CYP17A1 Gene Editing    

Cytochrome P450 enzymes (CYPs) are a ubiquitous class of heme-containing proteins, which can catalyze many key biological transformations, including hormone metabolism and xenobiotic detoxification. CYP activity is closely related to specific cell types and tissues, and deregulation can contribute to human disease. Due to their prevalence, potent and selective CYP inhibitors have been aggressively pursued as pharmaceuticals, chemical tools, and more recently insecticides.

The Physiology and Disease of CYP17A1

The multifunctional enzyme cytochrome P450 17A1 (CYP17A1) belongs to the CYP superfamily and plays a key role in steroidogenesis, a process that is upregulated in prostate cancer. The human CYP17A1 gene is located on chromosome 10q24.3. This gene is expressed in the adrenals and gonads, with minor amounts in the placenta, brain and heart. The same mRNA and protein are expressed in the adrenal and gonad. The 17-hydroxylase activity of CYP17A1 is required for the production of the glucocorticoid cortisol, whereas the 17,20-lyase activity results in androgens (and in turn estrogens). Most clinical mutations in CYP17A1 that have been reported lead to the loss of both 17-hydroxylase and 17,20-lyase activities. The loss of all or most CYP17A1 activities results in 17-hydroxylase/17,20-lyase deficiency (17OHD), a form of congenital adrenal hyperplasia. The phenotype of 17OHD is mainly composed of hypertension and hypokalemia— from the accumulation of the mineralocorticoids 11-deoxycorti-costerone (DOC) and corticosterone upstream of cortisol, plus sexual infantilism—from a lack of androgen and estrogen synthesis. An interesting variant of 17OHD has been reported in a few patients, which results in the loss of solely the 17,20-lyase activity. This loss of the C—C bond activity leads to the loss of the production of 19-carbon androgens, which results in undervirilization of 46, XY infants and pubertal failure in 46, XX children.

CYP17A1 Inhibitors

A more common condition involving CYP17A1 is not enzyme deficiency, but androgen-dependent cancers and hyperplasias. Prostate cancer is typically androgen-dependent, and medical or surgical castration induces remission for most patients in the early stage of the disease. Later, the disease progresses despite low testosterone (T) synthesis, a condition called castration-resistant prostate cancer (CRPC). CYP17A1 inhibitors abiraterone acetate, ketoconazole, and newer agents have been developed to treat these diseases. The androgen-dependent-cancer patient usually takes the CYP17A1 inhibitor and a glucocorticoid, prednisone, to lower adrenocorticotropin (ACTH) and prevent the accumulation of cortisol precursors that lead to hypertension and hypokalemia. A more recently designed CYP17A1 inhibitor, Orteronel, was derived from naphthylmethylimidazole and formulated to have highly selective c17,20-lyase inhibition. Preclinical in vitro (human and monkey adrenal cells) and in vivo (monkeys) studies have shown a 5.4 times more potent inhibition of c17,20-lyase than 17a-hydroxylase as well as a greater reduction in T and DHEA compared to cortisol. The potential benefit for this greater c17,20-lyase inhibition is to reduce the excess of mineralocorticoid, thereby reducing the demand for corticosteroids.

CYP17A1 Gene Editing Services

CRISPR/Cas9 Platform^CB, one of the leading biotechnological companies specializing in gene editing, is dedicated to offering comprehensive CRISPR/Cas9 gene-editing services to a wide range of genomics researchers. Based on our platform, we can help you effectively CYP17A1 gene deleted, inserted or point mutated in cells or animals by CRISPR/Cas9 technology.

• CYP17A1 Gene Knockout: We offer CYP17A1 gene knockout cell line and knockout animal model generation service with high quality. Typically, we develop CRISPR-mediated gene editing cell lines including HEK239T, Hela, HepG2, U87, but we can use other cell lines according to your requirements. Our one-stop KO animal model generation service covers from sgRNA design and construction, pronuclear microinjection to Founders genotyping and breeding.
• CYP17A1 Gene Knockin: CRISPR/Cas9 Platform^CB provides the one-stop CYP17A1 knock-in cell line and knockout animal model generation services, including point mutation and gene insertion. Our expert staff has succeeded in dozens of CYP17A1 knock-in cell line generation projects, including stem cells, tumor cells and even difficult-to-handle cells. We also have extensive experience in incorporating CRISPR/Cas9 technology into animal models, which have been fully recognized by our clients.

If you have any questions, please feel free to contact us.

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