blood brain therapy disease cure

Overcoming the Blood Brain Barrier to Treat Neurological Diseases

Overcoming the Blood Brain Barrier to Treat Neurological Diseases


by Ryan Mateja, PhD

The blood-brain barrier (BBB) is a highly selective semipermeable membrane that plays a fundamental role in protecting and maintaining homeostasis of the brain. It is mainly composed of densely packed endothelial cells connected by tight junctions which protect the brain from invading pathogens and neurotoxic molecules while simultaneously ensuring the brain gets adequate nutrients.

While being highly complex and selective is instrumental to the protection provided by the BBB, it also creates a challenge to neuroscientists trying to discover and create therapeutic agents to treat central nervous system (CNS) pathologies. Because of this, CNS medicines have a high risk of failure and as a result disorders of the CNS represent one of the largest areas of unsatisfied medical needs.1

In the USA, the cost of discovery and development of new compounds can total $100 million dollars to reach phase I clinical trials and $1 billion dollars to bring your product to the patient. Despite this high cost, 95-97% of brain-directed pharmaceuticals never make it to the consumer since most are incapable of crossing the BBB in vivo.2

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blood brain therapy disease cure
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Blood brain barrier is our brain’s lifeline and a guardian against microorganism infections. Its highly selective permeability makes infections of the brain very rare. But the blood brain barrier protection also poses a challenge to therapies, especially immune and biologics based approaches

What are the mechanisms behind molecules traversing the BBB? Passing between endothelial cells, also known as the paracellular pathway, is normally utilized for ions or solutes that are traveling along a concentration gradient. Traveling through the endothelial cells is called the transcellular pathway, or transcytosis, and can occur through either passive or active mechanisms. Active transport is required for larger hydrophobic molecules such as proteins or nutrients, while passive transport is reserved for smaller lipophilic molecules (less than 500 Daltons in size). Here lies the challenge, how do we use our understanding of how the BBB works to circumvent its intrinsic protections and allow therapeutic agents to enter to treat neurological diseases?

Methods of passing the blood brain barrier


Traditionally, attempts to circumvent the BBB involved disrupting it to allow the passage of drugs between endothelial cells (paracellular pathway). This was normally accomplished by either osmotic disruption using agents such as mannitol, or through chemical disruption by creating an inflammatory reaction. Both of these methods result in widening of the intracellular junctions allowing paracellular transport. Recently, new and promising methods of passing the BBB are being investigated. These emerging strategies involve either the use of carrier agents, like cells or nanoparticles to deliver drugs, or a circumvention of the BBB completely.


Cell-based drug delivery uses stem cells or immune cells as carriers to deliver therapeutic agents. One major advantage of this technique is that the cells are naturally recruited to sites of tissue damage. Studies show that IV administration of these cell types has resulted in their accumulation in brain tumors.3,4 Specifically, in a mouse model of metastatic brain cancer where breast cancer was shown to have widespread micro and macro metastasis, engineered stem cells efficiently targeted metastatic tumor deposits in the brain. Furthermore, the stem cells were engineered to secrete an apoptosis-inducing ligand and were shown to suppress metastatic tumor growth and prolong survival.5


Nanoparticles (NPs) are promising carriers for drug delivery due to their small size, high solubility and capability for surface modifications to enhance their ability to carry drugs across the BBB. Lipid-based NPs are self-assembled vesicles similar to the lipid bilayer of cells, able to carry both hydrophobic and hydrophilic drug molecules through receptor mediated transport. Polymeric NPs are able to encapsulate a wide variety of therapeutic agents such as chemotherapeutic drugs, proteins and nucleic acids and mainly pass the BBB through endocytosis. Their flexibility in how their properties (size, shape and even surface charge) can be tailored to specifically cross the BBB makes them excellent candidates for drug delivery vehicles. Metallic NPs, which are characteristically dense and solid, cannot encapsulate drugs within them but instead can have therapeutic agents conjugated to their surface. The smaller size of metallic NPs provides them an advantage in crossing the BBB and typically cross it through passive diffusion or carrier-mediated transport.6


Rather than figuring out how to pass through the BBB, however, another viable approach is to bypass the BBB completely. One method by how this can be accomplished, although the mechanism is not fully understood, is the intranasal administration of drugs. Intranasal administration allows the passage of drugs across the nasal olfactory epithelium or nasal mucosa to reach the brain directly. In fact, chemotherapeutic drugs, small molecules, proteins and nanoparticles have all been delivered to the brain using this method.7

So how are techniques like these used in the treatment of CNS diseases?

Crossing the BBB to treat neurological diseases


While there are many applications for using these methods to treat any neurological disease, Alzheimer’s disease (AD) is one area that is being heavily researched. AD is the major cause of dementia worldwide, affecting over 5 million people in the USA alone.8 One of the hypothesis regarding the pathophysiology of AD involves disruption of the BBB, making it more permeable and allowing amyloid beta and neuron-binding autoantibodies to enter and adhere to astrocytes. Normally, astrocytes clear surface-bound antibodies, but in AD it’s thought that due to the increased amount passing through the BBB the astrocytes get overwhelmed causing them to die and leave behind amyloid beta plaques.9 The gene for the amyloid beta precursor is on chromosome 21. Interestingly, patients with trisomy 21, better known as down syndrome, have an extra copy of chromosome 21 and almost universally exhibit AD-like disorders by the age of 40.10


One of the most useful new tools to fight disease are therapeutic antibodies, but because of their large size they have limited applications for neurological diseases like AD due to their inability to pass the BBB. New data shows that short pulses of focused ultrasound can temporarily disrupt the BBB and allow the passage of drugs and therapeutic antibodies. In a murine model of AD, the combination of ultrasound-induced BBB disruption and anti-amyloid beta antibodies reduced plaque size and number and resulted in increased glial activation and improved cognitive outcomes.6 Ultrasound disruption of the BBB is also being studied as a way to deliver exogenous genes into the brain and treat AD using gene therapy.6


NPs have also shown promise in breaking down amyloid beta plaques by allowing the passage of neuroprotective peptides through the blood brain barrier. NP-mediated passage of either NAPVSIPQ or nerve growth factor, both neuropeptides, has been shown to ameliorate spatial learning deficits, reverse amnesia and improve memory in mice models of AD.2

Future prospects


Once successful ways of passing through the BBB to treat a disease like AD are proven, it is only a matter of time before the same technology can and will be used to treat other neurological diseases. Currently, there is a lot of hope and intense research in the area of passing the BBB to treat patients with Parkinson’s disease, Multiple sclerosis, stroke victims and even lysosomal storage diseases.1,2,11 Furthermore, the advancements made in nanotechnology while investigating treatments for neurological diseases will surely be applied in other therapeutic ways. In fact, the once far off concept of a tiny microscale robot swimming along a person’s veins, carrying drugs to disease brain cells or infected tissues is becoming a reality.12 Wirelessly controlled implantable microchips for osteoporosis are showing promise, and there is even a camera shaped like a pill which can be  utilized to monitor real-time pathology and drug release throughout areas of the gastrointestinal tract.13,14 Sometimes, in order to think big, you have to first think really small.


References


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