Polyplus Transfection last week announced that it has received an €80,000 ($107,776) grant from France’s Muscular Dystrophy Association (AFM) to upgrade its in vivo-jetPEI reagent-manufacturing processes to meet current good manufacturing practices, and to fund development of new quality-control procedures and conduct stability studies.
“With the help of the AFM funding for the development of a cGMP manufacturing process, in vivo-jetPEI will be available to customers for use in clinical trials,” Polyplus CEO Joelle Bloch said in a statement.
Meanwhile, in the US, University of Southern Mississippi researcher Faqing Huang recently received a two-year grant, worth $164,250 in its first year, from the National Cancer Institute to develop a folate receptor-mediated delivery technique for siRNAs.
“Although folate receptor-mediated delivery of functional agents by endocytosis to cancer cells has been shown to be efficient and highly specific towards FR-positive cancer cells, the chemistry of direct coupling between folate and siRNA has not been readily achievable until now,” Huang wrote in the grant’s abstract.
“Capitalizing on the recent RNA bio-conjugation methods developed in [my] laboratory, this proposed research will develop a novel folate receptor-based siRNA delivery strategy against specific target genes in FR-expressing cancer cells.”
GMP De Rigueur
Polyplus’ in vivo-jetPEI technology essentially comprises an optimized formulation of polyethylenimine, a cationic linear polymer that condenses nucleic acids into nanoparticles capable of diffusing into tissues and entering cells via endocytosis. According to the company, the agent does not trigger inflammatory responses after systemic administration and does not generate neutralizing antibodies.
In 2005, researchers from the Philipps-University School of Medicine in Marburg, Germany, published data showing that polyethylenimine could be used to deliver siRNAs intraperitoneally into mouse tumors.
Last year, the same researchers published data demonstrating that polyethylenimine-complexed siRNAs could penetrate subcutaneous tumor xenografts and inhibit tumor growth in mouse models when delivered subcutaneously or intraperitoneally.
Polyethylenimine has already been used in humans with an experimental gene therapy, and ramping up its manufacturing processes to cGMP standards will allow Polyplus to widely market the in vivo-jetPEI technology for therapeutic applications.
Polyplus CSO Patrick Erbacher told RNAi News this week that the company expects to have its cGMP manufacturing processes in place shortly and begin delivering the product to a customer for use in a gene therapy clinical trial by July.
Although the company initially expects in vivo-jetPEI to be used in gene therapies, it is also courting partners interested in using the technology for RNAi-based therapeutics.
“In principle, siRNA may become the basis for developing the next generation of antiviral and anti-cancer agents with high potencies and low side toxicities. However, no therapeutically acceptable delivery methods of siRNA are currently available.”
Anne-Lise Monjanel, managing director of sales and marketing at Polyplus, said that the company is already collaborating with one undisclosed biotech firm on using the transfection technology for therapeutic RNAi applications.
She declined to elaborate.
“In principle, siRNA may become the basis for developing the next generation of antiviral and anti-cancer agents with high potencies and low side toxicities,” according to USM’s Huang. “However, no therapeutically acceptable delivery methods of siRNA are currently available.”
To address this problem, Huang and colleagues at the University of Southern Mississippi aim to take advantage of the abundance of folate receptors on the surface of many types of cancer cells by linking a therapeutic agent, in this case siRNA, to the vitamin.
The approach is expected to spare normal cells, which express folate receptors at much lower levels.
The researchers plan to synthesize folate-conjugated siRNAs targeting the cancer cell marker urokinase plasminogen activator receptor, then examine the compound’s cellular delivery and activity in KB cancer cells.
“We will test the hypothesis that down-regulation [of] uPAR expression in cancer cells by folate-conjugated siRNA will effectively inhibit the cellular activity of uPAR associated with tumor growth,” Huang wrote in his grant abstract. “RNAi effects will be assessed by determining the expression of uPAR at mRNA and protein levels and by cellular functional analysis of uPAR.”
Huang stated that he expects delivery of the folate-siRNA “will be more efficient and specific than other current available methods,” and that the RNAi agents will suppress tumor growth through uPAR silencing.
“Results from the proposed research will likely lead to the development of general strategies and methods for FR-mediated delivery of siRNA against specific target genes in FR-expressing cancer cells and, therefore, may lead directly to cancer therapeutic applications,” he added.
Huang’s grant project is set to run through March 2009.