Research Lectures at Nobel Forum
September 12, 2019, 16.00
Gilla Kaplan, Consultant, Gates Medical Research Institute, Honorary Prof. University of Cape Town
Venue: Nobel Forum, Nobels väg 1
Host: Professor Birgitta Henriques Normark Department of Microbiology, Tumor and Cell Biology
Title: Thalidomide re-purposed then reinvented: The road less traveled immune modulation in leprosy and tuberculosis
Thalidomide (a-N-phthalimido-glutarimide), synthesized in 1956, was marketed as a safe, potent, nonbarbiturate sleep inducing sedative, and used as an anti-emetic to quell morning sickness of first trimester pregnancy. In November 1961 the drug was removed from the market following reports of catastrophic fetal abnormalities. While still available, thalidomide was found to resolve the pathological manifestations of the acute reactional state of lepromatous leprosy, erythema nodosum leprosum (ENL), characterized by a painful vasculitic rash, fever, muscle and joint pain, malaise, lymphadenopathy, weight loss and progressive peripheral neuropathy. Thalidomide became the treatment of choice for ENL, in the absence of an understanding of the cause of the development of the reactional state or the mechanism of action of the drug.
To understand the factors involved in the development of ENL we set out to determine how thalidomide interrupted the ENL process using in vitro models of leukocyte function. In 1991, the drug was found to decrease TNF- production by LPS stimulated monocytes in vitro in a dose dependent and selective manner. Other cytokines including IL-1and IL-6 were unaffected. We then showed that the drug reduced the high levels of TNF- in Patient with ENL while reversing the clinical signs and symptoms of the reactional state. Thalidomide was next shown to reduce TNF- in patients with tuberculosis with and without HIV-1 infection, thereby reversing the wasting and inflammatory reactions in both diseases, as well as reducing the viral load in patient with HIV infection. The activity of the drug in TNF- induced diseases including graft-versus host disease, sarcoidosis, scleroderma, LPS induced shock and other acute and chronic inflammatory diseases was evaluated and confirmed.
In order to obtain drugs with increased anti-TNF- activity and reduced or absent toxicities, novel TNF- inhibitors were designed using thalidomide as a template. Molecules with up to 50,000-fold increased anti-TNF- activity and two different modes of action were identified in 1996. One class of drugs, shown to be non-teratogenic and safe to use potent phosphodiesterase 4 inhibitors (PDE4i), were identified and developed for preclinical testing followed by clinical evaluation. The selected PDE4i, when combined with antibiotic treatment of mice and rabbits with pulmonary tuberculosis or tuberculous meningitis, were shown to reduce disease pathology and accelerate mycobacterial clearance from the infected tissues. CC11050, one of the most potent PDE4i, is currently undergoing testing as a host directed therapy to improve treatment of pulmonary TB and to reverse the pathogenesis of ENL in leprosy patients. The results of these studies and their potential therapeutic impact will be discussed.