Hypoxia Regulatory Element Targeting Strategy of AAV Vector
Creative Biolabs has been providing high-quality services and products to biological scientists all over the world with the aim to promote the progress of life medicine. The development of gene therapy provides a promising therapeutic option for patients with genetic diseases or cancers, in which the correct delivery of therapeutic genes is the key to patient's recovery. We design targeted adeno-associated virus (AAV) vectors by physiological differences between normal tissues and tumors, and can accurately deliver the selected therapeutic genes to the affected tissues and organs.
Introduction of AAV Vector
Recombinant AAV (rAAV) has been increasingly used as a delivery vehicle in gene therapy for various experimental projects over the past two decades. AAV has not been detected to be pathogenic to humans, rarely causes the body's immune response, and has a stable gene expression ability and a wide range of tissue trends, making it popular with biomedical workers. However, because of its low expression level and poor tissue specificity due to the wide range of hosts, preclinical and clinical gene therapies still have some limitations. In any case, developing an AAV vector with maximum efficiency and minimal cytotoxicity is critical for successful gene therapy. In the field of cancer therapy, the safety of rAAV depends largely on its targeting, that is, how to make the gene accurately direct to the target cancer cells without affecting the surrounding normal cells is the key step.
Figure 1. Adeno-associated Virus for Cancer Gene Therapy.
Hypoxia Regulatory Targeting Strategy
An important physiological feature of human solid tumors is the presence of an anoxic microenvironment. A clinical study using oxygen electrodes to measure oxygen levels in brain tumor tissue of patients has found that there are a large number of hypoxic cells in each tumor. Hypoxia in solid tumors not only strengthens the resistance of tumors to chemotherapy and radiotherapy, but also further increases the invasiveness and diffusivity of cancer. The anoxia stems from changes in the expression of some genes in tumor cells. For example, the α subunit of HIF-1 protein is overexpressed in cancer cells. Its function is regulated by oxygen molecules, which will activate the expression of a series of genes when the cell is deprived of oxygen, and finally affect the activity of cancer cells.
Although the presence of hypoxic cells in human brain tumors is an important factor in cancer treatment resistance, this physiological difference between normal tissues and tumors also provides an idea for designing cancer-specific gene therapy protocols. Scientists at Creative Biolabs limit the expression of therapeutic proteins to cancer cells by using transcription targeting vectors. To generate an rAAV in which the transgene can be regulated by hypoxia, we inserted a DNA fragment containing the 9XHRE and LacZ reporter genes into the AAV vector. Under hypoxic conditions, the vector increased gene expression by 79 to 110-fold. We believe that this hypoxia-regulated rAAV vector will be a useful delivery vector for cancer-specific gene therapy.
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