Delivery of Cerebral Dopamine Neurotrophic Factor with Microbubbles and MRI-guided Focused Ultrasound
Neurotrophic Factors Challenge, 2014
The research from this grant has continued with the supplementary grant:
- Delivery of Cerebral Dopamine Neurotrophic Factor with Microbubbles and MRI-guided Focused Ultrasound (Supplement)
Neurotrophic drugs regenerate and protect brain cells damaged by Parkinsonís disease, but canít penetrate the blood brain barrier (BBB). With direct needle or catheter drug delivery, an inadequate amount of the diseased region is treated. Focused ultrasound can precisely target brain regions and can use microbubbles to bend and stretch blood vessels, which safely and temporarily opens up the tight junctions that form the BBB, allowing for active drug delivery. We have a novel means to combine trophic drugs to microbubbles and demonstrate non-invasive, targeted delivery in pre-clinical models as a first step to clinical adoption.
We will combine cerebral dopamine neurotrophic factor (CDNF) with microbubbles (MBs) using an efficient, clinically scalable method and confirm CDNF bioactivity. CDNF-MBs will be injected intravenously into pre-clinical models. Magnetic resonance (MR)-guided focused ultrasound will target MBs to the substantia nigra and striatum to open the BBB in a safe, reversible, and repeatable manner. The ultrasound will then pop the MBs for noninvasive CDNF delivery. BBB openings will be confirmed in real time using MR, and damage to brain tissue and evaluation of pharmacokinetics (biodistribution) of CDNF in the brain will be assessed.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Focused ultrasound and drug-loaded microbubbles offer advantages for the delivery of trophic drugs over current methods: (i) non-invasive drug delivery to reduce patient trauma and risk, and treatment costs, and to broaden the treatable patient population; and (ii) precision targeting and drug delivery throughout the brain regions damaged by Parkinsonís (substantia nigra and striatum) to increase drug efficacy. CDNF is a promising trophic factor with efficacy in Parkinsonian models at substantially lower doses than GDNF and with better diffusion through brain tissue. CDNF-MBs and focused ultrasound treatment have the potential to halt and reverse disease progression.
We hope to demonstrate safe, precise, non-invasive delivery of therapeutic doses of CDNF to the substantia nigra and striatum in rodent models. CDNF pharmacokinetics (biodistribution) and delivery efficiency (delivered versus administered drug) will be assessed to guide clinical scale up.
Artenga and collaborators combined a trophic drug to microbubbles (MBs) and used focused ultrasound (FUS) to non-invasively deliver the drug through the blood brain barrier (BBB) with precise targeting to Parkinsonís disease (PD)-affected brain regions. Our clinically scalable technology demonstrated adjustable, high drug loading on MBs while maintaining the drugís potency.
Trophic drugs such as CDNF repair and protect dopamine nerve cells damaged by PD but cannot penetrate the BBB and must be administered with direct delivery. Our non-invasive delivery will permit treatment in early stage PD patients who have a greater number of dopamine nerve cells available to regenerate. Non-invasive, targeted BBB drug delivery using MBs and FUS could be used with a variety of PD drugs and adapted to other CNS disorders.
CEO at Artenga, Inc.
Location: Ottawa, Ontario, Canada
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