Sep. 29, 2011

New Experimental Molecule Neutralizes Lupus Autoantibodies

Generation of a unique small molecule peptidomimetic that neutralizes lupus autoantibody activity.
Bloom O, Cheng KF, He M, Papatheodorou A, Volpe BT, Diamond B, Al-Abed Y. (2011).  Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10255-9. Epub 2011 Jun 6.

What is the topic?

Lupus in humans and animals is marked by production of autoantibodies (antibodies against one’s self) that can cause inflammation, as well as damage components of cells (such as double-stranded DNA or cardiolipin) of one’s own body. In particular, antibodies to double-stranded DNA (ds-DNA) contribute to organ damage. For years, researchers have investigated the possibility of inhibiting the actions of lupus-related autoantibodies to reduce the extent of such damage. Further research in this area has the potential to facilitate the development of new therapies for people with lupus. Typically, such research is first tested on animals to ensure efficacy and safety before being conducted in humans.

What did the researchers hope to learn?

The researchers hoped to learn about the potential efficacy of a newly designed small molecule, called “FISLE-42,” in inhibiting the attachment of lupus-related autoantibodies (from different sources, such as humans or mice) to ds-DNA, kidney, or brain cells from mice. FISLE-42 was made to mimic the structure and activity of a previously identified small molecule, called “D-DWEYS,” which inhibits lupus-related autoantibodies in mice when injected directly into the body, but is ineffective when taken by mouth. 

Who was studied?

The subjects were adult male C57BL /6 mice. These mice are very commonly used in research and do not spontaneously develop lupus. 

How was the study conducted?

The researchers synthesized a new small molecule, called FISLE-412, at the Laboratory of Medicinal Chemistry at The Feinstein Institute for Medical Research in Manhasset, New York. This molecule was tested for its ability to inhibit lupus-related autoantibody attachment to ds-DNA isolated from mice, as well as to components of kidneys extracted from mice, and to living brain cells of mice. 

What did the researchers find?

The researchers found that FISLE-42 inhibits the attachment of multiple kinds of lupus autoantibodies to ds- DNA and cardiolipin (an important component of cells) isolated from mice. Interestingly, the greater amount of FISLE-42 that was added to mouse ds-DNA, the less lupus autoantibodies were able to bind to it (an effect known as “dose-dependence”). In addition, FISLE-42 inhibited attachment of lupus autoantibodies to ds-DNA taken from blood of human lupus patients. Importantly, FISLE-42 did not inhibit attachment of lupus autoantibodies to cellular components not typically implicated in lupus disease activity. 

When FISLE-42 was added to components of kidneys removed from mice, multiple kinds of lupus autoantibodies were much less able to bind to the mouse kidney parts. In addition, FISLE-42 reduced the attachment of lupus autoantibodies obtained from human lupus patients to the mouse kidney components to varying degrees. 

Also, when FISLE-42 was added to components of brain cells (part of the “hippocampus” - a portion of the brain important for learning and memory, and which is affected in people with lupus), FISLE-42 completely blocked the ability of lupus autoantibodies to cause death of these brain cells. 

What were the limitations of the study?

Currently, it is unknown whether FISLE-42 can be as effective if given by mouth to either animals or humans. Also, it is unknown whether oral administration of FISLE-42 will in itself elicit antibodies that are potentially damaging to cells of animals or humans. 

What do the results means for you?

These studies demonstrate that FISLE-42 can inhibit the potentially damaging actions of a number of different lupus-related autoantibodies – both in mice and humans. Importantly, these studies suggest that even blocking the actions of only a portion of lupus-related autoantibodies can be effective in combating lupus disease activity. As noted by the authors, these studies provide hope for the development of more specific, less toxic therapies for lupus. However, much more animal research is needed before this molecule can be tested in living humans with lupus.

 


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