Jan. 28, 2010 - A ghostly "suicide" drug wafts into immune cells in joints,
making the cells self-destruct and reducing rheumatoid
arthritis in mice.
The drug, technically a BH3 mimetic dubbed TAT-BH3, is a man-made molecule.
One part of the molecule lets it drift through cell walls. The other part
mimics a chemical signal missing in the macrophage immune cells that build up
inside joints afflicted by rheumatoid arthritis (RA).
Because they are missing this signal, macrophages in RA joints don't die off
as they are supposed to do. They live on, destroying bone and inflaming the
joint, says Harris Perlman, PhD, associate professor of medicine at Chicago's
Northwestern University Feinberg School of Medicine.
"In RA, there is this persistent inflammation that never shuts down. Part of
the reason is these macrophages are missing a protein they need to die off,"
Perlman tells WebMD. "So this drug says OK, let's replace this protein. Let's
bring back the death pathway."
Perhaps because normal cells aren't clinging to life like the zombie
macrophages involved in RA, the drug doesn't kill normal macrophages. The
drug was not toxic to mice.
But in mice with RA,
injections of TAT-BH3 cut bone erosion by as much as 39% and thinned the
too-thick lining of the joint by up to 34%.
Perlman says that by hitting it's Bim-protein target, TAT-BH3 has
therapeutic effects that go beyond just killing macrophages.
"This drug does far more than cause cell death," he says. "We
think this Bim protein has multiple functions and may be a great target for
Perlman's team and others are making their molecule more appropriate for
human treatment. One approach they are trying is to use tiny nanoparticles to
speed the BH3 mimetic through cell walls. Much work remains before their drug
prototype is ready for human studies.
Other BH3 mimetics, with targets different from the so-called Bim protein
that is the focus of the Perlman study, are being developed as cancer treatments. Some already
are showing promising results in clinical trials.
The Perlman study appears in the February issue of Arthritis &