sc-rAAV8 via Lumbar Puncture as Spinal Analgesic Drug Delivery Systems

Project: Research project

Description

DESCRIPTION (provided by applicant): Lumbar puncture (LP) is an attractive route for delivering novel therapies to the nervous system because it is safe in patients;performed at the bedside;and FDA-approved for conventional drugs. However, its use for gene delivery has to date been ineffective;has not met safety principles;and has failed to target neurons. We have developed highly effective gene transfer to the primary sensory neurons of the dorsal root ganglia (DRGs) via LP, i.e. intrathecally (IT), using self-complementary recombinant adeno-associated virus serotype 8 (sc-rAAV8). A single administration of sc-rAAV8 expressing the analgesic gene prepro- -endorphin (pp EP) or a mutant form of the rat anti- inflammatory gene interleukin-10 (rIL10/F129S) led to highly significant (p$100 billion/year in the US alone (as stated in PA-07-282). This application proposes a gene therapy approach, which, if the Research Plan succeeds, will become a candidate for clinical development in patients with severe pain from advanced malignancies. IT sc-rAAV8 may serve as a tool for proof-of-mechanism trials, e.g. to validate microglial activation as therapeutic target in humans, and may also become a new drug for otherwise intractable chronic pain. Public Health Relevance: Chronic pain affects 50 million Americans and incurs costs of >$100 billion/year in the US alone (as stated in PA-07-282). Spinal tap is an attractive route for delivering novel therapies to the nervous system for a variety of diseases but particularly for pain. The reason is that the spinal cord functions as a "pain gate" able to open wide and thereby to facilitate pain signal transfer or to "close" and thereby control pain. A spinal tap is is safe in patients;performed at the bedside;and FDA-approved for conventional drugs. We have developed a gene therapy method administering new gene vectors by spinal tap, which control pain. Specifically, we find in a rat model that a severe type of pain, chronic neuropathic pain can be controlled for >3 months by our approach. In the research proposed in this application, we wish to study and improve our approach further in order to evaluate, whether it is a viable treatment approach for future development for human use with a special focus on severe pain from advanced cancer.
StatusFinished
Effective start/end date2/16/0910/31/15

Funding

  • National Institutes of Health: $422,134.00
  • National Institutes of Health: $341,265.00
  • National Institutes of Health: $409,705.00
  • National Institutes of Health: $437,372.00
  • National Institutes of Health: $441,991.00

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Dependovirus
Spinal Puncture
Drug Delivery Systems
Analgesics
Pain
Genes
Chronic Pain
Genetic Therapy
Endorphins
Pharmaceutical Preparations
Intractable Pain
Spinal Ganglia
Nervous System
Interleukin-10
Therapeutics
Serogroup
Research
Anti-Inflammatory Agents
Human Development
Neuralgia

ASJC

  • Medicine(all)
  • Neuroscience(all)