Adeno-associated virus in the context of "Gene therapy"

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⭐ Core Definition: Adeno-associated virus

Adeno-associated viruses (AAV) are small viruses that infect humans and some other primate species. They belong to the genus Dependoparvovirus, which in turn belongs to the family Parvoviridae. They are small (approximately 26 nm in diameter) replication-defective, non-enveloped viruses and have linear single-stranded DNA (ssDNA) genome of approximately 4.8 kilobases (kb).

Several features make AAV an attractive candidate for creating viral vectors for gene therapy, and for the creation of isogenic human disease models. Gene therapy vectors using AAV can infect both dividing and quiescent cells and persist in an extrachromosomal state without integrating into the genome of the host cell. In the native virus, however, integration of virally carried genes into the host genome does occur. Integration can be important for certain applications, but can also have unwanted consequences. Recent human clinical trials using AAV for gene therapy in the retina have shown promise.

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👉 Adeno-associated virus in the context of Gene therapy

Gene therapy is medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

The first attempt at modifying human DNA was performed in 1980, by Martin Cline, but the first successful nuclear gene transfer in humans, approved by the National Institutes of Health, was performed in May 1989. The first therapeutic use of gene transfer as well as the first direct insertion of human DNA into the nuclear genome was performed by French Anderson in a trial starting in September 1990. Between 1989 and December 2018, over 2,900 clinical trials were conducted, with more than half of them in phase I. In 2003, Gendicine became the first gene therapy to receive regulatory approval. Since that time, further gene therapy drugs were approved, such as alipogene tiparvovec (2012), Strimvelis (2016), tisagenlecleucel (2017), voretigene neparvovec (2017), patisiran (2018), onasemnogene abeparvovec (2019), idecabtagene vicleucel (2021), nadofaragene firadenovec, valoctocogene roxaparvovec and etranacogene dezaparvovec (all 2022). Most of these approaches utilize adeno-associated viruses (AAVs) and lentiviruses for performing gene insertions, in vivo and ex vivo, respectively. AAVs are characterized by stabilizing the viral capsid, lower immunogenicity, ability to transduce both dividing and nondividing cells, the potential to integrate site specifically and to achieve long-term expression in the in-vivo treatment. ASO / siRNA approaches such as those conducted by Alnylam and Ionis Pharmaceuticals require non-viral delivery systems, and utilize alternative mechanisms for trafficking to liver cells by way of GalNAc transporters.

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Adeno-associated virus in the context of Alipogene tiparvovec

Alipogene tiparvovec, sold under the brand name Glybera, is a gene therapy treatment designed to reverse lipoprotein lipase deficiency (LPLD), a rare recessive disorder, due to mutations in LPL, which can cause severe pancreatitis. It was recommended for approval by the European Medicines Agency in July 2012, and approved by the European Commission in November of the same year. It was the first marketing authorisation for a gene therapy treatment in either the European Union or the United States.

The medication is administered via a series of injections into the leg muscles.

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Adeno-associated virus in the context of Onasemnogene abeparvovec

Onasemnogene abeparvovec, sold under the brand name Zolgensma among others, is a gene therapy used to treat spinal muscular atrophy, a disease causing muscle function loss in children. It involves a one-time infusion of the medication into a vein. It works by providing a new copy of the survival of motor neuron (SMN) gene that produces the SMN protein.

Spinal muscular atrophy stems from a mutation in the survival motor neuron 1 (SMN1) gene, causing survival of motor neuron protein deficiency vital for motor neuron survival. Onasemnogene abeparvovec, a biologic medication utilizing adeno-associated virus (AAV9) virus capsids containing an SMN1 transgene, is administered to motor neurons, boosting SMN protein levels. Common side effects include vomiting and elevated liver enzymes, while more severe reactions involve liver issues and low platelet count.

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Adeno-associated virus in the context of Valoctocogene roxaparvovec

Valoctocogene roxaparvovec, sold under the brand name Roctavian, is a gene therapy used for the treatment of hemophilia A. It was developed by BioMarin Pharmaceutical. Valoctocogene roxaparvovec is made of a virus (AAV5) that has been modified to contain the gene for factor VIII, which is lacking in people with hemophilia A. It is an adeno-associated virus vector-based gene therapy. It is given by intravenous infusion.

The most common side effects include increased levels of the liver enzymes alanine aminotransferase and aspartate aminotransferase (signs of possible liver problems), increased levels of the enzyme lactate dehydrogenase (sign of possible tissue damage), nausea (feeling sick), and headache.

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Adeno-associated virus in the context of Etranacogene dezaparvovec

Etranacogene dezaparvovec, sold under the brand name Hemgenix is a gene therapy used for the treatment of hemophilia B. Etranacogene dezaparvovec is an adeno-associated virus vector-based gene therapy which consists of a viral vector carrying a gene for clotting Factor IX. The gene is expressed in the liver to produce Factor IX protein, to increase blood levels of Factor IX and thereby limit bleeding episodes. Hemophilia B is a genetic bleeding disorder resulting from missing or insufficient levels of blood clotting Factor IX, a protein needed to produce blood clots to stop bleeding.

The most common adverse reactions include liver enzyme elevations, headache, mild infusion-related reactions and flu-like symptoms.

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LINKED FROM (PARENTS)
← Gene therapy ← Alipogene tiparvovec ← Onasemnogene abeparvovec ← Valoctocogene roxaparvovec ← Etranacogene dezaparvovec
LINKS TO (CHILDREN)
Primate → Genus → Dependoparvovirus → Family (biology) → Parvoviridae → Nanometre → Satellite (biology) → Viral envelope → DNA → Base pair → Viral vector → Gene therapy → Isogenic human disease models → Vectors in Gene Therapy → Genome → Adeno associated virus and gene therapy of the human retina →