Shire punts on bioscaffolds for cell-based regenerative medicine*

7 August 2012 Mark Ratner Dublin-based Shire demonstrated its continuing interest in cell therapy and biomaterials in April, paying a potential $200 million for Pervasis, a developer of endothelial cell–based therapies for vascular repair, located in Cambridge, Massachusetts. It was Shire’s…

7 August 2012

Mark Ratner

Dublin-based Shire demonstrated its continuing interest in cell therapy and biomaterials in April, paying a potential $200 million for Pervasis, a developer of endothelial cell–based therapies for vascular repair, located in Cambridge, Massachusetts. It was Shire’s second cell therapy–oriented acquisition since mid-2011, when it acquired Advanced BioHealing of Westport, Connecticut, for $750 million in cash. Shire sees regenerative medicine as an emerging specialty area anchored by a biologics-based infrastructure—much the same kind of opportunity as enzyme replacement therapy was seven years ago, when it spent $1.57 billion to acquire Transkaryotic Therapies of Lexington, Massachusetts (Box 1). Although other pharmaceutical firms have yet to show interest in the space, Shire’s interest reflects a growing understanding of how to apply biomaterials to deliver factors and cells for a variety of therapeutic applications more effectively than in the past.

The original goal of tissue engineering was to develop an actual replacement tissue. “A program was deemed finished and successful once the structure was finished and the tissue architecture recapitulated in a way that held truest to the original,” says Elazer Edelman of the Harvard-MIT Biomedical Engineering Center in Cambridge, Massachusetts. “I think we have learned that this is an extraordinarily difficult task.” If some groups are still trying to rebuild architectures from the ground up, others are now de-cellularizing organs, leaving only a cytoskeleton or tissue skeleton. In cases where a disease is of the cells of the organ, the skeleton of the organ may be intact: by stripping away everything but the extracellular matrix, one could then re-seed healthy cells and in that way take advantage of the natural matrix of the organ, or scaffold. Indeed, says Edelman, cellular engineering need not fully recapitulate a cell’s architecture to recapture the natural homeostatic control they can provide.

Edelman’s laboratory has focused on blood vessel repair using endothelial cells; he devised Pervasis’ lead product Vascugel, which is adult human allogeneic endothelial cells layered on a modified porcine collagen mesh. Vascugel is placed over the damaged endothelium and the cells secrete compounds that inhibit thrombosis, for instance, transforming growth factor (TGF)-beta-1, heparin sulfate, nitric oxide and others, allowing the underlying endothelium an opportunity to regenerate.

“A good deal of what blood vessels or liver or cells do is to control their environment,” Edelman says. Paracrine signaling is a key biological feature of cell therapy, but Vascugel also illustrates the importance of how they are presented. “Cells do not exist in a free state—they exist adherent to a scaffold,” he says. By choosing a scaffold with the proper porosity and surface texture and surface roughness, matching what the cell expects to see, “one can control the cell state,” he says, and by controlling the cell state, engineer a functional tissue without engineering a structural tissue.

Surprisingly, first-generation materials like porcine collagen, which has long been used as a hemostat (to staunch blood flow in surgery), are not being superseded by more sophisticated synthetic biomaterials, adds David Mooney of MIT. “I certainly didn’t expect that five or ten years ago.” Partly, it’s due to their track record of use in humans and a record of biocompatibility and safety of materials. As with Vascugel, “Those same materials are being used, but they are being used in new ways and they are having additional functionality added on to them,” says Mooney.

There are three flavors of biomaterials now, which vary in their dependence on and utilization of the local cellular environment. The first delivers a therapeutic in a predefined dose released at a certain rate, over a certain time, and is not dependent on the local conditions. “That may be desirable because the local conditions may change from person to person,” says Mooney. If the degree of inflammation varies, for example, a preprogrammed delivery system may offer more consistency.

The second flavor, by contrast, leverages the back-and-forth signaling between an implanted cell therapy and the cells in the local microenvironment to regulate the release or activity of some of these molecules, such as growth factors or morphogens. The third uses an external control, such as ultrasound, to release drugs or proteins more or less on demand.

Biomaterials “seem to provide protection from the host environment and can induce the cells to proliferate within the device and feed out in a steady stream,” says Mooney. The cells are protected temporarily and fed out over time into the local environment. And although scaffolding usually implies the cells form a new tissue around the material, in this case, the material acts as a temporary home or residence for the cells, which eventually move outwards to participate in regeneration. The approach leads to “a vast improvement in the biological outcome,” he says.

Although makers of cell therapies have yet to develop the ultimate scaffold—one with its own [an integrated] vasculature—even that prospect is on the horizon. London, Ontario–based Sernova, for example, is about to start trials with a subcutaneous pouch the size of a matchbook and made from biocompatible materials approved by the US Food and Drug Administration for permanent use in the body. The pouch vascularizes and forms a natural chamber for delivering human islets. After implantation, a tissue matrix forms around the pouch—mimicking the natural environment and allowing the islets to stay in place and expand, in effect forming the ultimate scaffold for an artificial organ.

Scaffolds are also becoming more important in the delivery of mesenchymal stem cells, which in the past have been injected or infused locally at the site of tissue repair. Chemical, mechanical (e.g., material stiffness) and structural aspects can regulate the fate of those cells in a fairly precise manner, says Mooney, with clinical implications for tissue regeneration. And there’s already a lot of interest in their hematologic activity due to paracrine effects and their ability to manipulate local inflammation. This anti-inflammatory capacity is evidenced by Columbia, Maryland–based Osiris Therapeutics’ use of injectable mesenchymal stem cells in graft-versus-host disease, for which it gained recent regulatory approvals in Canada and New Zealand (Nat. Biotechnol. 30, 571, 2012). “I think the immunology and the mechanisms underlying [the signaling] component of how they are functioning is fairly open at this time,” he says. “They have potent effects but how to regulate that I don’t think is very clear yet.”

“In an ideal world, we’d prefer to not have to transplant cells at all,” says Mooney, instead tapping the power of cells that exist in the body that look like they have tremendous potential therapeutically. Instead of ex vivo manipulation and reintroduction of the cells, the idea is to do that all in vivo. The premise is to place biomaterials in the body with the right recruiting signals to recruit the cells of interest. “In that way, we create an environment distinct from the host environment, and now we potentially have a lot of control over those cells,” he says.

In cancer therapy, for example, a biomaterial scaffold could be implanted in the body at a location remote from the malignant growth—thereby avoiding tumor-associated immunosuppressive cells, cytokines and other factors that confound immunogenicity—and be used to present a tumor antigen to progenitors of dendritic cells (recruited from elsewhere in the body) that would then be activated and induced to migrate to the lymph nodes where they would interact with T cells and generate a potent anticancer T-cell response. Mooney’s laboratory is gearing up to do a clinical trial later this year or early next year to do just that.

Nature Biotechnology