Targeted Genetics presents advances in systemic gene delivery technology.
In a study presented yesterday, the Lipid Polycation DNA delivery system was used to deliver E1A, a proprietary tumor inhibitor gene, systemically to mice transplanted with human head and neck tumors. tgLPD-E1A was administered weekly beginning six days after tumor cells were transplanted into the animals. These cells express basal levels of HER-2/neu. At 13 weeks, 70 percent of the animals treated with tgLPD-E1A were tumor free, compared to only 10 percent of animals receiving either lipid alone or 5FU, and only 50 percent of animals receiving a lipoplex-E1A control.
"We have now demonstrated that intravenous delivery of tgLPD-E1A is able to inhibit tumor growth in animal models of breast and head and neck cancers," said Dr. Anklesaria. "These data show that the Lipid Polycation DNA gene delivery system may enable the systemic delivery of therapeutic genes, an important step in the evolution of gene delivery technologies. Significantly, tgLPD-E1A was seven-fold more effective at inhibiting tumor growth than was 5FU, a chemotherapy agent frequently used to treat head and neck tumors in humans. We are very encouraged by these results and are moving forward aggressively in the development of the Lipid Polycation DNA delivery system. Systemic delivery of E1A may provide a new gene therapy approach to treating patients with metastatic disease or other cancers that are not amenable to treatment by direct injection."
Previous studies(1) have shown that tgLPD-E1A also inhibits tumor growth in a mouse xenograft model of breast cancer tumors. Significantly, the combination of tgLPD-E1A and paclitaxel inhibited tumor growth three-fold more efficiently than did paclitaxel alone. These data and studies evaluating tgDCC-E1A in combination with chemotherapy indicate that E1A sensitizes tumor cells to chemotherapeutic agents(2). Targeted Genetics is evaluating tgDCC- E1A (the company's local gene delivery formulation) in Phase II trials for head and neck cancer and in Phase I trials in combination with chemotherapy for ovarian cancer. Data from the Phase II trial are to be presented at the 36th American Society of Clinical Oncology Annual Meeting in May of this year. Patient enrollment in the Phase I trial is expected to be completed by the end of the year. The company intends to begin human clinical trials of tgLPD-E1A in 2001.
"These data suggest that we are moving closer to attaining the holy grail of gene therapy -- a systemic delivery system," said Dr. Barrie J. Carter, executive vice president and director of research and development at Targeted Genetics. "Our ability to deliver genes systemically will expand the number of diseases that may be treatable with gene therapy approaches. We are very excited about the progress we are making in developing a variety of synthetic gene delivery systems, including formulations for systemic and local delivery."
Targeted Genetics is developing a variety of synthetic gene delivery systems, both on its own and in collaboration with Elan Corporation, plc (Westmeath, Ireland; 0902-4666). In July 1999, Targeted Genetics and Elan established a joint venture, Emerald Gene Systems, to develop advanced gene delivery technologies. The joint venture combines the company's expertise in vector development and manufacturing with Elan's leadership in novel drug delivery technologies. The addition of Elan's targeting technologies to delivery vehicles such as Lipid Polycation DNA may provide targeted, systemic approaches for the delivery of therapeutic genes.
"The promising clinical and pre-clinical data that we are generating in studies of both our DCC and Lipid Polycation DNA delivery platforms validate our plan to develop multiple gene delivery strategies," said H. Stewart Parker, president and chief executive officer of Targeted Genetics.
"We were the first company to bring adeno-associated virus vectors into the clinic and we are leading the charge to develop a synthetic systemic gene delivery system. Our excellence in the development of both viral and synthetic gene delivery technologies reflects our robust capabilities in identifying and developing promising approaches for clinical and commercial applications. Our multiple gene delivery technologies will enable us to capitalize on the growing number of genes identified through genomic discovery efforts and to deliver the right gene to the right patient using the right vector."
Targeted Genetics, in collaboration with Dr. Leaf Huang, PhD, Joseph Koslow professor of pharmaceutical sciences at the University of Pittsburgh's School of Pharmacy, is developing a series of improved synthetic delivery systems based on various formulations of cationic lipids. In one of these systems, designated "LPD" for lipid-polycation-DNA, the DNA is condensed through the addition of a polycation to form small, degradation resistant cores encapsulated in a lipid shell. The resulting Lipid Polycation DNA formulation contains particles of defined size, which have enhanced stability and gene transfer efficiency. Pre-clinical experiments in non-tumor bearing mice have shown that the Lipid Polycation DNA system is able to deliver genes systemically through intravenous administration.
E1A is a tumor inhibitor gene. Previous laboratory and animal studies have demonstrated E1A's ability to suppress metastases, induce apoptosis (programmed cell death) and reverse the over-expression of HER-2/neu, a cancer-causing gene. In patients with cancer, over-expression of the HER-2/neu oncogene is correlated with poor prognoses, increased tumor formation and metastasis and resistance to chemotherapeutic agents. Targeted Genetics is currently testing E1A in Phase II trials in patients with head and neck cancers and Phase I trials in patients with ovarian cancer.
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|Comment:||Targeted Genetics presents advances in systemic gene delivery technology.|
|Publication:||BIOTECH Patent News|
|Date:||Apr 1, 2000|
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