Delivery of Cerebral Dopamine Neurotrophic Factor with Microbubbles and MRI-guided Focused Ultrasound (Supplement)

Promising Outcomes of Original Grant:
We achieved our key goal of non-invasive, targeted delivery of therapeutic doses of CDNF drug to the brain regions affected by Parkinson’s [striatum (ST) and substantia nigra (SN)] in pre-clinical models. We conjugated CDNF to clinically scalable microbubbles with high drug loading and stability. We showed that the drug’s potency to regenerate and protect neurons was unaffected by the microbubble conjugation in cell model bench testing. However, we only produced data with five models, found unexpected effects to the SN cells, and have yet to demonstrate that the drug is delivered throughout the ST and SN.

Objectives for Supplemental Investigation:           
Our goals:
a) Complete the original study design with sufficient models for statistical significance. We will demonstrate precision, non-invasive blood brain barrier (BBB) delivery of therapeutic doses of CDNF drug to the substantia nigra and striatum. 

b) Avoid effects to the neurons in the SN caused by the treatment.  We will optimize ultrasound intensities and duration to open the BBB exclusively in the SN and ST in a safe and reversible manner.

c) Establish the neuroprotective dose of CDNF microbubbles in an in vitro cell model of neurodegeneration. Cells will be challenged with a parkinsonian neurotoxin with/without CDNF microbubbles and the drug alone.

Importance of This Research for the Development of a New PD Therapy:      
Neurotrophic drugs like CDNF regenerate and protect brain cells damaged by PD but can’t penetrate the BBB. Direct needle or catheter delivery has limited clinical use. Noninvasive drug delivery for early-stage patients throughout the diseased regions may be critical to improving patient response. It would also reduce trauma. Our approach can serve as a platform for BBB delivery of a variety of PD drugs, including new viral gene therapies.