Gelsolin: Another Potential Therapy for CF Sputum!

by Thomas P. Stossel, M.D.

Fall 1994

[Note: Figures are not available in online format.]

A twenty-year-long research project with no apparent relationship to cystic fibrosis may have led to a new and unexpected therapeutic agent for the disease. It has long been believed that long stringy strands of DNA released by dying white blood cells that appear in huge numbers in the airways of CF patients are an important contributor to the stickiness and rigidity of airway secretions. But how did those white blood cells move there in the first place? My colleagues and I have worked on that question for many years.

The white blood cells actively crawl into the airways. This crawling depends on remodeling another set of long stringy fibers composed of assemblies of a protein called actin that invests the inside surface of the cells. The actin fibers are chains of individual subunits, called monomers, arranged like beads on a string. In 1979 we discovered a cellular protein called gelsolin that participates in the remodeling of cellular actin by cutting the long actin filaments at random points between the beads on the strings into shorter bits (see Figure 1). Since long actin filaments entangled together form a structure like a sponge, defined by chemists as a "gel," this cutting action disentangles the actin filaments and dissolves the gel to a liquid or "sol," which is why we named the protein gelsolin.

When we learned a couple of years ago that Genentech scientists were promoting DNase I as a therapy for CF, we were aware that in addition to being an enzyme that degrades DNA, DNase I could also shorten long actin filaments by slowly removing the individual subunit molecules, the beads, from the filament ends (see Figure 1). Actin is present in white blood cells in large amounts, in quantities as great or greater than DNA. We therefore asked three questions:

  1. could actin filaments released from white blood cells be contributing to the stiffness, the "gel"-like consistency of CF sputum?
  2. could DNase I be working in part by shortening actin filaments? and
  3. might gelsolin work to loosen the toughness of CF sputum by severing actin filaments contained in it?

In a paper reported in Science (February 1994), we reported affirmative answers to questions one and three; question two is not yet resolved. In particular, gelsolin seemed to be as good or better than DNase I in diminishing the viscosity of CF sputum (see Figure 2); there was also some evidence to suggest that gelsolin and DNase might have cumulative effects, which make sense in that the two compounds have different ways of shortening actin filaments (see Figure 1).

Gelsolin is an attractive candidate as a mucolytic agent, because it turns out that in addition to being a component of cells, gelsolin circulates in extracellular fluids, presumably to cut up actin filaments released from broken cells. Therefore, human gelsolin instilled into an airway is unlikely to pose problems of toxicity. We had cloned the gelsolin gene some years ago and had shown that gelsolin can be synthesized by recombinant DNA technology.

Currently Biogen, Inc., a major biotechnology firm in Cambridge, Massachusetts, has taken on the task of producing sufficient quantities of human gelsolin and preparing it in suitable form for clinical trials. In the meantime, my colleagues and I have initiated a project dedicated to understanding how actin and DNA interact in CF sputum to influence its properties and to develop techniques for directly visualizing effects of DNase I, gelsolin and other mucolytic agents on the sputum structure.

Should gelsolin turn out to be a useful therapy, it will be a testimony to the value of basic science and clinical medicine working together. More importantly, it will be an example of how taking the long view in research support can pay off. For 20 years the National Institutes of Health (NIH), specifically the Pulmonary Branch of the National Heart Lung and Blood Institute, supported our work on cell crawling without any idea that it might lead to a treatment for CF.

Editor's Note: Thomas P. Stossel, M.D. is a Senior Physician in the Hematology-Oncology and Experimental Medicine Divisions at Brigham & Women's Hospital, and Professor of Medicine at Harvard Medical School, Boston, Massachusetts. For additional information on how to support NIH research funding see Stossel's article "Beyond CFRI: Research Funding and the National Institutes of Health" in this issue.

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