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Adeno-associated virus vector (AVV)–based gene therapy
Spinal muscular atrophy$†
Onasemnogene abeparvovec (OA) is the second AAV vector-based gene therapy to be approved by the FDA and also the second gene therapy approved for the treatment of SMA. SMA is a rare inherited autosomal recessive neurodegenerative disorder characterized by muscle weakness and wasting due to progressive loss of motor neurons in the brain stem and spinal cord. SMA is due to insufficient expression of SMN protein by the SMN1 gene.40,126 With an estimated incidence of 1 in 10,000 live births, infantile-onset SMA is the most severe and common form of the disease.126,127 Infants with SMA begin having problems with head control, sucking, swallowing, and breathing before the age of 6 months, and most succumb to respiratory failure before or during early childhood.41,126,127 Prior to FDA-approved options, traditional treatment was supportive/palliative care.
The first FDA-approved AAV-based gene therapy, voretigene neparvovec for retinal dystrophy, employs an AAV serotype 2 vector and is administered once into each eye by subretinal injection. The first gene therapy for SMA, nusinersen, an antisense oligonucleotide, was engineered to alter the splicing of SMN2 pre-mRNA to boost the secondary (unreliable and variable) production of functional (full-length) protein.128 Nusinersen is administered via periodic intrathecal injection to pediatric patients up to the age of 16 years. In contrast to these two firsts, OA is indicated for newborn infants of full gestational age and for children <2 years of age who have biallelic mutations in the SMN1 gene.40 It is engineered as a one-time, one-hour intravenous infusion to introduce a fully functional and enduring copy of the human SMN1 gene into cells to normalize the production of SMN protein for the entire life of each transduced cell.40 Given the promise for improved quality of life, prolonged survival, and reduction in burden-of-care for infants and children with SMA, FDA granted OA breakthrough therapy status.41
OA is made via a proprietary platform developed by AveXis, Inc., and it consists of a suspension of recombinant scAAV9 capsids containing a transgene encoding human SMN protein along with a cytomegalovirus enhancer/chicken-β-actin hybrid promoter to facilitate broad, sustained, constitutively active gene expression over time.127–130 AAV vectors are nonpathogenic, replication-defective viruses of the parvovirus family.131,132 AAV9 capsids were selected as the vector for OA due to their unique ability to cross the blood-brain barrier and deliver DNA to target neurons in the CNS.131,132 Devoid of any viral DNA, recombinant AAV (rAAV) has been described as a “protein-based nanoparticle engineered to traverse the cell membrane, where it can deliver its DNA cargo into the nucleus of a cell.”131 Transgenes encoded within rAAV tend to form circular concatemers or monomers that persist as episomes in the nucleus of host cells with little integration into the host cell genome.131,133 scAAV DNA cargo consists of an inverted complementary single DNA strand that folds and base-pairs to form double-stranded DNA upon delivery to the host cell nucleus for rapid onset of protein expression.131–133
The recommended dose of OA is 1.1 × 1014 vector genomes/kg.40 Prior to administration, patients must be assessed for anti-AAV9 antibodies.40 Due to CD8+ T cell–mediated immunity directed against AAV antigens expressed on the surface of transduced cells (associated with liver enzyme elevations), immunosuppressive therapy with systemic corticosteroids must be started prior to OA administration in all patients.132 Corticosteroids are continued for 30 days (or longer in the presence of liver dysfunction) followed by a slow (28-day) taper.132
A total of 41 patients in the U.S., ranging in age between 0.3 and 7.9 months, have been treated with the recommended dose of OA (NCT02122952,134 NCT03306277 [STR1VE],135 NCT03421977 [START],136 and NCT03505099 [SPR1NT]137). FDA approval was granted on the basis of better survival and better motor function, the need for less supportive care, and achievement of developmental motor milestones (such as sitting without support and even walking unassisted) than would be predicted from the natural history of the disease.127,138 As a condition of FDA approval, ongoing assessments of efficacy and safety are expected to continue for an unprecedented total of 15 years after treatment.41 As of the March 2019 data cutoff, 19 of 21 patients treated in the ongoing STR1VE clinical trial (NCT03306277)135 were alive without the need for permanent ventilation support, and 10 had reached developmental motor milestones (i.e., head control and the ability to sit without support).127,138 OA therapy is expected to cost $2.1 million, potentially with payment over time.138,139 Given that outcomes from clinical trials appear to be best in infants who are treated before disabilities requiring supportive care become apparent,127,132 genetic screening has been added to the U.S. HRSA Recommended Uniform Screening Panel for newborns.140
Chapter 3. Pharmacodynamics: Molecular Mechanisms of Drug Action > Pharmacotherapies That Modify Specific Genes and Their Transcription and Translation
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals