The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers

Carl G. Hellerqvist, Ph.D.

Professor of Biochemistry, Emeritus
VICC Member
Researcher

Contact Information:

Vanderbilt University Medical Center
634 Robinson Research Building
Nashville, TN 37232-0146
615-322-4339

Research Specialty

Identification of an anti-pathoangiogenic agent and its target protein with applications in cancer, RA, ulcers and paralysis.

Research Description

Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101), which we have previously described as GBS Toxin. We have recently demonstrated with an ELISA assay that CM101 is present at high concentrations in the plasma and spinal fluid of neonates diagnosed with GBS sepsis. Furthermore, we isolated large quantities of biologically active CM101 from the neonate's urine. We are currently exploring means to block the respiratory distress with direct application to the nursery.

We hypothesized early that CM101 would bind to embryonic receptors in the neonatal lung and would bind to the neovasculature in human tumors. CM101 binds in vivo to the vasculature of human tumors, and in a mouse tumor model causes inflammatory reactions at the tumor site that lead to retarded tumor growth or regression depending on treatment regiment. CM101 treatment, in cancer patients in Phase I clinical trials and in tumor bearing mice over-rides the tumor immunoprivilege, which allows the tumor to grow, and allows inflammatory cells to invade the tumor and induce tumor apoptosis and ablation.

Current research is aimed at an understanding the molecular biology of the anti-pathoangiogenic properties of CM101. We have research interests in several areas:

I. Spinal Cord Injury. CM101 by inhibiting inflammatory angiogenesis prevents secondary inflammatory injury to the spinal cord and scarring. This allows animals to recover from paralysis. CM101 by the same mechanism accelerates wound healing and prevents scar formation. The mechanisms of these events are under investigation.

II. Stem Cell Transplantation in Chronic Spinal Cord Injury. By a mechanism not quite understood, CM101 in picomolar concentration stimulates the differentiation of stem cells into neurons. When these neurons are transferred to the spinal cord cavity created by surgical removal of the gliosis in chronically paralyzed mice, which are treated with i.v. infusions of CM101, the animals show remarkable recovery of motor and sensory function. Functional MRI is being applied to demonstrate the neuronal recovery. The mechanism of CM101 induced differentiation into neurons is under investigation.

III. Clinical and pre-clinical data reveals that the inflammatory response induced by CM101 binding to a target protein in the pathologic vasculature initiates a break down of the immunoprivilege the tumor has created in the host. Leukocyte p53 mRNA is up regulated and tumor apoptosis is induced in p53 negative tumors. The mechanism of this induction remains unsolved.

IV. We have expression cloned the target protein HP59, which CM101 binds to and are addressing the pathophysiology seen in our animal models and in patients in response to CM101 treatment. We have demonstrated by immunohistochemistry that HP59 is uniquely present only in pathologic angiogenesis and aim to develop specific targeting agents for drug development.

V. We have initiated a vaccine program where mice are immunized with HP59-derived peptides. We have attenuated growth of subq implanted tumors by inhibiting angiogenesis and vasculogenesis and i.v. challenges with melanoma cells are not lethal to other immunized mice. These tumor resistant mice have given birth to normal size litter demonstrating that the pathologic and physiologic angiogenesis are distinctly different in expression of HP59.

VI. We are applying our immunization model to better understand the anti-pathoangiogenic properties of CM101 which makes it applicable to rheumatoid arthritis, wound healing, reperfusion injury, spinal cord injury and other diseases driven by pathologic angiogenesis.

Publications


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