There were three major areas of Dr. Weiss’ research activities:
- Studies on the isolation, regulation, and inhibition of the multiple molecular forms of cyclic nucleotide phosphodiesterase isozymes;
- Studies on antisense oligonucleotides and antisense RNA; and
- Studies on the regulation of the adrenergic receptor-linked adenylate cyclase system.
Cyclic nucleotide phosphodiesterases
Dr. Weiss and co-workers developed rapid phosphodiesterase assays, separated different isozymes of phosphodiesterase in various tissues by electrophoretic methods and showed that drugs could selectively inhibit several isozymes of phosphodiesterase. His laboratory showed that a single cell type may contain more than one form of phosphodiesterase; different forms of phosphodiesterase could be induced or activated by certain neurohormones (e.g. norepinephrine) and intracellular proteins (e.g. calmodulin); and that there are different forms of phosphodiesterase in different tissues including the mammalian brain and lung.
His studies on the inhibition of the multiple molecular forms of phosphodiesterase have provided the basis for the development of many commercially marketed drugs and experimental drugs across several therapeutic areas that have as their mechanism of action the selective inhibition of one or more isozymes of phosphodiesterase, including drugs for cardiac failure, asthma, stroke, psoriasis, erectile dysfunction and schizophrenia.
Antisense oligonucleotides and antisense RNA
In related studies, Dr. Weiss’ laboratory made discoveries on: 1) The role of calmodulin in neuronal differentiation and proliferation; 2) Behavioral and biochemical correlates of dopamine responses in brain; 3) Development of antisense oligonucleotides and antisense RNA as pharmacological tools to study calmodulin and dopamine receptors, and as pharmacological agents for gene therapy in brain; and 4) Reversal of dopaminergic supersensitivity: preclinical mechanisms and clinical applications.
These studies laid the foundation for the therapeutic use of antisense oligonucleotides and antisense RNA in a variety of disease states. More recent clinical studies by many others have produced new types of antisense treatments, and several drugs are currently on the market and many others are in clinical development using the concept of antisense therapy, including in cancer, Huntington’s disease and other neurological diseases.
Modulation of adrenergic receptor-linked adenylate cyclase system
Using the pineal gland as a model, Dr. Weiss and colleagues were the first to show that the beta-adrenergic receptor-linked adenylate cyclase system is modified chronically by a variety of physiological factors and pharmacological perturbations. These studies show that long-term changes that occur following physiological or pharmacological alterations in adrenergic input may be explained by a common biological principle: that is, the degree to which an adrenergic-innervated structure can be stimulated is inversely related to the degree to which it had been previously stimulated. This hypothesis may provide a biochemical basis for explaining the altered responsiveness of the adrenergic system seen in aging and in males vs. females and may explain the mechanism for drug supersensitivity and drug tolerance.