Over the last two decades my natural tendency to pursue research projects closer and closer to future clinical impact has taken me from a very focused study of the mechanisms of regulating gene expression in the retina to understanding retinal diseases that cause most new cases of blindness in the United States each year. Those diseases involve damage to the integrity of the blood-retinal-barrier and even the loss of blood microvessels that nourish the neural retina. As you can see, poking around my website, we work on things like Vascular Endothelial Growth Factor and Wnt (“wint”) signaling to understand what keeps endothelial cells of the retinal blood vessels happy and then to understand how these normal system are perturbed to cause harm.
Along the way, I have worked with Dr. Kim Drenser MD PhD and Dr Michael Trese MD, of Associated Retinal Consultants (Michigan) and the Ophthalmology department in the Beaumont Health System. An atypical Wnt-protein called Norrin has emerged as a protein essential for development of a human baby’s neural retinal vasculature. Long before I came to this project area, real human Families with an inherited condition called Norrie Disease had Sons who were missing a full retinal vasculature, similar to very young premature infants who suffer the same physical problem: a lack of blood supply to nourish an oxygen starved retina. While it was a very rare inherited condition, the eventual discovery of the gene (NDP) and its protein (Norrin) made it clear that this protein is essential to form the initial blood vessels of the neural retina.
Research we have done in animal models, and research in other laboratories, have also revealed that Norrin is also required to establish a strong blood-retinal-barrier which is formed by the endothelial cells that line the interior of blood vessels. But, how can we possibly use this information for a future therapeutic tool? One way would be to make a protein based on human Norrin in large enough and pure enough amounts to be used for both more testing in models and hopefully clinical trial use in human subjects one day. The first step is to come up with a biotechnological solution to make the protein and purify it and to fold it in its required natural 3-D shape so that it has the same activity as Norrin protein made naturally in the retina.
The later project is what I have contributed, using my knowledge and experience designing and producing proteins in bacteria (E. Coli strains used for protein production), to the production of a Norrin activity protein. After demonstrating some preliminary data on this process, I wrote a research plan submitted with a local small business firm Retinal Solutions LLC (Michigan) to obtain NIH STTR (Small business technology transfer) funding to initially iron out the process to make the protein pure, and free of toxic impurities, suitable for testing in the mammalian eye. These begin with a Phase-1 STTR, if one is successful at obtaining the funding. STTR grants require a company, like Retinal Solutions LLC, to work with a non-profit academic partner (that would be me and Oakland University) to develop a technology with the goal of benefiting US citizens with future medical treatments, drugs, and devices.
I am pleased to note that as the Primary Investigator on the project, we obtained funding for the one year Phase-1 STTR from the National Eye Institute (NIH), and we started this developmental research this Fall 2019. In this project, the basic scientist like me, works with my clinical colleagues at Retinal Solutions LLC (Dr. Trese, Dr. Drenser) to identify a clinical need and bring science to bare on the problem. While there are no guarantees of success in any drug development, clear scientific evidence for the genetic necessity of Norrin to make retinal blood vessels simply makes Norrin an excellent candidate as a therapeutic tool, a factor, that would be needed to repair and regenerate the retinal microvasculature and its strong blood-retinal-barrier. Even if Norrin is not the solution on its own, it would likely be one of the essential members required for a therapeutic team. As a protein that is already natural in the neural retina, there is also a much reduced likelihood that there would be any toxicity or ill effects. One this is for certain, just thinking about this as a dream and not trying to see if the dream can come true is not something we wish to do.
So wish us lots of luck as we make Norrin in bacteria, refold it, and put it through our testing in the Eye Research Laboratory and the protein purity characteristics testing by Retinal Solutions LLC. If all goes to plan, then the next future step will be the Phase-II STTR to get this Protein therapeutic closer to future use in human clinical trials. That is the dream, one step at a time.