Transcriptional Adjusting

Recombinant adeno-associated virus (AAV) vectors have been extensively tested in preclinical studies for a variety of diseases because of their stable gene expression, nill or few immune responses and broad tissue or cell tropisms. Ideally, the safe and effective AAV vectors for the treatment of human diseases can target to the desired tissues. However, recombinant AAV vectors have limitations to specifically transfer the interested genes into targeted tissues or cells as receptors are not unique on the target cell surface. As a pioneer company in the gene therapy area, Creative Biolabs is capable of offering transcriptional adjusting service to develop AAV vectors with specific targeting.

Transcriptional Strategy for AAV Vectors Retargeting

The expression cassette of AAV vectors includes 3 parts: enhancer-promoter, the coding sequence, and a polyadenylation signal. The expression of the therapeutic gene is regulated by the upstream enhancer-promoter sequence. Therefore, optimal tissue-specific transcriptional regulatory sequences have been utilized to improve the targeting capability of rAAV vectors. The strategy to construct AAV is to use tumor or tissue-specific promoters which are critical for replication to control the expression of viral genes. And thus, viral genes selectively express in cancer cells and kill these cells. In this condition, recombinant AAV vectors could replicate selectively in some types of cells and replication-attenuated in normal cells.

Figure 1. AAV vectors for the expression of large transcripts and for gene correction. (Zacchigna, 2014)

Currently, numerous regulatory sequences have been used to construct retargeting AAV vectors for the treatment of numerous diseases. These regulatory sequences include neuron-specific enolase gene (NSE) promoter for brain cells, thyroxine-binding globulin gene (TBG) promoter for liver cells, creatine kinase (CK) promoter for muscle cells. What's more, multiple tumor-specific transcriptional regulatory sequences, such as CEA promoter preferentially activated in adenocarcinoma cells, a-fetoprotein (AFP) promoter in hepatocellular carcinoma cells, human telomerase reverse transcriptase (hTERT) promoter in 85%-90% tumor cells, have also been applied in the gene therapy process of tumors.

Services

Working in the field of gene therapy for years, Creative Biolabs has gained abundant experience in retargeting AAV vectors' construction. Aided by our advanced technology platforms, we are able to help worldwide researchers construct required AAV vectors with different promoters to target specific cells or tissues. Particularly, our professional scientists have developed several inducible gene expression systems, such as tetracycline (Tet), RU486 and Cre-loxP, by appropriate tissue-specific enhancer-promoters. Our transcriptional adjusting services to develop AAV vectors with specific targeting mainly include but are not limited to the followings:

• Specific Promoter Driven Targeting of AAV Vector
• Hypoxia Regulatory Element Targeting Strategy of AAV Vector

Creative Biolabs is dedicated to offering expertise strategies to promote drug discovery programs through a collection of efforts. Our rich experience and streamlined management enable us to successfully develop high-quality AAV vectors with specific tropism. If you are interested in our service, please don't hesitate to contact us.

Reference

1. Zacchigna, S.; et al. (2014). Adeno-associated virus vectors as therapeutic and investigational tools in the cardiovascular system. Circulation research. 114(11): pp.1827-1846.