Drug discovery efforts in AD at P2D Biosciences focus on a disease-modifying therapeutic approach that targets the neuroinflammatory response to elevated levels of cytokines such as TNF-a and IL-1, believed to underlie neuronal loss in Alzheimer’s disease. S. Prasad Gabbita, Ph.D., vp R&D at P2D Biosciences, gave a talk entitled, “Small Molecular TNF-Alpha Inhibitors for Alzheimer’s Disease.”
Postmortem evidence has shown that TNF-a levels are elevated in the brain, cerebrospinal fluid, and serum of patients with AD. Preclinical study results support a role for TNF-a in neurodegeneration.
Dr. Gabbita pointed to findings from three separate studies completed during the past 12 months: one showed TNF-a to be a critical signaling mediator in the development of synaptic deficit and cognitive impairment in an Abeta mouse model; another study demonstrated improved function of brain vasculature resulting in decreased hippocampal neuronal loss following administration of thalidomide, a TNF-a inhibitor.
The third study, in an Abeta-induced impairment model, produced evidence that thalidomide could enhance learning ability and memory in mice.
“We are developing compounds that are up to 70-fold stronger inhibitors than thalidomide,” explained Dr. Gabbita. “We have identified four lead compounds and are now focused on modifying these small molecules to improve their ability to cross the blood brain barrier and to optimize their toxicity profile.”
The company plans to test these compounds in two AD models, one created by direct delivery of Abeta into the mouse brain and the other a transgenic mouse model.
“When the first signs of probable AD appear, a significant number of neurons in the temporal cortex and hippocampal regions of the brain have already died, and this is irreversible,” stated Ajay Gupta, Ph.D., chairman and CEO of Osta Biotechnologies. Osta is developing a novel class of drugs based on the inhibition heme-oxygenase-1 (HO-1) protein, a stress protein that catabolize heme to biliverdin, free iron, and carbon monoxide. The HO-1 gene is “exquisitely sensitive” to oxidative stress and is induced in brain and other tissues in disease and trauma, according to Dr. Gupta.
Hyman Schipper, M.D., Ph.D., professor of neurology and medicine at McGill University has demonstrated that HO-1 protein is significantly overexpressed in AD-affected temporal cortex and hippocampus compared to control brain tissue. Furthermore, HO-1 upregulation by transient transfection of the human HO-1 gene or by stimulation of endogenous HO-1 expression promotes intracellular oxidative stress, increased mitochondrial permeability, and iron deposition in the mitochondria.
Dr. Schipper’s work has also shown that gial iron sequestration makes cocultured neurons increasingly sensitive to oxidative injury.
Dr. Schipper and Dr. Gupta believe that the induction of the astroglial HO-1 gene may constitute a “common pathway leading to pathological brain iron deposition, intracellular oxidative damage, and bioenergetic failure in AD and other human CNS disorders.” Targeting HO-1, however, could provide an early therapeutic intervention for the treatment of AD.
In a talk entitled, “Suppression of Glial HO-1 Activity as a Potential Neurotherapeutic Intervention in AD,” Dr. Schipper described the efforts under way at Osta to develop a potent, brain-permeable small molecule inhibitor of HO-1 that does not affect HO-2, a noninducible form of HO involved in cellular housekeeping activities and is important in neuroprotection.
Osta has demonstrated that overexpression of HO-1 in cultured astrocytes can damage nearby neurons, resulting in cell death. Osta has also shown that its small molecule HO-1 inhibitors are selective and potent and can attenuate oxidative damage to the glia over expressing HO-1.
At therapeutic doses of up to 100 mg/kg/day, the company’s lead HO-1 inhibitor did not cause any significant toxicity in mice. Osta, in collaboration with Walter Szarek, Ph.D., at Queen’s University (Kingston, Ontario), has designed and synthesized about 200 analogs of these HO-1 inhibitors and is now studying their pharmacokinetic and pharmacodynamic properties.