Advantages of siRNA
Within only a few years, siRNA technologies have matured from what seemed, to many, to be an over-hyped experimental footnote to a powerful and documented experimental protocol. Much of the prior skepticism stemmed from the limitations encountered using earlier technologies, such as anti-sense inhibition. However, siRNA gene silencing distinguishes itself from the earlier genre of gene inhibition technologies in that it utilizes a natural endogenous regulatory mechanism, RNA interference.

RNAi can be rationally designed to block the expression of any target gene, including genes for which traditional small molecule inhibitors cannot be found. Areas of therapeutic applications include virus infections, cancer, genetic disorders and neurological diseases.

Delivery of siRNAs to the target tissues is an important consideration. siRNAs can be delivered to cells in culture by electroporation or by transfection using plasmid or viral vectors.

The advantages that siRNA provides over the alternative technologies are numerous: decreased time, decreased cost and increased specificity. Using siRNA to generate a knock-down of a targeted gene can be performed in days versus months or years as compared to the time necessary using the traditional methods.

As important as speed is for many researchers, cost is equally important. Experiments using siRNA can be performed at a fraction of the cost of generating genetic knock-out models and dominant negatives. In addition, siRNA mediated gene knock-down has been shown to be highly sequence specific.


siRNA achievements at Transgene
As all cells have the RNAi machinery and any gene is a potential target, any disease caused by or greatly exacerbated by the expression of a dominant gene can in principle be treated by RNAi. This means that the list of potential indications is long.

RNA interference (RNAi) is a powerful gene-silencing process that holds great promise in the field of cancer therapy.
We at TBL have designed an efficient and simple-to-use novel vector, ‘AaVeeTek’ that allows the production of siRNAs within the cells.

TBL has identified specific genes associated with solid tumors such as Breast and Liver cancers and also in some neuro-degenerative conditions such as Parkinson’s disease and Alzheimer’s.. The in-vivo mouse xenograft models have demonstrated that the siRNA based products from TBL have shown remarkable effect in silencing those genes and decreasing the size of cancer tumors in a highly specific manner.


Scientific Rationale behind our approach
Most of the significant recent advances in cancer treatment have been based on the great strides that have been made in our understanding of the underlying biology of the disease. In the past 100 years our grasp of the biology of cancer has come a very long way. We now have a working knowledge of how tumors initially form, grow and spread. Importantly, vast amounts of information about features distinguishing tumor from normal cells is being accumulated, resulting in frequent, major new insights into cancer biology. Since the discovery of RNA interference (RNAi) in 1998, researchers have hoped to use the gene-silencing technique to shut down cancer-causing genes. The development of targeted biologics that recognize tumor cell surface antigens and of specific inhibitors of pathways dysregulated in cancer cells or normal cellular pathways on which a cancer cell differentially depends has provided hope for converting our increasing understanding of cellular transformation into intelligently designed anticancer therapeutics. However, new drug development is painfully slow, and the pipeline of new therapeutics is thin. The discovery of RNA interference (RNAi), a ubiquitous cellular pathway of gene regulation that is dysregulated in cancer cells, provides an exciting opportunity for relatively rapid and revolutionary approaches to cancer drug design. Although it has only been 9 years since RNAi was shown to work in mammalian cells, about a dozen phase I to II clinical studies have already been initiated, including four for cancer. So far there has been no unexpected toxicity and suggestions of benefit in one phase II study

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In recent years 19 - 21 base pair double stranded RNA molecules called, siRNA have emerged as a mechanism to inhibit cancer causing genes.
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siRNA can be expressed from can be packaged into virus for persistence expression and efficient delivery called shRNA.
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Traditional retroviral vectors randomly integrate into genome and generate insertional mutagenesis. Adenoviral vectors trigger unacceptable levels of immune responses. Both vectors had serious limitations for human trials and FDA restricted their usage.
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Due to the safety efficacy and potency provided by Adeno-associated virus (AAV) makes it a better alternative vector.
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We provide evidence for the effective of use of our proprietary, new generation AAV vectors that are not only self-complimentary AAV vectors (scAAV) for efficient gene silencing but also has capsid mutations to enhance the transduction by 20 fold.
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EzH2 (Enhancer of Zeste 2) is a key component in metastasis of breast cancer whose inhibition provides a unique opportunity for the treatment.
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The significance of this approach is that it provides unique opportunity for targeted silencing of metastasis promoting gene and this specificity is not amenable to conventional chemotherapy.

 
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