Bridging the Barrier

Traumatic brain injury (TBI) is driving a silent epidemic. The condition, which is initially caused by mechanical impact to the brain, affects sixty-nine million people each year and is a leading cause of death and disability in children and young adults. Though initial symptoms can include headache, nausea, and fatigue, they can gradually worsen as a result of secondary injury and lead to the onset of neurological dysfunctions including Alzheimer’s and Parkinson’s disease. But treatment remains a challenge. After the event of a TBI, the blood-brain barrier (BBB) is physically breached for a short period of time. Treatment through it would be ideal, but the extent to which the barrier is compromised varies among the patient population. Another challenge is the short window of time for treatment, which prevents repeated dosing that might be required over the long span of secondary injury that can last for months to years.  Previously used approaches for treatment of TBI were rendered because of these limiting factors.

But beyond TBI, the BBB has been historically difficult to penetrate. This barrier prevents molecules in the circulating blood from non-selectively crossing into the brain tissue – preventing the translation of many promising drugs. Though this challenge may be considered difficult to contend with, I believe that they are not insurmountable. Nanotechnologies are emerging as pertinent drug carriers, enabling the penetration of therapeutic agents across the BBB. 

Molecular Trojan Horses

Using a Trojan Horse mechanism, nanoparticles can be engineered to encapsulate therapeutic agents. Their size and surface properties can be fine-tuned to enable them to cross the BBB, thereby delivering therapeutic agents into the brain. These ultrafine particles can also prevent the degradation of labile agents, such as siRNA, in blood and facilitate their entry into the target cells, without premature degradation. At the Center for Nanomedicine at Brigham and Women’s Hospital, we have developed a platform that can therapeutically deliver drugs into the brain, across both physically breached and intact BBB – which could prove important in the treatment of TBI and its related conditions. 

Our platform relies on the precise engineering of the surface properties of nanoparticles – helping to maximize their transport across the BBB. Poly (lactic-co-glycolic acid), or PLGA – a biodegradable and biocompatible polymer – was also used as the base material for nanoparticles. This platform was then used to encapsulate a siRNA designed to inhibit the expression of tau protein – a microtubule-associated protein, which is thought to play a key role in neurodegeneration. It is also involved in the progression of secondary injury following TBI. 

In collaboration with Jeffrey Karp from Brigham and Women’s Hospital and Rebekah Mannix from Boston Children’s Hospital, we tested the coated particles in both healthy mice and those with TBI. Our investigation in the healthy population allowed us to identify a unique nanoparticle design that maximized the transport of the encapsulated siRNA across the intact BBB and also significantly improved uptake by brain cells. Using this information, we intravenously administered the nanoparticles across the BBB of TBI-affected mice. This resulted in a three-fold higher delivery of siRNA to the brain when compared with non-engineered nanoparticles – an improved delivery that occurred irrespective of whether the nanoparticles were infused within or outside the window of physically breached BBB.

Compared to TBI-affected mice treated with saline, our engineered nanoparticles loaded with anti-Tau siRNA (a proof-of-concept drug) showed a 50 percent reduction in the expression of the protein. As the next step, we want to explore potential targets for several neurological diseases. In this study, we used the TBI model to develop the technology, but our approach can be useful for other neurological diseases that require drug delivery to the brain. Our technology has the potential to deliver large molecule biological agents, such as proteins, which are typically challenging to formulate. I’m looking forward to seeing where this can best be applied. Beyond our own discoveries, it’s important that the industry continues to work towards the goal of treating neurological disease.

Moving forward

Though many pharmaceutical companies have neuroscience programs that cover various neurological disorders, the majority are focused on the discovery of novel targets. It would be great to see more efforts towards the amalgamation of novel target identification with technologies that can enable the translation of promising therapies to improve their therapeutic efficacy.

Regulators must also contribute to these efforts. They already play a crucial role in facilitating the translation of novel therapeutic approaches into viable products. But they could be involved right from the beginning and through all stages of drug development; after all, the process of developing therapeutics is lengthy, complex, and extremely costly. There are several issues that can arise, either due to the therapeutic agent itself or due to the associated technology. An expert regulator can guide the early development process to avoid any potential regulatory hurdles and can therefore help companies and researchers to find the most appropriate regulatory path forwards.

Ultimately, all aspects of industry need to work together seamlessly to help bring novel solutions to the fore. Patients are waiting, so we must all strive to create drugs that work effectively for them.