Glioblastoma (GBM) is the most common primary brain tumor and it is rapidly and uniformly fatal due in large part to its highly invasive nature. Aggressive therapy involves resection followed by radiation and chemotherapy, but median survival even with the most aggressive therapy is still less than 20 months. New approaches are desperately needed. An effective GBM gene therapy is attractive since numerous powerful genetic targets have been recently identified, yet clinical trials have failed to provide meaningful benefit thus far. New methods to overcome long-standing barriers to effective gene delivery throughout brain tumors are needed, including to the highly invasive tumor front that cannot be completely resected and where the blood brain barrier remains intact. We propose a new approach that takes advantage of: (i) image-guidance to focus the delivery of intravenously-administered biodegradable DNA-loaded nanoparticles (DNA NP) to all areas of the tumor, (ii) advanced image-guided focused ultrasound techniques to overcome the blood brain barrier (BBB) and enhance DNA NP delivery into the tissues and cells, (iii) DNA NP made of biodegradable polymers that are highly effective in vivo, including the capability to rapidly spread within the brain tissue that may allow them to more effectively reach cells within the tumors, and (iv) tumor-specific promoters that eliminate transgene expression in off-target tissues. This approach will allow repeated dosing in a minimally invasive manner (only i.v. injection) into the brains of patients to help control or potentially cure GBM. We will test the hypothesis that the combination of: image-guided gene delivery to the entire tumor, inclusive of the invasive tumor front, using focused ultrasound techniques, small (~50 nm) and highly stable DNA NP capable of rapidly penetrating brain tumor tissues and providing high in vivo transfection, and an additional degree of control provided by a tumor-specific gene expression promoter, will provide safe and effective GBM gene therapy in animals that can be reapplied as needed to treat the disease. If successful, the proposed approach could be translated to the clinic rapidly using widely-tested suicide genes (as will be studied here) while additional preclinical studies are performed to test the effectiveness of therapies directed to new promising genetic targets in GBM. The approach could also be applied to other neurological disorders in the future, such as Parkinson's disease.

Public Health Relevance

An effective gene therapy for glioblastoma multiforme (GBM) has yet to be realized due to difficulty in overcoming the blood brain barrier (BBB) as well as achieving widespread and efficient gene transfer to invasive GBM tumor cells in the brain. We propose to develop unique DNA delivery systems in conjunction with transient disruption of BBB by focused ultrasound that allow tumor-selective gene transfer with unprecedented penetration of therapy throughout the brain. Success in this project should lead to a human clinical trial for brain tumor patients, and the approach could also be used with numerous exciting therapeutic genes for brain cancer and potentially other highly disseminated neurological disorders, such as Parkinson's disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Gene and Drug Delivery Systems Study Section (GDD)
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Salomon, Rachelle
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Johns Hopkins University
Schools of Medicine
United States
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Mastorakos, Panagiotis; Zhang, Clark; Song, Eric et al. (2017) Biodegradable brain-penetrating DNA nanocomplexes and their use to treat malignant brain tumors. J Control Release 262:37-46
Mead, Brian P; Kim, Namho; Miller, G Wilson et al. (2017) Novel Focused Ultrasound Gene Therapy Approach Noninvasively Restores Dopaminergic Neuron Function in a Rat Parkinson's Disease Model. Nano Lett 17:3533-3542
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Berry, Sneha; Mastorakos, Panagiotis; Zhang, Clark et al. (2016) Enhancing Intracranial Delivery of Clinically Relevant Non-viral Gene Vectors. RSC Adv 48:41665-41674