By Mary Welch

When a starfish loses an arm, it grows another. One puzzle that has intrigued scientists ishow to make the human body grow a part back or augment a part that is too small to befunctional.

Cambridge, Mass.-based Reprogenesis Inc. has taken up that challenge and is makingheadway in tissue formation with one product, Natrolin VR, starting Phase III trials, andanother, Natrolin SI, which should enter Phase III by the end of the year.

"Our technology allows us to create new tissue in vivo," said Daniel Omstead,president and CEO. "When you try to isolate cells from one part of the body and thentransplant them back into another body location, they don't do well. They tend to die. Ourtechnology involves using a biodegradable viscous liquid called a hydrogel that allows thecells to live when transplanted. In addition, when the hydrogel resorbs, the cells startmaking their own matrix, with the result being new tissue formation in the body."

Founded in 1993, Reprogenesis' principal technology is based on combining cells with ahydrogel matrix that can be injected into the body with endoscopic techniques or throughsurgery.

The licensed technology is based on discoveries by Robert Langer of the MassachusettsInstitute of Technology, in Cambridge; Joseph Vacanti, of Children's Hospital andHarvard Medical School, both in Boston; and Charles Vacanti, of the University ofMassachusetts, in Worcester.

"They are the fathers of tissue engineering," said William Romeo, Reprogenesis' vicepresident of finance and chief financial officer.

A matrix is a 3-D structure that supports the cells in such a way that they continue normaltissue generation. Reprogenesis' products are based on obtaining cartilage cells (calledchondrocytes) isolated from a small biopsy of the ear and growing them. These cells arethen combined with a hydrogel. The cells and matrix are endoscopically delivered into thebody, prompting cell and tissue growth.

Three Approaches Under Pursuit

"Our company is involved in three approaches," said Omstead. "First, we create tissue notnormally present to augment a structure or organ. Second, we repair or restore a physicalbody structure or organ. Third, we repair or restore a physiological function."

The company's most advanced work is in augmenting the bladder. In the trials forNatrolin-VR, Reprogenesis uses its technology for the treatment of vesicoureteral reflux, aurological disorder found in 1 percent of all children.

"Basically, the opening from the ureter to the bladder is too large and the urine goes backto the kidney. It goes the wrong way. It can lead to kidney damage or loss of function,"said Omstead.

Currently, surgery is required to correct this disorder. What Reprogenesis does isendoscopically implant cells that bulk up the tissue at the ureter-to-bladder junction to prevent the urine from flowing backwards. Normal bladder function is not affected,however.

"We're creating a nodule of tissue that narrows the opening," Omstead said.

The same theory is behind Natrolin-SI, which is in trials to treat adult stress incontinence.Natrolin-SI augments weakened bladder tissue with a permanent cellular implant, avoidingsurgery and the inconvenience of adult diapers or insertables.

Both of these products are funded by a $26 million research and developmentcollaboration with American Medical Systems, of Minnetonka, Minn., a subsidiary ofPfizer Inc., of New York

In another application of the technology, the company's efforts at creating tissue involveprocedures such as growing a nipple after a woman has had a mastectomy. More than25,000 women a year undergo breast reconstruction following a mastectomy and thecreation of a nipple is an expensive procedure, and possibly not a cosmetically satisfyingone.

In preclinical trials, Reprogenesis has grown a "nipple-like" projection by endoscopicallyplacing a cell hydrogel nodule just below the surface of the skin. The projection will geteven more pronounced as the cells grow naturally.

The company, which expects to enter Phase I trials within a year, hasn't finalized whichkind of tissue will work best. Muscle, fat or cartilage are among the options. In the sameway, Reprogenesis and its collaborators are creating a whole new bladder in dogs with nobladder or one that is too small.

Technology Also Targets Restenosis

The company also is using its technology to prevent restenosis, or reblockage of arteriesor veins after angioplasty or stenting.

More than 1 million people undergo arterial bypass procedures yearly. About 20 to 50percent of those patients will require subsequent treatment, like angioplasty, because theartery or veins become blocked again.

"We believe that when the balloon is inserted into the muscle vessel (an artery or vein), theendothelial cells that prevent muscle vessel propagation — which eventually becomesthe clog — may be damaged," said Romeo. "We believe that an endothelial cellimplant, which inhibits restenosis, may be effective in preventing the need for bypasssurgery. The cells grow back and prevent the arterial muscle cells from growing andclogging up the arteries." Tests on pigs have proved promising.

With the exception of the $26 million alliance with AMS, the company, which has 35employees, has no other collaborators but expects to have at least one more within a year.Reprogenesis has raised $6 million from investors including Essex Woodlands HealthVentures, of The Woodlands, Texas; Hambrecht & Quist Healthcare Investors, ofBoston; and Piedmont Venture Partners, of Charlotte, N.C. The company expects to goafter more private financing or file for an initial public offering by the end of 1998.

Reprogensis was founded by Chairman James McNab ,who started Parker MedicalAssociates, of Charlotte. Omstead was senior vice president of research and developmentof Providence, R.I.-based CytoTherapeutics Inc. before joining Reprogeneis in his currentposition. Romeo was vice president of finance at Alpha-Beta Technology Inc., inWorcester, Mass.

"Basically our technology was developed at MIT and Harvard, and Jim McNab, who is anentrepreneur, heard about it and personally invested in the technology. He's been in themedical field for years and was able to get the Pfizer deal because of the technology," saidOmstead.

"Our goals for the next year are to have another product in clinical trials and get anothercollaboration," said Romeo. "We're going to make it." *