Editor's Note: Science Scan is a roundup of recently published biotechnology-relevant research.
Lupus nephritis, diabetic nephropathy and Immunoglobulin-A disorder produce forms of kidney inflammation. These conditions are typically marked by abnormal cell proliferation or extracellular matrix accumulation of glomeruli or nephrons in the kidney. The conditions can sometimes lead to kidney failure and the eventual need for dialysis or organ transplantation. These diminish the quality of life for patients.
The September issue of the Journal of the American Society of Nephrology carries what its authors term, "a novel therapeutic approach to treating kidney inflammation." It's title: "A fully human monoclonal antibody (CR002) identifies PDGF-D as a novel mediator of mesangioproliferative glomerulonephritis." (PDGF stands for platelet-derived growth factor.)
Its principal authors are at CuraGen Corp., of New Haven, Conn.
The paper notes that "PDGF-B is of central importance in mesangioproliferative diseases; PDGF-D is a new PDGF isoform. Low levels of PDGF-D messenger RNA were detected in normal rat glomeruli. After induction of nephritis in rats, PDGF-D mRNA and protein expression increased significantly from days four to nine in comparison with non-nephritic rats. In addition, PDGF-D serum increased significantly in the nephritic animals.
"These rats were treated on days three and five with different amounts of a fully human PDGF-D-specific neutralizing monoclonal antibody (CR002), equal amounts of irrelevant control mAb or peripheral blood serum by intraperitoneal injection."
CuraGen's director of corporate strategy and industrial relations, Fred Aslan, told BioWorld Today that his company isplanning Phase I trials of CR2002 in 2004, testing an initial group of patients suffering from IgA kidney inflammation. An investigational new drug application is in progress.
Joint Development Of Both New Blood Cells & Fat Cells Bode Well For Curbing Cancer, Obesity
The key physiological processes of angiogenesis - the growth of new blood cells - and adipogenesis - development and growth of fat cells - appear to be so closely interwoven that interfering with one process affects the other. Those findings, from researchers at Massachusetts General Hospital (MGH), could eventually help to solve problems ranging from cancer to obesity to the replacement of transplant organs.
Their report, released online Oct. 2, 2003, appears in Circulation Research. It is scheduled for print in the Oct. 31 issue.
"It really looks like angiogenesis and adipogenesis are joined at the hip," observed the article's senior author, tumor biologist Rakesh Jain at MGH. "These new findings are helping us to understand just how closely these processes work together and identify new ways of controlling these functions to meet important medical challenges."
A 2002 study from the laboratory of Judah Folkman, at Children's Hospital in Boston, found that when anti-angiogenesis agents were given to mice genetically programmed to incur obesity, the animals did not gain weight. The current MGH journal reveals the mechanism behind that interaction. The paper's title is "Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis." The co-authors began their research examining how fat-cell precursors (preadipocytes) grow into mature adipocytes (fat cells).
They first implanted normal preadipocytes beneath the skin of immune-deficient mice. As expected, the cells developed into mature fat cells. But not only did blood vessels extend to supply the growing tissue, they also formed efficient, organized networks - something that rarely happens outside of natural growth conditions. To block fat-cell differentiation, the co-authors implanted mice with preadipocytes that had an inactivated protein required for fat cells to mature. Not only did the implants neither grow nor mature, but there was virtually no blood vessel development. Similarly, introduction of an antibody against a protein key to angiogenesis prevented blood vessel development in the implants, and also kept the fat-cell precursors from maturing.
Detection Of Antibodies Identify Multiple Sclerosis Patients Who Don't Respond Well To Interferon
Danish research published in The Lancet, dated Oct. 11, 2003, highlights how the detection of antibodies to interferon-beta - used for multiple sclerosis (MS) patients - could be important in identifying those who do not respond well to the therapeutic. INF-beta is the first-line treatment for relapsing-remitting MS, but the drug can induce neutralizing antibodies against itself, which might reduce its effectiveness.
The co-authors, from Copenhagen University Hospital, measured neutralizing antibodies every year for up to five years among 541 patients with MS. Enrollment randomly selected all patients who started INF-beta in Denmark between 1996 and 1999. Their report in The Lancet bears the title "Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis."
The time to first relapse was substantially longer (by 244 days) for patients who were antibody negative after one year of interferon-beta treatment, compared with patients who were antibody positive. The yearly relapse rate increased more than 50 percent in subjects who were antibody positive.
"Our findings," the paper's lead author commented, "suggests that the presence of neutralizing antibodies against interferon beta reduces the clinical effect of the drug. In patients who are not doing well on INF-beta, the presence of such antibodies should prompt consideration about a change of treatment to other drug therapies such as glatiramer acetate or mitoxantrone."
Antibiotic Self-Resistance Mechanisms Contribute To Drug Resistance Among Pathogenic Bacteria
Like a bodyguard leaping in front of an assassin's bullet, a bacterial protein sacrifices itself to thwart its own deadly antibiotic. The finding reveals how some bacteria resist the toxins that they themselves produce for self protection against other microorganisms, as described in Science, dated Sept. 12, 2003. The title: "Resistance to Enediyne antitumor antibiotics by CalC self-sacrifice." Its co-authors studied a pathogen that produces an antibiotic, which destroys invaders by breaking up their DNA. They say it is the first example in which an antibiotic molecule and a protective protein are both destroyed to neutralize a bacterium's own chemical weapon.