A Constant Hurdle in Drug Delivery
When it comes to achieving success in drug development, picking the right drug target and developing an effective inhibitor (or activator) is only half the battle.
A drug candidate may appear promising in cell-based testing—and even in preclinical testing—but still fail to work in humans. It simply does not get to where it needs to be in a high enough concentration to be effective. This rings true for any number of drugs in development, but is most often the case with drugs targeting sites within the brain.
In this issue, we will focus on one of the biggest technical challenges involved in drug delivery—getting drugs across the blood-brain barrier.
Term of the Week: Blood-Brain Barrier
Tiny capillaries crisscross the brain to bring nutrients to and waste away from the tissue. These capillaries are lined with cells that fit so tightly together most substances—including 95% of all drugs—are prevented from making it over the border. This mostly impenetrable border is the blood-brain barrier (BBB).
Some substances that do make it through the BBB are water, oxygen and certain hormones (such as estrogen and testosterone) via diffusion. Glucose, the all-important energy source of the brain, uses special transport proteins to shuttle itself into the brain.
Breaching the BBB
Getting large therapeutic proteins past the BBB and into the brain is one of the great drug development challenges. Below are four different methods currently being pursued:
There are many effective therapeutic antibodies, however there is no mechanism for getting them into the brain. Enter Genentech (South San Francisco, CA) who, still in the research phase, is testing a possible solution in the form of a bispecific antibody (BsA). This antibody takes advantage of a naturally occurring process called receptor mediated transcytosis—or the use of a receptor to transport something across the cell membrane.
Driving the bispecific antibody across the BBB is the transferrin receptor, which normally transports iron. One arm of the BsA loosely binds to the transferrin receptor so it can easily be released once inside of the brain. The other BsA arm binds to and inhibits a protein called beta-secretase, which is required for the production of β-amyloid. β-amyloid is a protein thought to play a role in the progression of Alzheimer’s.
AngioChem (Montreal, Quebec) takes advantage of a receptor called LRP-1, which naturally transports a variety of proteins across the BBB. By analyzing the range of proteins transported by LRP-1, AngioChem came up with a sequence of 19 amino acids to attach to and guide medicines to the LRP-1 transporter. Currently in Phase II, the company is targeting paclitaxel, a potent anti-cancer drug to treat brain cancer.
Researchers at the University of North Carolina (UNC) work with another natural process, called exosome-mediated delivery, to break through the BBB. Cells release exosomes, or nano-sized fat capsules, to transfer material from one cell to another. In the lab, these vesicles are isolated and loaded up with a therapeutic payload. UNC researchers are using exosomes to deliver the anti-inflammatory enzyme catalase (a Parkinson’s drug) to mice via a nasal spray.
Spinal Muscular Atrophy
AveXis (Dallas, TX) uses the adeno-associated virus (AAV) to deliver SMN proteins to motor neurons in Spinal Muscular Atrophy (SMA) infants. SMA affects the motor nerve cells in the spinal cord, taking away the ability to walk, eat, or breathe—it is the number one genetic cause of death for infants. AAV serotype 9 is delivered intravascularly and then crosses into the brain; it is the only serotype to cross the BBB in therapeutic doses. Currently in Phase I/II at Nationwide Hospital (Columbus, OH), it is the first clinical trial using systemic gene therapy.
Cocktail Fodder: Multiple Sclerosis And The BBB
Part of the disease process of multiple sclerosis (MS) is a breakdown of the blood-brain barrier, likely caused in part by chronic inflammation. This breakdown is what allows white blood cells (such as T-cells and macrophages) to enter the brain and attack the myelin sheath, the insulating lipid layer that surrounds neurons. Certain biologics—like Biogen’s (Cambridge, MA) Tysabri—normally are unable to cross an intact BBB and actually take advantage of the breakdown to penetrate the brain to treat MS.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.