Unprecedented siRNA penetration across the blood brain barrier in mice could aid therapy for variety of human neurological disorders.
Previous research has identified biological pathways leading to neurological disorders and has developed promising molecular agents to target them as a result. However, translating these discoveries into clinically approved treatments has been hampered by the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain.
Longevity.Technology: Understandably, the brain is very choosy about what it lets through its barrier. Overcoming this hurdle to deliver therapeutic agents has been a research focus of late, with simulations on a chip, nanodiamond technology and transferrin-cloaked antibody shuttles demonstrating encouraging results. The accumulation results from the Brigham study are also encouraging as current treatments for neurodegeneration and neurodegenerative diseases impose a substantial burden on global healthcare.
To facilitate the successful delivery of therapeutic agents to the brain, a research team at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform; this can facilitate therapeutically-effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), the researchers observed that the delivery system showed three times more accumulation in the brain than conventional methods of delivery. In addition, the delivery was therapeutically effective, opening the doorway to future treatment of numerous neurological disorders.
Previously developed approaches for delivering therapeutics into the brain after TBI rely on the short window of time after a physical injury to the head, when the BBB is temporarily breached. However, after the BBB is repaired within a few weeks, physicians lack tools for effective drug delivery.
“It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB .”
“Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”
This novel technology could enable treatment of secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s and other neurodegenerative diseases; these can develop months or even years after the BBB has healed.
“To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired .”
The therapeutic used in this study was a small interfering RNA (siRNA) molecule designed to inhibit the expression of the tau protein, which is believed to play a key role in neurodegeneration. Poly(lactic-co-glycolic acid), or PLGA, a biodegradable and biocompatible polymer used in several existing products approved by the US FDA, was used as the base material for nanoparticles.
The researchers studied the surface properties of the nanoparticles to maximise their penetration across the intact, undamaged BBB in healthy mice. By modulating the surface chemistry and coating density on the nanoparticles, they identified a unique nanoparticle design that maximised the transport of the encapsulated siRNA across the intact BBB and significantly improved the uptake by brain cells.
A 50% reduction in the expression of tau was observed in TBI mice who received anti-tau siRNA through the novel delivery system, irrespective of the formulation being infused within or outside the temporary window of breached BBB. In contrast, tau was not affected in mice that received the siRNA through a conventional delivery system .
“In addition to demonstrating the utility of this novel platform for drug delivery into the brain, this report establishes for the first time that systematic modulation of surface chemistry and coating density can be leveraged to tune the penetration of nanoparticles across biological barriers with tight junction,” said first author Wen Li, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine .
“The technology developed could allow for the delivery of large number of diverse drugs … this could be a game changer …”
Rebekah Mannix, MD, MPH, of the Division of Emergency Medicine at Boston Children’s Hospital and a co-senior author on the study, further emphasised that the BBB inhibits delivery of therapeutic agents to the central nervous system (CNS) for a wide range of acute and chronic diseases. “The technology developed for this publication could allow for the delivery of large number of diverse drugs, including antibiotics, antineoplastic agents, and neuropeptides,” she said. “This could be a game changer for many diseases that manifest in the CNS .”
In addition to targeting tau, the researchers now have studies underway to attack alternative targets using the novel delivery platform.
“For clinical translation, we want to look beyond tau to validate that our system is amenable to other targets,” Karp said. “We used the TBI model to explore and develop this technology, but essentially anyone studying a neurological disorder might find this work of benefit. We certainly have our work cut out, but I think this provides significant momentum for us to advance toward multiple therapeutic targets and be in the position to move ahead to human testing .”