BRNI Research
Target Identification and Drug Discovery
Bryostatin
Because the PKC memory pathway and some of its important protein targets are also important for Alzheimer's pathophysiology, identification of new molecular steps for memory storage enabled the Institute to identify and develop drug candidates to treat both the memory loss and neurodegeneration of Alzheimer's disease, as well as to identify a molecular biomarker to potentially diagnose the disease in its early stages (See Diagnostic Development). One such drug, bryostatin, previously tested in cancer patients, was found by BRNI scientists to enhance memory in several animal models, reduce Alzheimer's disease brain pathology in Alzheimer's mice, and markedly improve their survival. The drug stimulates the brain to produce the proteins needed to store long-term memories , and also reduce levels of the toxic protein A*1-42 found in the characteristic brain lesions of Alzheimer's. In studies even infrequent, low doses of the drug improved performance on tasks requiring long-term memory.
While pharmacological therapies are currently available to reduce the memory loss that occurs in the early stages of AD, they do not treat its underlying cause. Bryostatin is unique in its potential to improve memory while also preventing further disease progression. It does this by increasing the non-toxic soluble APP* and reducing levels of the toxic protein beta amyloid A*1-42, a component of the proliferating growths characteristic amyloid deposits in the brains of AD patients. Bryostatin may also help to extend the lives of patients by reducing neuronal deterioration.
Research on bryostatin as a treatment for AD continues at an accelerated pace at the Institute. BRNI is currently working on organizing an Investigational New Drug application to gain FDA approval to begin human clinical trials.
Carbonic Anhydrase Activators
Other drugs developed by BRNI scientists are based on targets identified within the memory and Alzheimer's disease molecular pathways. These include the carbonic anhydrase activators for enhancing attention that target GABA ergic synaptic transmission (Fig. 6). This new class of drugs is being developed to treat attention deficit disorder as well as to enhance attention-gated learning. Our scientists discovered these new drug modalities by first identifying critical molecular steps involved in brain functions such as attention and attention-gated learning and memory. One such step involves an enzyme called carbonic anhydrase that regulates GABA ergic synapses in the brain. Many years ago carbonic anhydrase regulation by phenylalanine was implicated in a genetic disease that causes mental retardation. This disease, phenylketonuria,
involves a class of molecules, phenylalanine compounds, that is now being developed at BRNI to enhance learning as well as to treat attention deficit disorder.
Target Identification Byrostatin
Alkon DL, Epstein H, Kuzirian A, Bennett, MC, Nelson T. Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning. Proc Natl Acad Sci USA 102(45): 16432-16437, 2005.
Sun MK, Alkon DL. Dual effects of bryostatin-1 on spatial memory and depression. Eur J Pharmacol. 512: 45-51, 2005.
Etcheberrigaray R, Tan M, Dewachter I, Kuiperi C, Van der Auwera I, Wera S, Qiao L, Bank B, Nelson TJ, Kozikowski AP, Van Leuven F, Alkon DL: Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc Natl Acad Sci USA 101(30): 11141-11146, 2004.
Target Identification Carbonic Anydrase
Sun MK, Nelson TJ, Xu H, Alkon DL: Calexcitin transformation of GABAergic synapses: from excitation filter to amplifier. Proc Natl Acad Sci USA 96:7023-7028, 1999.