MUSC News Center
Award-winning entrepreneurial team merges bioengineering with medicine
Dawn Brazell | MUSC News Center | October 31, 2014
|Researchers hope nanotechnology will revolutionize drug delivery for transplants and other conditions. Above, TRaMs (shown in red) are targeted to endothelial cell surface markers and internalized into the cell.|
Compared to more established research companies, ToleRaM Nanotech, LLC is the proverbial new kid on the block. But this company, with a potent mix of MUSC researchers, took home top honors in the 2014 BioProcess International Awards last week in the category of Emerging Companies.
In her typical effervescent style, researcher and nanotechnologist Ann-Marie Broome, Ph.D., had the perfect analogy. “You put us all together and shake us up and wait for someone to yell, Yahtzee!”
It’s a word being said frequently by the company’s founders whose slogan on their company website reads 'small solutions to big problems.' The company focuses on expediting research for the focused delivery of drugs via specifically targeted nanoparticle devices. The goal is a big one: to decrease rejection of transplanted organs and to lower the debilitating side effects that transplant patients may experience.
The three founders of the company are: Broome, a biomedical engineer who has her MBA in bioscience entrepreneurship; Satish N. Nadig, M.D., Ph.D., a transplant surgeon who also has a Ph.D. in immunology; and Carl Atkinson, Ph.D., an expert in immunology and the innate immune system.
Nadig, the company’s chief medical officer, said it was an honor to be recognized. “We’re the infant company of the three finalists in that category that were chosen. The idea is novel and the need is so high that they felt it was something they wanted to highlight.”
That need is what motivated the group to form their company in January 2014, he said. “What ails our transplant patients is that all of them are susceptible to infections, and cancers, diabetes and general systemic consequences of their very powerful immunosuppressant medications. It’s a double-edged sword because they need these medications to keep them from rejecting their organs.”
Broome, who works on a nanoscale at dimensions that are just tiny fractions of the width of a human hair, studies different drug delivery constructs that mimic biological membranes, such as micelles and liposomes, to build a bubble-like structure that has ‘special ingredients’ added. These ingredients control how and when the nanoparticle homes in or ruptures within a region.
“We take FDA-approved drugs that have chemical characteristics ideal for packaging but that have significant side-effects associated with them thereby limiting their widespread use,” she said. “We encapsulate the drugs to put them in stealth mode and deliver them specifically to a localized region. They are released only to that area, eliminating the adverse side effects.”
Nadig said their research could revolutionize the way doctors deliver medications in transplantation.
“A major hurdle for us is something called operational tolerance. It’s the Holy Grail of transplantation,” he said. “Operational tolerance is defined as tolerance to the organ while keeping your global immune system intact. That is something this delivery system would potentially achieve.”
In other words, it potentially will lower rejection of a transplanted organ while allowing the patient to be able to fight off infection and go about a normal life. This is exciting to the team given that chronic rejection is one of the leading causes of graft loss in the long term, even today, he said.
“That’s 20 percent of people on the transplant list that need a re-transplant because they’ve lost their organ to chronic rejection. There are about 100,000 people on the list just for kidney transplants.”
The team’s rapamycin nanocarrier, referred to as TRaM for targeted rapamycin micelle, allows a drug that isn’t widely used around the time of the operation because of its side effect in keeping wounds from being able to heal, to be used in a targeted fashion because it is one of the best drugs to use immunologically. It allows the suppressive T-cells to proliferate, which is good for the transplant as it allows the patient to tolerate the organ, he said.
Broome designed the TRaMs to have tracking fluorophores and various other molecules that target the organ or tissue to be transplanted so that delivery and therapeutic response can be monitored noninvasively and in real time. The nanoparticles are also created to respond to changes in the environment.
“By physiology, whenever a cell envelops the nanoparticle, pH sensitive materials in the shell of the nanoparticle allow them to rupture within the cell,” she said. “We use the cell’s own ability to regulate pH to release the drug where it will benefit most.”
They are working on several ways to deliver the payload of bio-designed nanoparticles. The first phase is to study soaking the donor organ with TRaMs before transplant. Another approach is to deliver it intravenously during re-perfusion (when the blood flow is returned) in a transplant, a process that the surgeons can control, Nadig said.
The company has filed three patents on the technology it uses. A potential rollout for the first phase of treatment as a perfusion additive for donor organs will be much faster – a 2- to-5 year timeline given no setbacks. If experimentally successful, they estimate the time to reach clinical trials for a drug delivery system administered intravenously will be on a 7-to-10 year timetable.
Nadig said that is what’s great about entrepreneurship, and that he hopes researchers who have a bias against industry will reconsider if such a model could work for them. In the basic science realm, it might take 20 years for their research to be translated to the bedside.
“Having a company and having the development go through the company in certain iterations speeds the process up. The reason we formed this company is to be able to use this technology and streamline its ability to go the bedside. It’s often faster through industry.”
And this is a team that believes in fast.
Nadig came to the Medical University of South Carolina in August 2013 just a few months after Broome arrived in the Department of Radiology. Describing it as serendipity, Broome said she was thrilled to be contacted by Nadig before he even arrived. Her specialty in drug delivery meshed perfectly with his need for targeted drug deliveries.
“The second day I got here, we were running experiments,” said Nadig, who also tapped into the impressive work of Atkinson, an established basic science researcher. “It’s allowed us to move at a breakneck speed.”
In the past year, they have won three national awards for abstracts; submitted a manuscript for publication and funding requests for 13 grants; landed the BioProcess International Award; and formed a company.
The pace isn’t slowing down. Atkinson said the potential is limitless and goes beyond transplantation. “By packaging and targeting drugs, we can protect them from the often toxic microenvironment they will encounter in the body and thus improve their efficacy,” he said.
The hope is other researchers will start exploring not only what can be formulated in nanoparticle payloads, but also how they can be given to the patient, such as in a nebulized form, Atkinson said. Changing the formulation potentially will broaden their application to a wide range of diseases of the respiratory tract, from sinusitis to emphysema - and beyond.
The three company founders meet every other week to share updates and revise experiments. Broome said the collaboration is rejuvenating because she expects patients to benefit from what she’s doing in the lab during her lifetime.
“You become so specialized that you miss the opportunities that are looking you right in the face. Between the three of us and our laboratories, we have a whole stable of thoroughbreds. We’re the Triple Crown of nanotherapeutics,” she said.
Nadig, who will be addressing the American Society of Transplant Surgeons about the concept of team science and impact on work-life balance in January, said that for many years medicine has worked in silos, but the future is team science.
“This is a clear example of team science at its best. One of the best things about MUSC is that we have various disciplines in close proximity, such as having a surgeon talk to an engineer who talks to an immunologist and we all come together to form a delivery platform that has very sophisticated immunologic and mechanistic abilities in a very sick patient population. That’s the coolest thing about this.”