Molecular Engineering Technology for Studying and Treating the Brain

By combining novel molecular engineering innovations and site-specific delivery of molecules to the brain, new approaches for treating and monitoring brain disorders could lead to higher efficacy, more accurate testing, and a better patient experience.

Developing new medical treatments is difficult, expensive, and often unsuccessful (1). Clinical trials often require years of research and hundreds of millions of dollars; even if the trials are successful, the resulting drug will likely only treat a single disorder. There are many potential reasons why drug development is so difficult, including various regulatory hurdles, the necessity of in vitro or animal models that only approximate the real human disease, the variability of disease pathogenesis in a human population, and the inability to measure all relevant aspects of human pathophysiology due to the invasiveness of available techniques. Therefore, there is a need to improve all aspects of therapy development, from understanding the physiology of human diseases to developing therapies to monitoring treatment progress.

Brain therapeutics are particularly challenging to develop, demonstrating the lowest success rate and longest development time of all classes of therapeutics (1). The reasons behind this difficulty include challenging systemic delivery, the need for spatially-specific targeting, and the brain’s vulnerability to injury. Molecule delivery to the brain is hampered by a specialized endothelium — i.e., the blood-brain barrier (BBB) — which precludes systemic delivery of many therapeutics (2). Second, even if a drug is successfully delivered, it is likely to have non-specific effects. The human brain is made up of hundreds of distinct regions performing different functions, all potentially requiring different treatments; however, a typical small molecule drug diffuses throughout the brain when administered systemically. Additionally, while the majority of drug development relies on finding a specific drug-target interaction, in some cases, this may not be sufficient to avoid side effects because chemically identical neurons can perform drastically different functions depending on where they are and which other neurons they connect to. For example, dopaminergic neurons are present in multiple brain regions. Depending on the location within the brain, they can control either movement or reward processing.

Another challenge for brain therapies is the organ’s vulnerability to damage. Spatially-specific brain therapy is commonly done with locally implanted devices, like in the Parkinson’s Disease (PD) treatments. To treat PD, implantable electrodes that deliver electric current are inserted into specific brain regions. These devices, however, require complex brain surgery, and their invasiveness precludes control of multiple or large brain regions without inducing potentially dangerous amounts of tissue damage. Additionally, such electrical devices lack the molecular selectivity of small molecule drugs and do not predictably act on specific cell types within the stimulated region. To address these challenges, a combination of noninvasive delivery methods and molecular engineering may provide the best of both worlds by providing site-specificity, noninvasiveness, and molecular selectivity. This article reviews several potential chemical and biomolecular engineering innovations in brain therapy applications.