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Interview with 2015 Medicine Innovation Program grant winners: Photodynamic Therapy System for Prevention and Treatment of UTIs in Neurogenic Bladder
Dr. Jeffrey Gelfand, in collaboration with colleagues from the Urology Department and the Wellman Center for Photomedicine has developed the “Phototonic Foley” a device that allows for delivery of photodynamic therapy directly into an infected lower urinary tract. In previous studies this methodology has demonstrated to result in significant bacterial killing. This innovation could represent a new platform for treating urinary tract infections (UTIs) that avoids antibiotic usage and treatment of UTIs in the setting of extreme bacterial drug resistance. Medicine Innovation Program (MIP) grant funding will be utilized to create a proof of concept animal model, the next step in moving this project forward prior to clinical and commercial development.
Project Background: I like to solve problems; that’s what motivates me. I see them and I try to overcome them. One of the problems we have in medicine these days is drug resistant bacterial infections. It turns out that in- hospital patients with urinary catheters all get colonized if not actually clinically infected after one week. It results in a lot of misery for these patients, and causes many deaths. It also turns out that this colonization is one of the largest breeding grounds for drug resistant gram negative organisms in the hospital. Patients with chronic urinary draining devices, catheters, supra-pubic catheters and so on typically have bacterial infections chronically, or colonization chronically, which is a breeding ground for drug resistance within the hospital.
The story of this project started years ago. In 2003 I was the PI of a State Dept. grant to redirect the activities of Russian scientists who had been involved in bioweapons research. I had a terrific MGH team with me including Timothy Brauns, M.B.A. and Dr. Michael Callahan, and we visited various laboratories in Russia. I had the opportunity to visit the St. Petersburg Medical Military Academy and a laboratory doing work on lasers and immunity. Specifically, they were using lasers on the skin to stimulate immunity in the skin so that an area that was gently stimulated by laser light could then be follow- on injected with a vaccine and the prior illumination by the laser would increase the vaccine response by several hundred percent . I thought that this was extraordinarily interesting. We found the idea intriguing and started working on this ourselves. We collaborated with our Russian colleagues and the first papers we published here at MGH about the lasers and immunity also credit the idea to our Russian collaborators. We came back and initiated, in the Vaccine and Immunotherapy Center (VIC), studies on the laser and how it might stimulate immunity. This has resulted in the new PI, Dr. Satoshi Kashiwagi, receiving an RO1 grant and subsequent publications that have indeed proven that we can stimulate immunity with the laser.
It then occurred to me that we might be able to improve a vaccine that is currently used to treat cancer, namely BCG, which is a weakened form of tuberculosis. BCG is used to treat bladder cancer and is live BCG bacteria and is placed into the bladder with a catheter in patients who have bladder cancer, largely not- yet invasive into muscle. The bacteria are retained for an hour; the patient then is drained of the bacteria, and if the bacteria are successful in boosting immunity, the patient is spared very debilitating surgery in the bladder. If unsuccessful, it often results in the loss of the bladder itself. So it’s a big deal for the patient whether this BCG vaccine is successful or not.
I contacted one of my colleagues in Urology, Dr. Frank McGovern, and Tim Brauns and I sat down and proposed that we would immunize patients in Urology with this type of cancer and the three of us together invented what we call the “Photonic Foley.” That is a three-way Foley catheter that has essentially three channels in the catheter itself. One channel is to infuse fluid, one channel is to draw fluid, and one channel is to contain a very thin fiberoptic cable. The fiberoptic cable runs into the bulb that is inflated to keep the catheter in the bladder. We developed a way of bringing laser light into the bladder with the objective of treating cancer this way.
I had gotten more and more involved with my colleagues at the Wellman Center for Photomedicine, so not only was I working with colleagues in Urology but also with colleagues in Dermatology and Wellman, and so I started attending some of their lectures. I sat in on a lecture by Michael Hamblin, PhD who talked about work in which he used laser light to activate a photoactivatable dye and to use this to treat bacterial infection. Specifically, he used methylene blue which is FDA- approved for installation in the bladder and potassium iodide, also FDA –approved. He was able, in vitro to dramatically drop bacterial colony counts by many millions in a few minutes. I realized that he had a drug combination that was not an antibiotic, and that we had a delivery system. I contacted Dr. Hamblin with Tim Brauns and we sat down and with Dr. McGovern and we proposed collaborating. Together we would try to treat refractory urinary tract infections associated with catheters.
This is an amazing institution. The fact that in one place we were able to find the Urologist who helped make it practical, the physicist who helped us in the design, the chemist who helped us design the drug, all without ever leaving the institution. That’s amazing, but that’s MGH.
Project Next Steps: I think the MIP did the very most critical thing by giving us the funds to get started; we now have the NIH grant which is designed to move this forward. But money for science and advice on device development are two different things, and what we need and seek from the MIP now is guidance and advice on how to get this to clinical use, which means developing it as a product that a company will produce. I. We want the advice and review of our colleagues on whether our approach appears to be scientifically sound and whether there are experiments we’re missing. We then will seek to develop this commercially, because if it isn’t made into a product, it isn’t helping patients.
Because infections in the hospital are often so resistant and so intractable and so deadly, what we want to do is to get this approach approved by the FDA for hospitalized patients. We are envisioning an initial device will be relatively small and not too expensive, and of course will involve single- use catheters attached to the multi-use laser. We expect to begin that way and demonstrate that this is a really valuable adjunctive therapy.
Then, I imagine, we will be able to actually further miniaturize this and use it for the literally millions of patients who self-catheterize. So patients who live at home with neurological disease, multiple sclerosis, spinal cord injury, who have essentially what we call neurogenic bladder and are unable to control and empty their own bladders and have to catheterize themselves three or four times a day should be able to use our second iteration. Self-catheterization inevitably leads to infection and those patients get multiply treated by multiple antibiotics and eventually develop very refractory UTIs. I treat them in the ID clinic all the time and frankly that is the genesis of part of this idea. The idea that we could essentially build a laser source the size of a flashlight that would be portable, rechargeable at home, with a disposable catheter that has a light element in it, and a squeeze bulb that contained the pre- made mixture of methylene blue and potassium iodide that’s squeezed into the bladder and quite literally lit up by the laser. We think this can be a home treatment device. That’s going to be years down the road, but I think we could move this into the hospital in three years.
Value of Medicine Innovation Program Funding: Usually the barrier to developing ideas is funding. I can’t tell you how absolutely critical the DOM innovation fund was. It gave us the money to start and once we got started we’re rolling forward.
The first information in laser and immunity was 2004, but it was only about a year ago that we realized that the “Photonic Foley” could actually be a source of antibacterial therapy. That’s what we proposed in the Innovation Grant and I’m thrilled to say we were granted that. That literally got us off the ground. Before that it was purely an idea, and thanks to the Innovation Grant, we have been able to develop data that just got us our first NIH grant.
To elucidate a bit more, because we had the MIP grant, I could approach the Chair of Urology, Dr. Michael Blute, and say “would you like to join in this effort,” and since Medicine had already validated what I was doing so it didn’t look so crazy, he gave us the opportunity to involve one of his senior fellows in Urology, Dr. Anton Wintner. Anton has developed a rat model of bladder infection and instillation of methylene blue and potassium iodide, has been able to use a tiny laser, and has been able to demonstrate with this miniaturized rat system that we can cause infection in the bladder of rat using a strain of resistant organism that came from humans but is capable of infecting rats, and that in turn is put into the rat bladder.
We put essentially 10 million E. coli bacteria into the rat bladder and in about 20 minutes of our treatment, they’re all gone. When we introduce methylene blue separately, or potassium iodide separately, nothing happens. When we introduce the laser alone, nothing happens. When we put them in together and light up the dye, it drops the colony counts dramatically. It’s important to point out that bacteria preferentially concentrate the dye as opposed to mammalian cells, so that in fact we are killing bacteria but not bladder cells. Of course, we will be doing the safety studies to prove this but if we can prove that we are reliably and statistically significantly reduce bladder infection in the rat and not in any way injuring the rat bladder, we will be on our way to introducing this into humans.
I think it’s important for us to realize that sometimes the greatest barrier to advances is amenable to the smallest investment. $30,000 changed this from an idea that was going nowhere to something that was able to get an NIH grant for half a million dollars, and it’s those early dollars that are so critical. I think that’s the take home lesson. Without that, I couldn’t have done this out of pocket, I couldn’t have done this without the manpower contributed by Urology, and I couldn’t have done this with without the photochemistry and physics advice of my Wellman colleagues. It’s a team, but without the money to hold that team together you’re just having coffee together and saying, “Wouldn’t it be great if.” And this turned “Wouldn’t it be great if” to “Wow, we’re really doing something.”
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