OHSU

Peter Kurre, M.D.

12/30/2009 - For years, the potential of using engineered viruses in gene therapy has held out great therapeutic promise while also presenting significant obstacles. Chief among the obstacles is the body's own multifaceted immune response.

Peter Kurrie, M.D.

For years, the potential of using engineered viruses in gene therapy has held out great therapeutic promise while also presenting significant obstacles. Chief among the obstacles is the body's own multifaceted immune response. The problem, as articulated by the authors of a May 2006 editorial in Nature Medicine, is that "the immune system, quite frankly, does not approve."

Simply injecting the viral genetic payload generally does not breach the defensive fortifications of the immune system in quantities sufficient to be of therapeutic value. The degraded viral particles are "either washed away to irrelevant tissues or captured by endothelium, circulating immune cells or antibodies," wrote the editorial authors Kevin Harrington and Richard Vile. This raises obvious bio-safety concerns for patients.

Alternative strategies based on viral modification of recovered cells outside the body rest on the belief that a viral vector is either integrated into the target cell in a heritable fashion or it is immediately degraded. Peter Kurre, M.D., happened upon what he calls an "accidental observation" that raises questions about this prevailing "either-or" dogma of immediate integration or degradation of these particles.

"We may have found a third way," said Kurre. Kurre is an Assistant Professor in the Department of Pediatrics and in the Department of Cell & Developmental Biology, OHSU School of Medicine.

The Kurre lab focuses on retroviruses as tools to place therapeutic genes into target cells; specifically, His lab works with human immunodeficiency virus derived lentivectors with the goal of modifying hematopoietic stem cells. These stem cells are precursors of all human blood components.

"The therapeutic genetic modification of the patient's own hematopoietic stem cells holds substantial promise for the treatment of blood and immune system disorders," said Kurre.

During a series of routine experiments designed to better understand and improve virus uptake and integration into hematopoietic stem cells, Kurre observed a prolonged intracellular retention of the viral particles in some precursor cells. Indeed, the unexpected capture and release of viral particles by target cells pointed to the possibility of a novel fate. "We are now seeking to understand the cellular mechanisms controlling the persistence of the particle."

What makes this especially intriguing is the fact that bone marrow precursor cells used in these experiments are equipped with molecules that are, in effect, cellular homing devices. When injected externally, the stem and precursor cells automatically travel to the bone marrow and target the stem cell niche – their home base.

The combination of targeting stem cells directly in their microenvironment with the delivery of viral payload has the potential to overcome current impediments to gene therapy for hematopoietic and immune disorders – if the precursor cells themselves serve as "carrier" cells. Studies by Kurre, recently published in the Journal of Virology, have demonstrated that capture and release of the lentivector by hematopoietic "carrier" cells, when combined with their established homing mechanisms, allows for direct in-situ genetic modification of murine bone marrow stem cells.

"Systemic delivery of captured virus by autologous cellular carriers may allow the virus particle to evade the immune system response, reach the target cells, and be handed off to stably integrate into the bone marrow stem cell. This strategy may finally allow repeat administration of viral therapeutics, a long elusive goal in the gene therapy field," said Kurre.

While conceptually attractive, such immune-privileged delivery will require a much improved understanding of particle capture and release mechanisms. "Given past clinical setbacks in gene therapy, patients have understandable concerns about the viral particle being released into other tissues, particularly reproductive tissues," said Kurre.

Originally from Hamburg, Germany, Kurre trained at the University of Chicago and the Fred Hutchinson Cancer Research Center in Seattle before he joined the faculty in 2004. At OHSU, he has been heartened by the collegiality of the faculty researchers. "I have enjoyed tremendous support from senior researchers whose sole reason for helping is the scientific advance possible. For a junior investigator, this is very rewarding," said Kurre.