Therapeutic potential of γ-secretase inhibitors and modulators

According to the beta-amyloid (A beta) hypothesis, compounds that inhibit gamma-secretase, the pivotal enzyme that generates A beta are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that gamma-secretase inhibitors, administered by the oral route, are able to lower brain A beta concentrations. However, scanty data are available on the effects of these compounds on brain A beta deposition after prolonged administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound (DAPT). gamma-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus and spleen in rodents. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Interestingly, some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate gamma-secretase and to selectively reduce beta-amyloid(1-42) (A beta 42) levels without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on A beta brain pathology and learning depend on their activity on gamma-secretase or on other biological targets. The first published clinical studies in healthy subjects and in AD patients with a gamma-secretase inhibitor, LY-450139, confirmed the dose-dependent inhibition of plasma A beta but evidenced a later rebound in A beta plasma levels and absence of a significant effect on cerebrospinal fluid A beta concentrations. Some observed gastrointestinal adverse events have raised concerns. Clinical studies with other potent gamma-secretase inhibitors will tell us if these pharmacodynamic and tolerability profiles observed in humans are typical of the pharmacological class or are compound-specific. Given the uncertain A beta reduction target and the potential for mechanism-based toxicity, it has been suggested that biomarkers for efficacy (cerebrospinal fluid A beta 42 levels) and toxicity (plasma adipsin levels) would be helpful in initial clinical trials with gamma-secretase inhibitors. A large ongoing Phase 3 study with (R)-flurbiprofen, a claimed selective A beta 42 lowering agent, will tell us if allosteric modulation of gamma-secretase is clinically effective.