Genetic engineering based novel therapeutic approach against Wilms` tumor

Wilms Tumor (WT) is the most common malignant tumor of the kidney in childhood. This tumor recapitulates a renal developmental program, and therefore it expresses a set of genes, which are expressed normally only during embryonic kidney development. These genes have an invaluable application for cancer gene therapy. We have previously shown that Six2, a transcription factor critical for renal progenitor maintenance, has overwhelming predominance in a subpopulation of WT cancer stem cells that fuels and propagates the tumor. We have also demonstrated that one can generate WT in mice by the transplantation of Six2-expressing cells in mouse embryonic kidneys. Thus, Six2 may serve as a biomarker of undifferentiated cancerous WT cells. Here we aimed to employ a technology that utilizes a toxin (DTA – Diphteria toxin A) to destroy only those tumor cells expressing Six2. We identified the Six2 regulatory element needed to generate the transgenic system that enables the expression of DTA solely in cells that express Six2. Next, we established the Six2-DTA system and validated it in-vitro. Moreover, since we plan to utilize the Six2-DTA system in WT patient derived xenografts, we searched for the serotype of an adeno-associated virus that is capable of infecting WT cells. Overall, our study has the potential to pave the way towards novel less-toxic targeted therapeutics in WT and provide proof of principle for addressing pediatric neoplasm by means of targeting crucial elements in an abnormally arrested developmental program.