Oncolytic AAV

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Adeno-associated virus (AAV) has been researched as a viral vector in gene therapy for cancer treatment as an oncolytic virus. Currently there are not any FDA approved AAV cancer treatments, as the first FDA approved AAV treatment was approved December 2017. [1] However, there are many Oncolytic AAV applications that are in development and have been researched.

Contents

Adeno-Associated Virus Therapy

AAV is a small virus that was found as a contaminant in adenovirus studies. [2] AAV is a non-pathogenic virus, so it is currently being investigated for many gene therapy applications including oncolytic cancer treatments due to its relatively safe nature. AAV also has little risk for insertional mutagenesis, a common problem when dealing with viral vectors, as its transgenes are normally expressed episomally. [3] It was found that AAV genome inserts in less than ~10% of occasions AAV infects a cell and the expression is less than when episomally expressed. [4] AAV can only package genomes between 2 – 5.2 kb in size when they are flanked with inverted terminal repeat sequences (ITRs), but optimally holds a genome of 4.1 to 4.9 kb in length. [5] This limits the therapeutic application of AAV as a cancer treatment as the gene the virus carries must be able to fit in less than 4.9 kb .

Targeting

AAV, and its many different strains, known as serotypes, to each have their unique cell-type targeting preferences, also known as tropism. In order to target viral vector gene therapies to disease sites, researchers often exploit the simplicity of the AAV virus capsid to mutate new targeting behaviors into the virus. In example, AAV has been mutated to target primary glial blastoma cells by combining regions of many AAV serotypes. [6]

On top of combining the serotypes, mutating foreign sequences into the capsid known to have certain behaviors has been used to target cancer sites. For example, Matrix metalloproteinases (MMPs) are known to be up-regulated in cancer sites. [7] By inserting an infection blocking tetra-aspartic acid residue into the capsid flanked by MMP cleavable sequences, a lab has developed a protease activatable virus (PAV) using AAV. In the presence of high concentrations of MMPs, the cleavable sequences are removed and the virus is “un-locked”, allowing infection in the neighboring diseased cells. [8] PAV is still being optimized. A study to change out the tetra-aspartic acid blocking residues revealed that the negative charge of the residues is likely what is needed to block transduction. [9] PAV is currently in investigation for targeting of ovarian and pancreatic cancer with the plan of delivering cytotoxic transgenes. [10]

Examples of Oncolytic AAV in Development

AAV-2-TRAIL: The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been studied when delivered by AAV serotype 2 capsids on human cancer cell lines. It was found that the different cell lines had different sensitivities to the AAV-2-TRAIL delivery and enhanced by pre-treatment of the cells with chemotherapy drug cisplatin. When mice with tumor xenograft models were injected with AAV-2-TRAIL intratumorally with and without cisplatin, tumor sizes were found to decrease equally significantly with cisplatin and AAV-2-TRAIL. The tumor weight decreased even more significantly when cisplatin and AAV-2-TRAIL where combined. [11]

AAV-2-HSV-TK: Herpes simplex virus type 1 thymidine kinase (HSV-TK) is a common anti-cancer therapy that converts the ganciclovir (GCV) into the toxic GCV-triphosphate within cells expressing the enzyme. This induces the cell and bystander toxicity to the neighboring cells. [12] When cultured with MCF-7 cancer cells, AAV2 delivery of HSV-TK significantly decreased viability of the cells only when in the presence of GCV. [13]

AAV-2-sc39TK: sc39TK is a five-codon substitution from HSV-TK where silent mutations have been introduced into the GCV-resistant spliced acceptor and donor sequences. The result is a hyperactive version of HSV-TK. When combined with GCV, these mutants also result in high levels of cancer cell death in-vitro. Furthermore, when injected into mouse xenograft models, tumor size has been shown to significantly decrease over a period of 30 days. [14] It has also been investigated in combination with AAV-2-mTOR which targets the mammalian target of rapamycin (mTOR), an investigated anti-cancer target. [15]

Oncolytic AAV Clinical Trials

AAV-DC-CTL: A clinical trial is currently in Phase I investigation of Oncolytic AAV treatments for stage IV gastric cancer in China. In these trials AAV has been used to deliver Carcinoembryonic antigen (CEA). CEA is normally produced in the gastric tissue of infants and would be used in these studies to target cancer cells for CEA specific cytotoxic-T-cell lysis. In this regard, the virus would be used to make cancer cells be recognized by the immune system for destruction. As a result, AAV will target cancer cells and the CEA specific cytotoxic-T-cells will target the cells that AAV infects. [16] [17]

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical technology

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

<span class="mw-page-title-main">Sedoreoviridae</span> Family of viruses

Sedoreoviridae is a family of double-stranded RNA viruses. Member viruses have a wide host range, including vertebrates, invertebrates, plants, protists and fungi. They lack lipid envelopes and package their segmented genome within multi-layered capsids. Lack of a lipid envelope has allowed three-dimensional structures of these large complex viruses to be obtained, revealing a structural and likely evolutionary relationship to the cystovirus family of bacteriophage. There are currently 97 species in this family, divided among 15 genera in two subfamilies. Reoviruses can affect the gastrointestinal system and respiratory tract. The name "reo-" is an acronym for "respiratory enteric orphan" viruses. The term "orphan virus" refers to the fact that some of these viruses have been observed not associated with any known disease. Even though viruses in the family Reoviridae have more recently been identified with various diseases, the original name is still used.

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

In the field of genetics, a suicide gene is a gene that will cause a cell to kill itself through the process of apoptosis. Activation of a suicide gene can cause death through a variety of pathways, but one important cellular "switch" to induce apoptosis is the p53 protein. Stimulation or introduction of suicide genes is a potential way of treating cancer or other proliferative diseases.

An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumour. Oncolytic viruses are thought not only to cause direct destruction of the tumour cells, but also to stimulate host anti-tumour immune system responses. Oncolytic viruses also have the ability to affect the tumor micro-environment in multiple ways.

Virotherapy is a treatment using biotechnology to convert viruses into therapeutic agents by reprogramming viruses to treat diseases. There are three main branches of virotherapy: anti-cancer oncolytic viruses, viral vectors for gene therapy and viral immunotherapy. These branches use three different types of treatment methods: gene overexpression, gene knockout, and suicide gene delivery. Gene overexpression adds genetic sequences that compensate for low to zero levels of needed gene expression. Gene knockout uses RNA methods to silence or reduce expression of disease-causing genes. Suicide gene delivery introduces genetic sequences that induce an apoptotic response in cells, usually to kill cancerous growths. In a slightly different context, virotherapy can also refer more broadly to the use of viruses to treat certain medical conditions by killing pathogens.

<span class="mw-page-title-main">Adeno-associated virus</span> Species of 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 replication-defective, nonenveloped viruses and have linear single-stranded DNA (ssDNA) genome of approximately 4.8 kilobases (kb).

<span class="mw-page-title-main">Viral vector</span> Biotechnology to deliver genetic material into a cell

Viral vectors are modified viruses designed to deliver genetic material into cells. This process can be performed inside an organism or in cell culture. Viral vectors have widespread applications in basic research, agriculture, and medicine.

A helper dependent virus, also termed a gutless virus, is a synthetic viral vector dependent on the assistance of a helper virus in order to replicate, and can be used for purposes such as gene therapy. Naturally-occurring satellite viruses are also helper virus dependent, and can sometimes be modified to become viral vectors.

Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.

Pelareorep is a proprietary isolate of the unmodified human reovirus being developed as a systemically administered immuno-oncological viral agent for the treatment of solid tumors and hematological malignancies. Pelareorep is an oncolytic virus, which means that it preferentially lyses cancer cells. Pelareorep also promotes an inflamed tumor phenotype through innate and adaptive immune responses. Preliminary clinical trials indicate that it may have anti-cancer effects across a variety of cancer types when administered alone and in combination with other cancer therapies.

Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.

<span class="mw-page-title-main">Alipogene tiparvovec</span>

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.

<span class="mw-page-title-main">Talimogene laherparepvec</span> Gene therapy medication

Talimogene laherparepvec, sold under the brand name Imlygic, is a biopharmaceutical medication used to treat melanoma that cannot be operated on; it is injected directly into a subset of lesions which generates a systemic immune response against the recipient's cancer. The final four year analysis from the pivotal phase 3 study upon which TVEC was approved by the FDA showed a 31.5% response rate with a 16.9% complete response (CR) rate. There was also a substantial and statistically significant survival benefit in patients with earlier metastatic disease and in patients who hadn't received prior systemic treatment for melanoma. The earlier stage group had a reduction in the risk of death of approximately 50% with one in four patients appearing to have met, or be close to be reaching, the medical definition of cure. Real world use of talimogene laherparepvec have shown response rates of up to 88.5% with CR rates of up to 61.5%.

Self-complementary adeno-associated virus (scAAV) is a viral vector engineered from the naturally occurring adeno-associated virus (AAV) to be used as a tool for gene therapy. Use of recombinant AAV (rAAV) has been successful in clinical trials addressing a variety of diseases. This lab-made progeny of rAAV is termed "self-complementary" because the coding region has been designed to form an intra-molecular double-stranded DNA template. A rate-limiting step for the standard AAV genome involves the second-strand synthesis since the typical AAV genome is a single-stranded DNA template. However, this is not the case for scAAV genomes. Upon infection, rather than waiting for cell mediated synthesis of the second strand, the two complementary halves of scAAV will associate to form one double stranded DNA (dsDNA) unit that is ready for immediate replication and transcription. The caveat of this construct is that instead of the full coding capacity found in rAAV (4.7–6kb) scAAV can only hold about half of that amount (≈2.4kb).

<span class="mw-page-title-main">Oncolytic herpes virus</span>

Many variants of herpes simplex virus have been considered for viral therapy of cancer; the early development of these was thoroughly reviewed in the journal Cancer Gene Therapy in 2002. This page describes the most notable variants—those tested in clinical trials: G207, HSV1716, NV1020 and Talimogene laherparepvec. These attenuated versions are constructed by deleting viral genes required for infecting or replicating inside normal cells but not cancer cells, such as ICP34.5, ICP6/UL39, and ICP47.

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.

James M. Wilson is an American biomedical researcher who serves as the Director of the Gene Therapy Program, Rose H. Weiss Professor and Director of the Orphan Disease Center, and Professor of Medicine and Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. Previously, he held the John Herr Musser endowed professorship at the Perelman School of Medicine.

Jean Bennett is the F. M. Kirby Professor of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania. Her research focuses on gene therapy for retinal diseases. Her laboratory developed the first FDA approved gene therapy for use in humans, which treats a rare form of blindness. She was elected a member of the National Academy of Sciences in 2022.

Mavis Agbandje-McKenna was a Nigerian-born British medical biophysicist, structural virologist, and a professor of structural biology, as well as the director of the Center for Structural Biology at the University of Florida in Gainesville, Florida. Agbandje-McKenna studied parvovirus structures using X-ray crystallography and cryogenic electron microscopy and did much of the initial work to elucidate the basic structure and function of adeno-associated viruses (AAVs). Her viral characterization and elucidation of antibody binding sites on AAV capsids has led to the development of viral capsid development and gene therapy approaches that evade immune detection and can be used to treat human diseases such as muscular dystrophies. Agbandje-McKenna was recognized with the 2020 American Society of Gene and Cell Therapy Outstanding Achievement Award for her contributions to the field. She died in 2021 from amyotrophic lateral sclerosis.

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