Alzheimer's disease (AD) is the most common neurodegenerative disorder, afflicting 5 million people in the U.S. alone. This U grant application will support studies leading to the filing of an Investigational New Drug (IND) application to the FDA for Brain-Derived Neurotrophic Factor (BDNF) gene delivery in AD. We have completed proof-of-concept studies in mice, rats and non-human primates, demonstrating that BDNF prevents entorhinal cortical neuronal cell loss, enhances synaptic markers, reverses molecular and biochemical features associated with AD, and improves learning and memory. These effects extend into the hippocampus, thereby treating key memory circuitry of the brain. Importantly, this approach provides a much-needed alternative to amyloid-modifying therapeutics currently under development, providing future possibilities for combined therapies if both prove to be partly effective. We propose gene delivery of BDNF because of the need to administer this protein directly into the brain and sustain its delivery over time. In the proposed work plan, we will manufacture adeno-associated virus serotype 2 (AAV2) vectors expressing human BDNF at a GMP facility, then use this clinical-grade material to perform IND-enabling studies in two species (rat and primates). In addition, we will generate expertise in accurately targeting and delivering AAV2-BDNF to the primate entorhinal cortex using real-time, MR-guided imaging. The following aims will be performed:
Aim 1 : Produce AAV2-BDNF for IND-enabling safety/toxicity/dosing studies.
Aim 2 : Optimize AAV2-BDNF gene delivery to the entorhinal cortex in non-human primates using convection-enhanced delivery and real-time MR guidance.
Aim 3 : Safety/toxicity/dosing/biodistribution studies in rodents and non-human primates.
Aim 4 : Draft and Submit an IND Application. Relevance: Successful completion of this work will lead to clinical translation of a new approach to prevent cell loss and stimulate neural function in a common, severe and disabling neurodegenerative disorder.

Public Health Relevance

Alzheimer's disease is the most common neurodegenerative disease, afflicting over 5 million people in the United States, and costs of treatment exceed $170 billion annually: accordingly, new and effective therapies are needed to slow this disorder and improve cognitive function. Studies have shown that the nervous system growth factor Brain-Derived Neurotrophic Factor (BDNF) can prevent neuronal death and stimulate function. Work proposed in this study will perform dosing and safety studies that, if successful, will lead to the filing of an application to test BDNF gene delivery in patients with Alzheimer's disease. DISCLAIMER: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus, the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZAG1-ZIJ-6 (M1))
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Refolo, Lorenzo
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Nagahara, Alan H; Wilson, Bayard R; Ivasyk, Iryna et al. (2018) MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther 25:104-114
Biane, Jeremy S; Takashima, Yoshio; Scanziani, Massimo et al. (2016) Thalamocortical Projections onto Behaviorally Relevant Neurons Exhibit Plasticity during Adult Motor Learning. Neuron 89:1173-1179
Tuszynski, Mark H; Yang, Jennifer H; Barba, David et al. (2015) Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol 72:1139-47
Nagahara, Alan H; Mateling, Michael; Kovacs, Imre et al. (2013) Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci 33:15596-602