How Exactly Does Gene Transfer via AAV Work?

Properly functioning genes within our DNA provide the blueprint for the production of proteins. Mutations affecting those genes can result in proteins with altered or zero function. Using gene transfer techniques might be an effective way to restore function of proteins within cells. Gene transfer can occur via adeno-associated virus (AAV) vectors because they can target both dividing and non-dividing cells to correct disease-causing improper protein function.

Therapeutic genes loaded inside an AAV can correct defective or missing protein function by injecting the AAV’s therapeutic genetic material to restore function of the proteins. A capsid encases the genetic material of the vector and helps target delivery to specific cells. Once inside the targeted cells, an episome is formed from the vector genome which allows for long-term expression of the therapeutic molecule. AAVs are nonpathogenic and can be administered by intravenous drip or direct injection to target tissues.

The unique life cycle of adeno-associated virus (AAV) and its ability to infect both nondividing and dividing cells with persistent expression have made it an attractive vector. An additional attractive feature of the wild-type virus is the lack of apparent pathogenicity. Gene transfer studies using AAV have shown significant progress at the level of animal models; clinical trials have been noteworthy with respect to the safety of AAV vectors. No proven efficacy has been observed, although in some instances, there have been promising observations. In this review, topics in AAV biology are supplemented with a section on AAV clinical trials with emphasis on the need for a deeper understanding of AAV biology and the development of efficient AAV vectors. In addition, several novel approaches and recent findings that promise to expand AAV’s utility are discussed, especially in the context of combining gene therapy ex vivo with new advances in stem or progenitor cell biology.

Adeno-associated virus (AAV) vectors are currently among the most frequently used viral vectors for gene therapy. At recent meetings of the American Society for Gene Therapy, nearly half of the presentations involved the use of AAV. This represents a significant turnaround. Historically, AAV has not been of great medical interest, because it has not been identified as a pathogen; thus, the lack of widespread knowledge of the virus initially inhibited its broad use as a vector. Twelve human serotypes of AAV (AAV serotype 1 [AAV-1] to AAV-12) and more than 100 serotypes from nonhuman primates have been discovered to date. The lack of pathogenicity of the virus, the persistence of the virus, and the many available serotypes have increased AAV’s potential as a delivery vehicle for gene therapy applications. This review will focus on the biology of AAV and its use as a vector for gene therapy.

Research earlier this year suggested genetic engineering to combat GlioblastomasL tumors that form from the astrocytes in the brain:

Researchers at Duke University have taken an alternative approach to fighting this disease using genetically engineered Salmonella typhimurium. The bacteria contain a mutation that depletes their purine stores. Since tumor cells are loaded with purine, the Salmonella would be expected to seek out those tumors. Once inside the tumor, they rapidly reproduce. Second, the addition of a p53 tumor suppressor protein and Azurian allows the bacteria to self-destruct inside the tumors without eliciting an immune response. The bacteria have been programmed to operate efficiently in hypoxic, purine rich environments only so the tumor is destroyed but local, healthy tissue remains unharmed.

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