Thirty years ago, chemonucleolysis—a minimally invasive procedure to relieve the excruciating pain of a herniated lumbar disk by injecting chymopapain, an enzyme derived from papayas—seemed like a good idea. The enzyme dissolved the soft, bulging disk nucleus, shrinking the disk and reducing its pressure on nerve roots.

The procedure had been available in Canada—and had been drawing enthusiastic patients across the border—for years. So when the U.S. Food and Drug Administration (FDA) finally approved chemonucleolysis with chymopapain, even the New York Times praised the decision. The treatment seemed to offer a less invasive, lower-cost alternative to surgery while achieving comparable success.

Twenty years later—in January 2003—the FDA halted the sale and distribution of chymopapain in the United States. Although many patients experienced excellent outcomes, chemonucleolysis with chymopapain was found to cause serious side effects at a higher-than-expected rate. The nonspecific enzyme digested structures in addition to the disk nucleus, leading in the worst cases to hemorrhage, pain, and paralysis. Because the enzyme’s effects are permanent, disks never regained their pretreatment height, potentially impairing biomechanics. In some patients, chymopapain triggered serious allergic reactions, including fatal anaphylactic shock.

But the concept of chemonucleolysis remained compelling, as did the good results experienced by many patients. That’s what attracted Sumit H. Rana, MD, to the possibility of reinventing the procedure to reduce its risks and maximize its benefits.

With a 2010 Orthopaedic Research and Education Foundation (OREF) Resident Clinician Scientist Training Grant, Dr. Rana is conducting a preclinical investigation of a new approach to chemonucleolysis that uses two novel compounds to shrink the disk nucleus and then restore disk height and biomechanics.

Enhanced impact, reduced risk
Dr. Rana is using his OREF funding to investigate a new one-two punch approach to chemonucleolysis. The first step involves injecting the disk nucleus with polylysine. Unlike chymopapain, polylysine is not an enzyme—it’s a simple polymer that works not by digesting tissue, but by replacing water molecules in specific nucleus structural proteins. That substitution shrinks the disk by reducing its osmotic pressure.

“Polylysine has several properties that make it a strong candidate for effective nucleolysis,” said Dr. Rana. “Its mechanism of action targets disk nucleus proteins, so its potential to affect other spine tissues is limited. And unlike an enzyme, it doesn’t permanently change protein structure. Over time, water molecules move back into their original sites in the proteins, restoring the original structure.”

This gradual reversion to natural chemistry may allow the disk to regain its height and optimal biomechanical properties. It is also the basis for the second step in Dr. Rana’s investigation—exploring whether following that first disk-shrinking step with injection of osteogenic protein-1 (OP-1), a bone morphogenetic protein, may speed the disk’s biomechanical recovery.

Dr. Rana’s preclinical investigation of polylysine and OP-1 is underway with three groups of rabbits. One group will receive injections of only polylysine. This group’s results may confirm prior preclinical studies suggesting that polylysine can shrink disk height by as much as 20 percent.

The second group will receive polylysine injections followed by injections of OP-1. Results in this group will provide preliminary data suggesting whether OP-1 enhances recovery of disk height.

The third group, the control, will receive injections of physiologic saline to benchmark the effects of the minimally invasive procedure itself against results of the two active treatment groups.

The clinical horizon
The next-generation approach to chemonucleolysis that Dr. Rana is exploring looks so promising that private companies have expressed interest in commercializing the technology. But this promising refinement will never reach patients without additional extensive research, in both preclinical studies and clinical trials.

Dr. Rana is eager to help develop that evidence base and to bring new treatment options to the clinic. “Disk disease is a primary cause of lower back pain and affects up to 85 percent of the U.S. population at some time in their lives,” he said. “It’s a major driver of healthcare costs, lost productivity, and decreased quality of life.”

Patient concerns are a key driver for Dr. Rana’s work. “I plan to specialize in spine after my residency. I’m especially interested in research and development of minimally invasive techniques and treatment options to improve patient outcomes and satisfaction with care,” he said. As an orthopaedic surgery resident at the University of California at San Diego (UCSD), he can take advantage of an extra year of residency devoted to basic science research.

“At UCSD, I treat a gamut of patients from all walks of life,” he explained. “Across the board, they share universal concerns—when can I return to work? Will I get back to 100 percent of the way I felt and functioned before? As clinicians and scientists, we need better treatment options so we can provide reassuring answers. OREF is helping us identify and apply the tools that will get us there.

“In 5 to 10 years, I hope to have a career in academic medicine providing clinical care, pursuing research, and mentoring residents. With the combined power of my OREF grant and the basic science component of my residency, I’m in a strong position to jumpstart my career as a clinician scientist,” Dr. Rana explained.

Sally T. Halderman is a contributing writer for OREF and can be reached at communications@oref.org