21 June 2001. The γ-secretase enzyme activity is a therapeutic
target in Alzheimer's disease. Yet its promise of lowering the Aβ42
burden has been under a cloud since1999, when Bart De Strooper and other
scientists found that the enzyme also cleaves Notch, a cell surface
receptor mediating cell fate decisions during development as well as in
adult self-renewing cells.
In the June 19 PNAS, researchers in Raphael Kopan's lab at Washington
University School of Medicine in St. Louis and others report that an
experimental γ-secretase inhibitor developed by coauthor Michael
Wolfe, now at Brigham and Women's Hospital in Boston, Massachusetts, impairs the
maturation of thymocytes, deepening earlier concerns that this approach
might cause immunodeficiency.
The scientists cultured fetal thymic lobes in 50 micromolar of the
inhibitor Cpd.11 and found T cell development arrested at two steps.
First, most immature thymocytes failed to progress from the early
CD4/CD8 double-negative stage to the intermediate CD4/CD8
double-positive stage. Second, when applied to CD4/CD8 double-positive
thymocytes, the inhibitor blocked the maturation of single-positive CD8
cells (the cytotoxic T cells.) Each lobe also contained 40 percent fewer
cells. Taken together, pharmacological γ-secretase inhibition
produced similar results to genetic manipulation of notch signaling.
The significance of thymocyte development in the elderly is unclear.
Conventional wisdom in immunology holds that most thymocyte maturation
occurs in children, yet recent studies in transplant patients and other
systems suggest that significant numbers of new T cells are being
generated during adulthood, possibly at sites other than the thymus.
Moreover, Notch has been implicated in the generation of red blood
cells, the myeloid lineage, and hematopoietic progenitors.
γ-secretase remains a target, says Kopan, especially if inhibitors
can be found that are more potent against APP than against
notch. Companies developing γ-secretase inhibitors could use this
assay to weed out candidate drugs preclinically, or the FDA could
require such testing, he adds.
Indeed, agrees Steven Paul of Eli Lilly and Company, industry scientists
have long known about this potential complication and are including such
testing in their research. A key question at this stage is whether the
therapeutic window between minimal interference with notch on the one
hand and clinically effective Aβ42 reduction on the other hand is big
enough for any of the current drugs to be safe and effective. γ-secretase programs are still being actively pursued at Lilly, Merck,
Bristol-Myers Squibb and elsewhere.-Gabrielle Strobel.
Reference:Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, Schroeter EH, Kopan R.
Gamma -secretase inhibitors repress thymocyte development. Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7487-91. Abstract