40.1 Disease associated clinical trials

Recently full-fledged clinical trials are being performed for cardiovascular diseases, cancer, and hematopoietic disorders. With the knowledge of tumor suppressor genes, p53 is being explored for treating cancer. Here we shall try to understand the efficacy of the recombinant adenoviral p53 agent for treating cancer.

Numerous clinical trials were conducted to carefully estimate the efficacy of the recombinant adenovirus containing the p53 tumor suppressor gene (rAd-p53). After many trials it was concluded that rAd-p53 was endured by patients without any serious side effects apart from development of fever, localized pain at the injection site and fatigue. rAd-p53 injection with the trademark Gendicine is being produced by Shenzhen SiBiono Gene Tech in china. On October 16 th , 2003 Gendicine was approved by the State Food and Drug Administration (SFDA) of China. Thus, Gendicine is the first gene therapy product of the world that was approved by a governing body. The anti-tumor effect of Gendicine is due to substitution of E1 region of the human serotype 5 adenovirus with the human wild-type p53 expression cassette driven by rous sarcoma virus (RSV) promoter. Gendicine administration to the tumor cells causes expression of p53 which triggers apoptotic pathways that gets amplified by the “bystander effect”. It also causes decrement in glucose uptake by cancer cells and inhibits multi drug resistance genes. As a result of downregulation of multidrug resistance genes the tumor cells become susceptible and lose resistance to chemotherapy and radiotherapy. Apart from the p53 gene the adenoviral vector is also believed to be a key player in mounting the immune response which limits the tumor growth. Side effects of radiotherapy have been found to be suppressed on administration of Gendicine with radiotherapy (GTRT). One death was reported when a high systemic dose of a wild type Ad-5 was injected to a patient for the treatment of ornithine transcarbamylase (OTC) due to the patient's strong immune response. Apart from this tragedy no other fatality has been recorded and Ad5 is believed to demonstrate the weakest pathogenicity level among the adenovirus family. The prescribed dose based on the various clinical trial is 1 vial for every injection (this 1 vial contains 1×10¹² VP).