such as adenoviruses), their safety needs to be determined. So far, the only approved gene replacement therapy for a pediatric neurological disorder is onasemnogene abeparvovec for SMA. In an animal study of non-human primates and piglets, using the same AAV serotype and gene therapy construct as onasemnogene abeparvovec, it was demonstrated that its administration led to the degeneration of the dorsal root ganglia cell bodies and their axons [75]. Following this, the FDA placed a hold on the clinical trial of the intrathecal form of onasemnogene abeparvovec (press release, additional source 22). The addition of miR183 targets in the vectors could help reduce transgene expression and, therefore toxicity, in the dorsal root ganglia [76]. This approach has the potential to achieve better transduction in the brain without the rate-limiting step of dorsal root ganglia toxicity.
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Onasemnogene abeparvovec is FDA-approved for treatment of SMA in patients under 2 years of age. In Europe, the label covers patients up to 21 Kg. All clinical trials of onasemnogene abeparvovec to date (NCT02122952, NCT03461289, NCT03837184, NCT03306277, and NCT03505099) have been open label, single-dose studies, and required screening for AAV9 antibody titers prior to dosing. The main adverse effects reported in the clinical trials with the intravenous delivery of onasemnogene abeparvovec were transient elevation in serum transaminases and potential hepatotoxicity, as well as a transient thrombocytopenia [26]. Treatment with a glucocorticosteroid 24 hours prior to infusion and for the following month is needed to reduce these effects. Thrombotic microangiopathy has been reported in several infants through post marketing surveillance[76].