Torrey Pines Institute for Molecular Studies and InvivoSciences, Inc. Initiate Research Collaboration to Accelerate Drug Discovery

Torrey Pines Institute for Molecular Studies (TPIMS), a non-profit research institution and leader in advanced methods of drug discovery, and InvivoSciences Inc., an innovative company providing screening for first-in-class drug discovery, announced today a new collaboration to accelerate drug discovery in cardiac disease. Under the terms of the agreement, Torrey Pines Institute will work with InvivoSciences to screen the TPIMS collection of compounds in
InvivoSciences’ 2012 Edison Award winning assay system. Financial terms of the deal were not disclosed.

Torrey Pines Institute has developed methods for the rapid synthesis and screening of compound libraries containing up to billions of compounds. The preparation of compound libraries in organized mixtures allows for the positional screening technique to be utilized, ultimately enabling the screening of billions of compounds in exponentially fewer samples.

InvivoSciences has developed an assay system with engineered tissue-based compound screening technology, including their PalpatorTM device and connective tissue constructs fabricated in MC96TM. The ready-to-use tissues and assay platforms produced by InvivoSciences provide three-dimensional (3D) geometrics and physical environments for cells, bridging the gap between cell-based systems and isolated organ tissue systems or animal models by mimicking the functions of living organisms, specifically those of humans.

Richard A. Houghten, Founder, CEO & President of Torrey Pines Institute said, “It is exciting to combine our libraries and screening techniques with the assay systems developed by InvivoSciences. Their assay approach closely models human disease so the potential to identify and develop disease-modifying therapies is significant.” Ayla Annac, Co-founder and CEO of InvivoSciences comments, “We are especially proud and pleased to establish a long-term relationship with the internationally recognized Torrey Pines Institute and recognize its entrepreneurial spirit and commitment to accelerate drug discovery.”

Wisconsin’s Biotech Industry Making a Global Impact

As a leading provider of 3D, ready-to-use human engineered tissues, Madison-based InvivoSciences has products and capabilities that are of interest to a global audience.

Reaching that audience is one of the many reasons Wisconsin biotechnology leaders and company representatives made their way to Boston in June for the 20th annual BIO International Convention.

Their presence was not left unnoticed, as by the end of the convention the Wisconsin biotechnology industry had taken its fair share of the global spotlight.

Small business has big showing

InvivoSciences was able to send out more than 250 requests for meetings and received a high response rate, but they were unable to accommodate all of the requests. “As a small company we could not send all of our employees to the convention,” says InvivoSciences Co-Founder, President and Chief Executive Officer Ayla Annac.

However, just as he does in the lab, Co-Founder and Chief Scientific Officer Dr. Tetsuro Wakatsuki made the most of his time. He met with close to a dozen pharmaceutical companies and several biotech companies, investors and universities, in addition to gaining invaluable face-to-face interaction with potential new customers.

As a result of these meetings, Dr. Wakatsuki is visiting several pharmaceutical companies in Japan, and says one will visit their Madison facility this month.

Dr. Wakatsuki was also a featured presenter at the Wisconsin Pavilion, sharing how his team provides services for major pharmaceutical and cosmetic companies through engineered, tissue-based content analysis. This technology won a bronze medal at the 2012 Edison Awards, one of the highest accolades a company can receive in the industry.

The benefits of state support

Attending a four-day conference in Boston can be quite costly for small businesses. To alleviate some of the financial burden, BioForward, a member-driven state association that is the voice of Wisconsin’s bioscience industry, and WEDC offered multiple scholarships.

InvivoSciences was one of eight companies to receive scholarships. According to BioForward Executive Director Bryan Renk, recipient companies participated in more than 300 partnering events.

Annac believes InvivoSciences would not receive nearly as much attention without the state. “We brought the company here because Wisconsin has a rich biotech and entrepreneurship understanding,” she says. “WEDC and the former Department of Commerce encourage this type of critical technologies that contribute strongly to the economic development of the state. We came to Wisconsin to be part of the biotech hub they support.”

That sentiment was reinforced by the annual Battelle/BIO State Bioscience Industry Development Report findings. According to the report released during BIO, Wisconsin’s biotechnology industry is one of the healthiest in the nation and grew faster than any other Midwest state during the recession.

The report also showed in 2010 that Wisconsin bioscience workers’ average wages ranged from $54,822 in agricultural feedstock and chemicals to $79,409 in the medical devices and equipment sector. During the same time, the average wages for Wisconsin private sector employees were $36,796.

Another measure of success is the relatively high percentage—nine percent in 2011—of U.S. clinical trials held here. Renk says that amount of clinical trials has a very positive economic impact on the state.

Research a key ingredient

Another BIO attendee, the Morgridge Institute for Research, came for another reason. The private, nonprofit interdisciplinary biomedical research organization is associated with the University of Wisconsin-Madison and came to promote the state’s research capabilities. It partnered with Cisco Systems to conduct life-sized, face-to-face video conference meetings between researchers on campus in Madison and convention attendees.

For a relatively new biomedical institute like Morgridge, BIO provided a great opportunity to get the word out about the world-class technology being developed in the state.

“We used the convention to highlight how our medical devices group is helping to solve a national crisis in the supply of a life-saving isotope,” says Zack Robbins, associate director of development for the Morgridge Institute. “We’re partnering with Wisconsin high-tech startup SHINE Medical Technologies to supply this medical isotope to hospitals across the U.S.”

SHINE is building a new plant in Janesville, Wis., that is expected to generate more than 100 new jobs. 

“Wisconsin’s research and technologies have really changed the world,” adds Robbins. “In addition to cheese, beer and the Packers, Wisconsin is the source of many critical biotech advances from stem cell science to vitamin D to medical imaging.”

When the 2012 BIO International Convention ended, Wisconsin organizations set their sights on next year’s convention, to be held in Chicago. InvivoSciences’ Annac believes Wisconsin will have a “larger, more forceful presence” at BIO 2013, something echoed by many state leaders.

$2 million to study role-switching cells in heart failure

The National Institutes of Health has awarded more than $2 million to a team of scientists from Washington University in St. Louis and InvivoSciences, a biotechnology startup with WUSTL roots, to construct artificial tissue models that will allow the rapid testing of new drugs for heart failure.

According to the Centers for Disease Control, about 5.8 million people in the United States have heart failure, and many of them will die of their disease.

Drugs used to treat heart failure, such as the ACE inhibitors or beta blockers, improve the symptoms and allow patients to live longer and feel better. They may even reverse pathological changes in the heart tissue to some degree.

But heart failure is still the leading hospital discharge diagnosis and trials for several promising drugs for this disease have been costly failures.

The WUSTL research focuses on the role in heart disease of role-switching cells called myofibroblasts that proliferate in over-stressed or injured hearts. In response to a heart attack, fibroblasts convert to this cell type, which secretes collagen and contracts the matrix of fibers around the injured heart tissue to repair the defect.

But heart cells never truly regenerate in the damaged tissue, and myofibroblasts compensate for their absence by forming a stiff, collagenous scar that interferes with the heart’s ability to maintain stable heart rhythms and to expand and contract forcefully to pump blood.

Fibroblasts also convert to myofibroblasts in response to high blood pressure, or hypertension. The resulting diffuse invasion of myofibroblasts also interferes with the electrical and mechanical functions of the tissue, and can lead to heart failure.

“Drugs that block the effects of myofibroblasts on the electrical or mechanical properties of heart tissue or that coax them to revert to fibroblasts might be more effective than current therapies,” says Guy M. Genin, PhD, associate professor of mechanical engineering and materials science in WUSTL’s School of Engineering & Applied Science, who is one of three co-primary investigators (PI) on the grant.

A wound-healer run amok
In the 1970s, a scientist at the University of Geneva in Switzerland discovered cells in healing wounds that seemed to be intermediate in character between fibroblasts, which secrete fibers such as collagen that make up the matrix that holds cells together in tissues, and smooth muscle cells, like those in the intestines and blood vessels.

These cells, which were named myofibroblasts to reflect their double nature, secrete fibers to fill in a wound and then contract to bring together its edges. And after the wound is healed, they disappear, either by committing cell suicide or perhaps by reverting to their original cell type.

But not always.

The heart is made up predominantly of two types of cells, Genin says: the fibroblasts, which maintain the collagen and other structural proteins within the heart, and the cardiomyocytes, which do the pumping.

After a heart attack, some of the fibroblasts will convert to myofibroblasts to restore tissue integrity, and many persist even after their work is done. If blood pressure is high enough to provoke fibroblasts to become myofibroblasts, the cells also may get stuck in their helper state.

The cardiomyocytes don’t proliferate, but the myofibroblasts keep dividing, gradually replacing healthy tissue with fiber-stiffened (fibrotic) tissue.

This phenomenon is not limited to the heart. Myofibroblasts can proliferate elsewhere in the body as well — although they may arise from different cell types in different tissues — and fibrotic remodeling of the kidney, liver (cirrhosis of the liver) and lungs follows a similar progression, Genin says.

The severe consequences of myofibroblast dysfunction motivate the effort to better understand these enigmatic cells.

Artificial heart tissue

“There’s a lot we don’t understand about what these cells do in the heart,” Genin says.

“We don’t know why conversion of fibroblasts to the contractile phenotype is sometimes helpful and sometimes harmful. We don’t know how these cells alter the electrical and mechanical properties of heart tissue, or the degree to which these changes are to blame for the ultimate shutdown of the heart.

“We think that a therapy that would control the number and properties of myofibroblasts in the heart might be useful, but we don’t know that for sure,” Genin adds. “Nor do we know how to reverse the transition to this cell phenotype once it has occurred.”

Many of these questions would be very difficult to sort out in real tissue, so the scientists use model tissues invented at WUSTL in Eliot Elson’s lab. Elson, PhD, the Alumni Endowed Professor of Biochemistry and Molecular Biophysics in the Department of Biochemistry and Molecular Biophysics at WUSTL’s School of Medicine, is the second of three co-PIs on the grant.

To make the tissues, the scientists crack open fertilized chicken eggs, pull fibroblasts and muscle cells out of the embryos’ hearts, and mix them together with collagen.

“Over the course of time, the cells interact with each other and the collagen to form pieces of artificial heart that beat on their own in a Petri dish,” Elson says.

The scientists can control the number of myofibroblasts in the tissue (most fibroblasts convert to myofibroblasts when they are plated out) and their distribution. In this way, they can mimic the fibrotic changes characteristic of a heart attack and those characteristic of hypertension.

“For a model of myocardial infarction, we want to create an island of wound-healing cells inside a patch of heart tissue, and for hypertension, we try to create what’s called interstitial fibrosis, in which the myofibroblasts are interspersed between the contractile cells,” Genin says.

The electrical and mechanical activity of the manufactured tissues then can be investigated with the help of a variety of sophisticated imaging and force measurement techniques, many developed at WUSTL in the laboratories of Elson and Genin, and of Igor Efimov, PhD, the Lucy and Stanley Lopata Distinguished Professor of Biomedical Engineering in the School of Engineering & Applied Science.

At the same time, the scientists are developing computer models that are digital analogs of the artificial tissues, including electrophysiological models pioneered by Yoram Rudy, PhD, the Fred Saigh Distinguished Professor of Engineering in the School of Engineering & Applied Science. The back and forth between the tissue models and the computer models will allow them to test basic biophysical theories explaining their experimental observations.

Drug screening with tissue constructs
Once they understand the basic cellular biophysics of failing heart tissue, they will transfer their work to tissue models that will make it much faster and safer to test drugs for heart failure and hypertensive heart disease, the scientists say.

They plan to make the transition to drug screening with the help of InvivoSciences, whose chief scientist Tetsuro Wakatsuki, PhD, the third PI on the grant, earned a doctorate in biophysics and a master’s degree in mechanical engineering at Washington University.

InvivoSciences makes engineered heart tissues from mouse embryonic stem cells and stem cells from differentiated adult tissues in humans, such as fat and skin. The company then uses biochemical methods to convert these undifferentiated cells to tissue- or organ-specific cells, such as cardiomyocytes and fibroblasts, and to generate artificial tissues from them.

“We’ll develop the science on the much less expensive chicken egg tissues and then we’ll start our own stem cell bank here and begin making these mouse-derived tissue constructs,” Elson says. The mouse constructs are more useful because of the molecular genetic tools available for mice.

Staggering investments of time and money have failed to produce new drugs for heart failure. The scientists hope that the artificial tissues will allow many more drugs to be tested under conditions closer to those within the human body. Their hope is that drug candidates that get as far as animal testing and clinical trials will then be more likely to be safe and effective.