Repairing and Regeneration, Medicine’s Holy Grail and our Technology Transfer Project

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.

Ken Mitton

On doing Science well.

As for many biomedical, basic-science research labs, my research flows and changes over time as we make new discoveries that lead us to new questions we form even as we uncover the answers to previous questions. That is the nature of basic science, and it is the way science investigation has always brought the most benefits to people and medicine in particular. While many organizations and countries have attempted to focus research support (funding) into specific diseases, it turns out that the overwhelming majority of high-impact medical discoveries have come from “serendipity”. That is, great useful ideas and tools were discovered to treat diseases simply by exploring how things work.

For example, drugs for controlling high cholesterol were not discovered by deciding to start making drugs for treating high cholesterol. In the course of biochemists investigating how our cells make cholesterol in the first place, chemicals were used to block enzymes to help figure out how cholesterol was made. Some of these chemicals were obviously the idea to become new drugs that could block cholesterol made in the body. Latanoprost, one of the later generation of drugs developed in the ’80s for reducing high intraocular pressure (IOP), was based on the discovery that prostaglandins made by some cells in the eye could increase the aqueous outflow in the eye, and reduce pressure. The basic science was elucidated in animal models. Again, a basic science discovery in the laboratory of physiologist Laszlo Bito at Columbia University was adopted by a Pharma company as the way to make drugs that mimic natural prostaglandins to produce this new class of drugs. As a result, thousands of people around the world have another class of drugs to reduce their intraocular pressure and reduce their risk of vision loss from Glaucoma.

So, you never really know where benefits will arise for biomedicine. That is why many research funding agencies, such as the NIH (USA) and the MRC (UK), understand the importance of funding physiologists and biochemists to explore how things work. In our case, how things work in the eye, and the retina of the eye.

Sincerely,

Ken Mitton

Lab News: Summer’s Start 2019

Current Lab Member and Lab Alumni News: May 2019

Dr Ken Mitton and Wendy Dailey attended ARVO 2019 (May) and presented research on VEGFA isoform regulation of primary human retinal endothelial cells. Also, on Norrin regulation of PLVAP expression in the same cell type. Dr. Mitton co-presented a third abstract with Tom Dzialozsynski, Western University (London Ontario) regarding Gensingoside effects on normalization of serum lipids and slowing of cataract formation in diabetic rats. John Trevithick, PhD, Professor of Biochemistry and Kinesiology (Western University), Tom and Ken’s former supervisor and long time friend and colleague was also on the abstract. Dr Trevithick passed away just over a year ago. The 2019 ARVO meeting was the first one ever outside the United States. Vancouver BC. We wanted to make sure that John Trevithick’s research was presented at this first ever ARVO meeting held in Canada. (Dr. Mitton obtained his PhD under John Trevithick at Western University, London Ontario). Without John Trevithick’s influence, the many many Michiganders trained in biosciences in our lab since 2001 would not have had their opportunities here. Life is connections, and at times a series of wonderful accidents. Peter Chen MD, graduated OUWB school of medicine. The second OUWB medical EMBARK program student in the ERI. Michael Sun has joined our group as the 5th EMBARK program student in the ERI, just completing his M1 year in our OUWB program. Michael will be working with us to help establish patient DNA sequencing for rare inherited retinal vascular diseases in our Pediatric Retinal Research Laboratory.

The 2019 Summer Undergraduate Program in Eye Research has begun, with six Oakland University Undergraduate science students learning about, and contributing to, the NIH and PRRF funded research projects in our group. You can learn more about this program at:

http://www.oakland.edu/ERI

Connections, fate, and why we pay forward in Science by teaching students.

This is basically a post on how I got here, to become a professor in the Eye Research Institute of Oakland University, and a scientist who has been lucky enough to discover many new biological mechanisms working in many teams of great researchers. It is also a round about explanation of why paying forward is so important in science and education. Continue reading