Stem Cell Innovations and the non-profit High Q Foundation this week said they plan to use SCI’s human pluripotent stem cells to develop Huntington's disease-specific cell systems for drug discovery.
Under the terms of the two-year alliance, Houston-based SCI will receive up to $1.1 million from the foundation for reaching certain undisclosed milestones. The company also said it has the right to further use, develop, and commercialize the cell systems resulting from the partnership.
The alliance is noteworthy because at this time, no way exists to stop or reverse the course of HD, and stem cells are considered a promising discovery platform for the disease.
The High Q Foundation chose to work with SCI because the company’s PluriCells, although not truly pluripotent, grow very easily, said Jamshid Arjomand, High Q’s director of basic research. This makes it easy to handle the cells for high-throughput screening campaigns.
Arjomand explained that because it is not known if the expression of mutant huntingtin protein is going to be problematic in the differentiation scheme, the foundation ideally wanted an inducible model.
The other reason that High Q wanted to work with SCI is that the company was willing to generate an inducible model of Huntington’s disease, and make the inducible cell lines available to the whole Huntington’s disease research community, Arjomand said.
To that end, the foundation would be able to distribute them to other companies and academic institutions that it works with.
“I think it’s very important that there are no restrictions and no licensing issues,” Arjomand told CBA News this week.
SCI CEO James Kelly said in a statement that the agreement “will allow us to accelerate our efforts in generating a unique panel of human neurodegenerative disease models, which will be integral in the further development of our potential products.
“Huntington's disease represents a great unmet medical need, and SCI is proud to assist High Q with its search for treatments that prevent or slow its progression,” he added.
SCI could not be reached for further comment before deadline.
The project is just beginning, said Arjomand, and of the multiple phases to the project, two are starting in parallel.
Arjomand said that one phase is a cell-differentiation program that will use wild-type PluriCells that do not have the mutant huntingtin protein inserted in them. SCI has come up with several possible methods for differentiation and will be testing them as part of the alliance.
The other phase will see SCI begin making the inducible constructs and making stable cell lines out of them. Arjomand told CBA News that he thinks these phases will merge over the next two years.
Once the inducible cells are made, the differentiation protocols that have been developed will be applied to them whether they express the mutant huntingtin protein or not, just to see if there is an effect. The researchers will then characterize the differentiation and the expression of the mutant huntingtin.
According to Arjomand, at a still-to-be-determined point, the partners will make those cells and the differentiation protocols available to the HD research community and other High Q partners who are doing the screening.
At the end of the first year of the two-year agreement, High Q hopes to have stable, inducible cell lines with a variety of polyQ lengths in the polyQ expansion, because it does not know which ones will yield the best phenotypic readout, said Arjomand.
He said that by the end of the second year, the foundation hopes to have the best differentiation protocols available applied to the cell lines in order for the cells to be characterized.
"I think it’s very important that there are no restrictions and no licensing issues.”
Parallel efforts are going on with mouse stem cells, Arjomand said. The foundation is having about a dozen transgenic and knock-in mouse models of Huntington’s disease made, and they are likely be available within the next six months to a year. He said that parallel differentiation protocols on mouse models are also being developed.
“We hope our industrial partners are motivated to publish their findings,” Arjomand said. “We will be encouraging them to do so, because that is the best way of letting the HD community know that these cells and reagents are available.”
While SCI focuses on the use of human stem cells, the lab of Ilya Bezprovanny, an associate professor of Alzheimer’s disease research at UT Southwestern, is taking a different approach. Bezprovanny and his team use an in vitro assay with cultured medium spiny striatal neurons from YAC128 transgenic mice to evaluate clinically relevant glutamate pathway inhibitors as possible therapies for HD (see CBA News, 11/3/06).
The biggest difference between these two approaches, Bezprovanny explained, is that he and his team will always be limited by how many cells they have because medium spiny striatal neurons, or MSNs, do not divide in culture.
His “primary neuronal culture” technique does have an advantage, however, Bezprovanny said. MSNs from the murine brain have all the same receptors, ion channels, and signaling pathways as neurons from the human brain. So hits from a screening campaign will very likely work in human brains in vivo.
It is probably reasonable to do the primary screen with the neuronal-like cells derived from stem-cell technology, for example, said Bezprovanny. Hits can be isolated from a large number of compounds with these cells that are easily grown. A secondary screen can then be done using cells from primary neuronal cultures to verify that whatever hits were isolated in the primary screen will still work in real neurons.
Bezprovanny said that the High Q Foundation supports his development of the screen based on primary neuronal cultures. He said that at the moment, his lab is working with Blue Shift Technologies.
The problem with the primary neuronal culture assay is that it involves manual counting and is very labor intensive, said Bezprovanny. Blue Shift Technologies developed an imaging machine that his lab is now testing to see if it can be used to automate the readout and do HTS analysis.