by Sharena Rice, contributing editor and James Cavuoto, editor
February 2023 issue, BioElectRx Business Report
February 28, 2023 | One of the fundamental challenges impacting the pharmaceutical industry’s growth in the CNS market is the difficulty in getting drugs to penetrate the blood-brain barrier. Two early-stage firms, Cerebral Therapeutics and Kurve Therapeutics, are pursuing novel technologies to circumvent this limitation.
Kurve’s controlled particle dispersion technology exploits the nasal cavities at alternative drug delivery mechanism. The firm’s “nose to brain” approach bypasses the BBB, using the olfactory bulb and cruciform plate. “The BBB does a very good job of keeping pathogens out of the brain,” said Marc Giroux, Kurve’s CEO. “But it also keeps out the medications you actually want to get in there.” In preliminary studies, Kurve’s technology has been shown to deliver up to 30 times more medication directly to the brain than infusions.
Cerebral’s approach to targeted brain drug delivery focuses on the intracerebroventricular route of administration. The company’s initial clinical program uses an implanted refillable catheter and pump system to deliver a continuous intracerebroventricular dose of a proprietary formulation of the anti-epileptic drug valproic acid. An optimal dose is delivered directly into the area of the brain responsible for seizure initiation and propagation. Cerebral recently reported preliminary clinical proof of concept data from a Phase 2a clinical trial demonstrating that epilepsy patients who failed multiple oral medications experienced significant and sustained reductions in seizure frequency and severity.
Yet another new approach from Korean investigators involves piezoelectric nanoparticles that can produce nitric oxide and generate direct current under high-intensity focused ultrasound. These nanoparticles can be systemically administered intravenously, rather than injected into the brain itself. They cross the BBB and accumulate in the brain parenchyma, where they can stimulate the release of dopamine by dopaminergic neurons. Although the nanoparticles accumulate in the brain, they are cleared from the other major organs over the span of 60 days.
In their recent study, “Deep brain stimulation by blood– brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound” published in Nature Biomedical Engineering, researchers from Pohang University of Science and Technology investigated the efficacy of this approach in a mouse model of Parkinson’s disease. The results showed that the ultrasound-responsive nanoparticles were able to alleviate the symptoms of Parkinson’s without causing overt toxicity. The release of nitric oxide temporarily disrupted the tight junctions in the blood-brain barrier, allowing the nanoparticles to accumulate in the brain parenchyma. The piezoelectrically induced output current then stimulated the release of dopamine by dopaminergic neurons, leading to an improvement in the symptoms of Parkinson’s disease.
According to Hyun Jin Kim, a co-author of this study, the group considered transportation across the blood brain barrier using nitric oxide, as well as how calcium influx is induced using piezoelectric effects by ultrasound stimulation on the cell. “We estimated the possibility of breaking the blood brain barrier obstacles and neural stimulation by combining piezoelectric and nitric oxide donor nanoparticles.”
They realized that nanoparticles may be used for neural stimulation.
Focused ultrasound has gained traction for its potential in neuromodulation, including for Parkinson’s disease. Focused ultrasound without the use of piezoelectric nanoparticles has been probed for the physical improvement of symptoms, but the nanoparticles have the potential to be linked with specific antibodies for greater precision in targeting cell types of interest using focused ultrasound.
For further development of medical applications, Kim thinks adequately modified piezo receptors, such as with a selective response to a distinct frequency range, would be great partners for local stimulation with focused ultrasound. This would give more options for changing neural activity in different ways. They believe the combination of antibody conjugate piezo-nano particles and piezo receptors would help improve the precision of treatments, as the particles and receptors are engineered for specificity to each other.
Using piezoelectric nanoparticles for neuromodulation may have potential to improve human lives if the techniques are further refined for safety and efficacy in animal studies. The non-surgical nature of this approach, combined with its ability to stimulate deep tissue in the brain, makes it a potential alternative to traditional DBS with electrode implantation. The findings of this study highlight the importance of continuing to explore new and innovative approaches for treating neuronal disorders, paving the way for the development of more effective and more accessible treatments in the future.
