While there are several thousand drugs available to treat a wide range of brain diseases, from depression to schizophrenia, they cannot penetrate the blood-brain barrier (BBB) into the brain.
The BBB, which protects the brain from pathogens that may be present in blood, also prevents most drugs from gaining access to the brain functional tissue, the parenchyma, a well-known challenge to the treatment of all brain diseases including neurodegenerative disorders like Parkinson’s disease and Alzheimer’s.
A team led by Elisa Konofagou, Robert and Margaret Hariri Professor of Biomedical Engineering and Professor of Radiology (Physics) at Columbia Engineering, has been developing a novel technique that could open up new ways to facilitate targeted drug delivery into the brain and enable drugs to treat brain diseases more focally.
The researchers used transcranial, focused ultrasound and intravenously injected microbubbles into the BBB to make a localized and transient opening that allows drugs to cross through the BBB reversibly and non-invasively.
Focusing on Parkinson’s disease, in collaboration with Serge Przedborski’s group in the department of neurology at Columbia University Irving Medical Center, they discovered that protein delivery and gene delivery across the BBB can partly restore the dopaminergic pathways, the neurons in the brain that are affected in early Parkinson’s disease.
“We found both behavioral and anatomical neuronal improvements in the brain,” says Konofagou, who led the study, published online on April 4 by the Journal of Controlled Release, and in print June 10.
“This is the first time that anyone has been able to restore a dopaminergic pathway with available drugs at the early stages of Parkinson’s disease.
We were able to curb the rapid progression of neurodegeneration while improving the neuronal function.
We expect our study will open new therapeutic avenues for the early treatment of central nervous system diseases.”
Focused ultrasound-induced blood-brain barrier openings in a mouse brain. Credit: Maria Eleni Karakatsani/Columbia Engineering
The team targeted the brain regions involved in early stage Parkinson’s and Alzheimer’s disease, such as the putamen and hippocampus.
The tool they developed for the study is a device that uses a neuronavigation system to direct the treatment in real-time.
The U.S. FDA has just assigned the team an Investigational Device Exemption (IDE) to use the device in clinical trials to test its safety in Alzheimer’s patients.
“Neurosurgeons use such systems all the time to guide them for neurosurgery,” says Antonios Pouliopoulos, associate research scientist in Konofagou’s lab who worked on the development of the clinical neuronavigation system.
“Our group just replaced the surgical instrument with an ultrasound transducer to perform our non-invasive procedure.”
Konofagou’s Ultrasound Elasticity and Imaging Laboratory is the only academic lab in the U.S. to receive FDA approval for ultrasound-assisted, blood-brain-barrier opening.
Other groups doing similar research either use nanoparticles to facilitate drug delivery or require MRI to guide the procedure.
Konofagou’s approach is MRI-independent and does not require any nanoparticles.
Her device is a single-element transducer that is much smaller, faster, and less expensive than current helmet-shaped, 1024-element transducer systems that use MRI guidance.
Because Konofagou’s system is portable, doctors will be able to treat patients anywhere in a hospital and, in the future, even at a patient’s home.
Treatment can be completed in less than 30 minutes, compared to three to four hours for MRI-guided therapy, and monitored in real-time, a unique feature of the new device.
The cost is 10 times less than the MRI-guided helmet.
The first trial with the device will be with Alzheimer’s patients, after which Konofagou plans to work with Parkinson’s patients.
Konafagou recently won a four-year $2.5M NIH grant to use a similar device for deep brain stimulation aiming to unveil the mechanism by which ultrasound excites neurons and to monitor the unveiled mechanism in human subjects.
In addition, she will be honored with the 2019 Engineering in Medicine and Biology Society’s Technical Achievement Award in Berlin this July for her “outstanding and pioneering contributions in the field of ultrasound imaging and therapy, and their application and clinical translation to the diagnosis of cardiovascular diseases, tumor diagnosis and treatment as well as brain drug delivery and stimulation.”
“We all have loved ones with neurodegenerative disorders,” Konofagou adds.
“My grandmother has been suffering from dementia for more than five years, so I know first-hand how essential it would be to have a simple device that can be wheeled into the patient’s home and offer a higher quality of life, especially for our rapidly aging population.
And there are so many deadly diseases like brain tumors that affect people of all ages, with no cure yet in sight. That’s why we want to bring our research so rapidly to the clinic.”
Parkinson’s disease (PD) is a largely idiopathic neurodegenerative disorder affecting approximately 2% of the population over 65.1
It is estimated that PD costs more than 14 billion dollars each year in the US alone,2 and its incidence is expected to double as early as 2040.3
One of the primary hallmarks of PD is the degeneration of dopaminergic neurons with cell bodies in the substantia nigra pars compacta (SNpc) and axon projections extending into the striatum.
The resulting dopamine deficiency leads to progressive and debilitating motor control deficits including bradykinesia, rigidity, and resting tremor.
While pharmacological dopamine replacement or surgical therapies like deep brain stimulation can ameliorate symptoms at early stages in PD, they are not neuroprotective, and the continued neuronal degeneration ultimately leads to a recurrence of symptoms.4,5
Furthermore, late-stage patients often develop motor symptoms that are refractory to dopamine replacement therapies or complications stemming from long-term dopamine-replacing drug use.6
Therapies that can slow or stop the neurodegenerative process have remained elusive.7
Gene therapy approaches aimed at slowing or reversing neurodegeneration in PD have been developed and tested in both preclinical and clinical settings for many years.
Neurotrophic factors, like the glial cell-line derived neurotrophic factor (GDNF), are attractive candidates for gene therapy due to their ability to protect neurons from continued degeneration, induce neuronal regeneration and sprouting, and enhance dopamine generation from the remaining neuronal population.8,9
Numerous gene therapy clinical trials for PD have been completed using genes that encode for neurotrophic factors like GDNF or its close structural and functional relative, neurturin (NTRN).
While these clinical trials showed safety, therapeutic outcomes were disappointing.
Going forward, it has been hypothesized that therapeutic outcomes may be improved by (a) enhancing delivery efficiency, transfection volume, and reproducibility of delivery within the target structures,10 (b) treating earlier stage (or even prodromal) patients prior to the onset of extensive irreversible neurodegeneration,11,12 and (c) further adjusting dosing parameters to ensure appropriate levels of neurotrophic factor expression throughout the target volume.
While advances in direct injection strategies, including convection enhanced delivery (CED), may improve outcomes, concerns over their invasive and risky nature have obviated the inclusion of early stage PD patients in clinical trials.
More effective and minimally invasive approaches that can be used for patients regardless of their disease stages are required.
To date, clinical gene therapy studies have relied upon direct administration methods that are invasive and may yield poor transgene distribution.
Systemic administration has not been considered because the blood–brain barrier (BBB) prevents nearly 100% of molecules larger than ~400 Da in size from entering the brain. Indeed, the BBB remains one of the most significant impediments to therapeutic delivery to the brain following systemic administration.13
To achieve efficacy, both viral vectors and nanoparticles with BBB-targeting ligands often require very high systemic doses, which can lead to peripheral adverse side effects.14
Other strategies for circumventing the BBB, such as intranasal administration or intra-arterial infusion of the osmotic agent mannitol, have been proposed and are being tested. However, they also have weaknesses that may hinder translation to the clinic, including invasiveness, inconsistency, and/or poor targeting and tissue distribution.15,16
MR image-guided focused ultrasound (FUS) is currently the only modality capable of noninvasively opening the BBB for spatially targeted therapeutic delivery into the brain.17
Through the activation of ultrasound contrast agent microbubbles (MBs) in stable cavitation, FUS permits the targeted delivery of nanoparticles as large as 100 nm across the BBB.17,18
Activated MBs exert mechanical forces on the vessel wall, temporarily disrupting tight junctional complexes19 and inducing active transport processes.20 Barrier function is typically fully restored within 4–6 h,21,22 and safety has been demonstrated in several large animal models.23,24
Advances in transducer technology now permit submillimeter precision, and with guidance from magnetic resonance (MR) imaging, it is possible to apply FUS across the human skull in an extremely localized manner, limiting the potential for unwanted side effects.25,26
Furthermore, MR imaging allows semireal time intraoperative treatment feedback and postoperative confirmation of success.
Indeed, MR image-guided FUS is now FDA approved for use in humans with Essential Tremor,26 and clinical trials for other CNS disorders including tremor-dominant PD are underway.27
e from magnetic resonance (MR) imaging, it is possible to apply FUS across the human skull in an extremely localized manner, limiting the potential for unwanted side effects.25,26
Furthermore, MR imaging allows semireal time intraoperative treatment feedback and postoperative confirmation of success.
Indeed, MR image-guided FUS is now FDA approved for use in humans with Essential Tremor,26 and clinical trials for other CNS disorders including tremor-dominant PD are underway.27
Once across the BBB, vectors must traverse a dense, nanoporous, and negatively charged extracellular matrix (ECM) that impedes the dispersion of traditional nanoparticles28,29 and viruses30 through both adhesive interactions and steric obstruction.
Importantly, it has recently been shown that sub-114 nm nanoparticles densely coated with hydrophilic and neutrally charged polyethylene glycol (PEG) are able to overcome this barrier and diffuse rapidly within the brain parenchyma.28,31–33
These “brain-penetrating nanoparticles” (BPN) can be complexed into nanosized and colloidally stable gene vectors.34,35
We have previously demonstrated that FUS can target BPN delivery to rat brain,18 which can provide robust and long-term reporter gene expression in the FUS-targeted region when the BPN is loaded with plasmid DNA.36
In the current study, we used a BPN formulation to deliver a GDNF gene-bearing plasmid (GDNF-BPN) to the striatum of PD rats whose BBB was transiently opened in a targeted manner with MR image-guided FUS.
We demonstrate a clinically relevant strategy to restore dopaminergic neuronal function without the need for invasive surgical procedures.
More information: Maria Eleni Karakatsani et al, Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson’s disease, Journal of Controlled Release(2019). DOI: 10.1016/j.jconrel.2019.03.030
Journal information: Journal of Controlled Release
Provided by Columbia University School of Engineering and Applied Science
