Alzheimer's Disease

Our Research

All of our projects depend on the creation and advancement of direct infusion of drugs and therapies into the brain. We have developed a technique in which lipid-like nanoparticles and other therapeutic agents can be infused directly into brain tumors to give enhanced drug efficacy with reduced side effects. For many years, and continuing still, we have been working on development of direct drug delivery into the brain including cell transplantation, gene transfer and growth factor infusions for Parkinson's disease. Through gene therapy, we are working to eliminate this inherited lipid storage disorder by restoring the activity of the gene responsible for Niemann-Pick disease, acid sphingomyelinase. Add description. Using our image-guided delivery techniques AADC activity in the brain, important in the synthesis of several neurotransmitters, may be restored by gene therapy in patients lacking the gene for AADC.

Monkey Brain with AADC expressionA 3D reconstruction of the entorhinal cortex (EC, blue) and other anatomical targets. Lines represent the temporal (green) and occipital (orange) approaches in humans compared with a more feasible route modeled in nonhuman primates.

Monkey Brain with AADC expressionThis panel shows 3D reconstruction of the EC and its location in the coronal (upper right), axial (lower right), and sagittal (lower left) planes superimposed on MR images of the brain. Line (purple) represents our proposed infusion route for brain modeling.

How do we see Alzheimer's Disease?

Alzheimer's disease (AD) is a common and tragic neurodegenerative disorder. There is a great need to develop novel and effective treatments to slow AD progression. Over the last 5 years we have tested the hypothesis that BDNF prevents the death and stimulates the function of cortical neurons that degenerate in AD. Results demonstrate that BDNF prevents entorhinal cortical neuronal cell loss, enhances synaptic markers, reverses molecular and biochemical features associated with AD, and improves learning and memory in various rodent and non-human primate models.

Our Project

In the early stages of Alzheimer's disease (AD), the brain pathology develops initially in the entorhinal cortex and progresses to other anatomical regions. Our previous findings demonstrate that delivery of brain derived neurotrophic factor (BDNF) *link* to the entorhinal cortex in different models of AD improves learning and memory, increases synapses, improves signaling and prevents neuronal death. A major goal of this translational program is to accurately administer BDNF to the entorhinal cortex using methods of gene delivery. We have developed real-time MR imaging and co-infusion of gadoteridol *link* to accurately target and distribute BDNF gene delivery into the entorhinal cortex of non-human primates, in preparation for human clinical trials. This work is supported by a grant from the National Institutes of Health.

Why gene therapy for BDNF administration?

Growth factors are relatively large and moderately charged proteins that do not cross the BBB. To reach the brain, they must be administered centrally. However, if growth factors are broadly distributed in the nervous system, they are not tolerated due to off-target adverse effects that include weight loss, pain and dysesthesias, and Schwann cell proliferation in the subpial space. Thus, they must be targeted to regions of degenerating neurons without broader CNS distribution. Moreover, in a chronic neurodegenerative disorder, growth factor treatment would need to continue for years. These requirements of central administration and regionally restricted delivery of sustained duration are met by gene delivery. Using current generations of gene therapy vectors, delivery can be regionally introduced and sustained over years; there is no apparent loss of expression, no detectable immune response in the brain, and no apparent toxicity.

Brain-derived neurotrophic factor (BDNF) is a hormone-like molecule in the brain that increases the survival and health of nerve cells. Several studies have shown that BDNF reduces nerve cell death, improves nerve cell function and improves cognitive function in animal models of Alzheimer's disease. Recent studies have shown that delivery of the BDNF gene to the brain can achieve the same results in animal models.

Our team collaborates with UCSD’s Dr. Mark H. Tuszynski on work of delivering the BDNF gene to the brain in animal models. We have proposed a study designed to pave the way for clinical trials of BDNF gene therapy in humans. For the current grant, our team develops techniques for using magnetic resonance imaging (MRI) to guide the delivery of the BDNF gene to the regions of the brain in non-human primates where it is expected to be effective. Those regions are the entorhinal cortex and hippocampus, the regions affected in the earliest stages of Alzheimer's disease.