International Stem Cell Corporation and preclinical CRO Absorption Systems last week said that Absorption Systems will use ISCO’s parthenogenetic stem cells, which are derived from unfertilized eggs, to develop a three-dimensional human cornea model in order to help drug makers measure the absorption, distribution, and ocular toxicity of ophthalmic therapeutics.
An ISCO official told CBA News this week that in the long term, the company hopes to provide an assay with a quantitative endpoint as an in vitro substitute for the commonly used in vivo Draize rabbit eye-irritancy test.
In addition, ISCO president Jeffrey Janus said the company intends sometime in the future to move the corneal tissue technology into the clinic because “there are about 10 million corneally blind people in the world who could benefit from a corneal transplant.”
Eventually, the partners envision that pharmaceutical companies would verify data obtained from the 3D model against internal data, but ISCO does not have the facilities to do that, Janus said.
“Its an excellent opportunity to partner with a company like Absorption Systems, because they can take the tissue, test it in their specialized equipment, and with their knowledge of assays and in vitro assays in particular, validate it, and then go out and show the pharma companies that yes, this model actually does mimic a human cornea relative to drug absorption,” Janus said.
He added that terms of the Absorption Systems alliance call for ISCO to manufacture the 3D corneal constructs for Absorption Systems, after which Absorption will be able to provide a service to drug makers to develop ophthalmic therapeutics.
The rabbit is by far the most frequently used preclinical model for assessing the in vivo and in vitro ocular absorption and toxicity of drugs. “We had established a model in our lab over the last few years of rabbit corneal and conjunctival tissues,” said Chris Bode, Absorption Systems’ vice president of corporate development.
According to a 2007 study by the European Union’s Registration, Evaluation, Authorization and Restriction of Chemical substances program, researchers perform about 3.9 million animal tests each year to assess the safety of chemicals, of which 18 percent were the Draize test.
“And it costs about €1.5 billion ($1.9 billion) to use the Draize test, so 18 percent of €1.5 billion is an estimate of the market size for the use of the Draize,” Janus said.
“The interesting thing about these constructs is that they self assemble. They grow in culture and form layers, just as you would find in an eye.”
He added that although he did not know if the corneal constructs would be less expensive to use than the Draize test, “it is very common that cell-based assays are less expensive than animal-based assays.”
He also pointed out that it is a very large market, because “you are talking about all chemicals,” including household cleaners, cosmetics, and toiletries.
Absorption Systems characterized those rabbit models extensively, but needed another model to see how well results from the rabbit model would potentially translate in the human eye.
“We have not yet received any constructs [from ISCO] to work with [but] … will get the first constructs in just a couple weeks,” said Bode. The company will start out with what he described as “some very basic studies that have not yet been done,” and these studies will form the basis for “what we do next.” He did not elaborate.
Bode added that Absorption Systems will be testing a series of 20 or so drugs that it had previously run through its rabbit in vitro models, and the company will also test those 20 drugs using an in vivo rabbit model.
“We will be able to compare and see how well the three different types of models [in vitro, in vivo, and the 3D corneal constructs] correlate,” he said.
Creating a Human Cornea
Approximately one year ago, in the course of using its parthenogenetic stem cells to develop a cellular therapy for macular degeneration, ISCO scientists made a discovery, Janus said. “When we were culturing these cells, which are technically retinal pigment epithelial cells, we noticed the production of these 3D corneal constructs.”
The researchers discovered that the constructs had certain characteristics when they were growing: They were clear, which is odd in cell culture. “They continued to grow until they were 10 mm or, in some cases, 20 mm in diameter,” Janus said.
ISCO sent its corneal tissue constructs to Excalibur Pathology in Moore, Okla., to undergo a blinded test. After performing histology testing on the constructs, Excalibur described the constructs as “having human cornea-like characteristics,” according to Janus.
The constructs, which have an epithelial layer with a stromal area that is about 0.5 mm thick, were also stained for human epithelial cell types that are found in the human cornea. Finally, after the researchers performed electron microscopy on the samples, they found the collagen structure to be similar to that of the human cornea.
“So we believe that we have created a human cornea,” Janus said. “The interesting thing about these constructs is that they self-assemble. They grow in culture and form layers, just as you would find in an eye.”
Cell lines from adult tissue do not self-assemble like that, so the stem cell seems to have an ability to create an organ-like structure in culture, Janus said.
Currently used cell lines are usually monolayers or multilayers of cells that are plated on top of each other in a very laborious manner. The multilayered nature of the construct is what makes it an attractive model, more so than the cell-line based models, Bode said.
There are some differences that ISCO is working on in the lab to perfect the corneal construct model, but “we immediately we saw a use for these constructs in toxicity testing,” said Janus.
The duration of the partnership is open-ended because it is in the early stages, said Bode. “We have some ideas about what might come out of it, but we do not really know until we do the science,” he said.
These 3D constructs would be a model for ocular absorption to which Absorption Systems would have exclusive access, at least for an undisclosed period.
As a CRO, Absorption has worked with drug makers such as AstraZeneca R&D Boston, Bayer, CGI Pharmaceuticals, Genzyme, Novasite, and Devgen.
“When we started developing our in vitro rabbit tissue models, we did not really know how many drug companies were developing ophthalmic drugs. Now we have a much better idea, and it’s a pretty good-sized market,” Bode said. “We were surprised to see that.”
He did not elaborate on the ophthalmic drug market, but said it is growing with the aging of the population — “the higher prevalence of macular degeneration in particular.”
Ocular distribution and absorption “is our main interest,” he said. “If there is an ocular toxicity or irritancy model that can come out of this, that would be great, too.”
According to Bode, such a 3D corneal model could mean several million dollars per year in revenue for Absorption Systems just as a model to evaluate the absorption of ocular drugs, “and that is significant for us.”
In addition, ISCO has plans beyond ocular distribution and absorption. “We have plans to take the corneal tissue into the clinic, because there are about 10 million corneally blind people in the world who could benefit from a corneal transplant, but for a lack of tissue outside the US, many of them are without their sight,” said Janus.
Corneal damage currently affects approximately 10 million people worldwide, Janus said. Household products are involved in about 125,000 eye injuries per year.