Friday, December 2, 2011

The Blood-Brain Barrier

I just finished rewriting my mcmanweb article on the blood-brain barrier, which I first published in 2003. Here is the new version in full ...

You may have heard of "antisense" therapy. The idea is to synthesize strands of RNA that bind to disease-causing strands of messenger RNA and thus stop them dead in their tracks. The technology is being researched for cancer and other diseases. Imagine being able to switch off depression before it happens.

The catch? There are many, but the big one is that any drug which targets our gray matter must first cross the blood brain barrier (BBB). The name conjures up a kind of cross between the Berlin Wall and a coffee filter, but in fact refers to nearly 400 miles of narrow capillaries throughout the brain, all filled with tightly packed endothelial cells that are exceedingly selective in what gets through. Endothelial cells are also present in capillaries in the body, but the spacing there poses no difficulty.

The BBB is to protecting the brain internally as the skull is to protecting it externally. The problem is the BBB does not differentiate what it keeps out. Life-saving chemicals, if they happen to be the wrong chemicals, simply won't get through. With very few exceptions, only small molecules soluble in fat clear the barrier. Only two percent of small-molecules get through. These include alcohol, caffeine, and nicotine.

Small-molecule compounds have been used to treat affective disorders, schizophrenia, chronic pain, and epilepsy, but they leave a lot to be desired. The problem, says William Pardridge MD of UCLA writing in the Jan 2003 Archives of Neurology, is that "small molecules are largely palliative medicines with often unfavorable safety profiles."

There are no chronic diseases, other than infectious diseases, that are cured by small-molecule drug therapy.

Large-molecule drugs have the potential to cure patients with neurological disorders, he notes, but none of them can cross the BBB. The following paragraph is worth quoting in full:

Despite the importance of the BBB to neuropathic agents, this area is underdeveloped in the neurosciences. To my knowledge, no pharmaceutical company in the world has a BBB drug delivery program! It is not unusual for an entire conference to be convened on a given neurologic disorder (eg brain tumors), with no discussion of targeting drugs through the BBB.

Writing six years later, in the Sept 2009 Alzheimers Dementia, Dr Pardridge points out that "even if Big Pharma wanted to start a BBB drug targeting program, there would be few personnel trained in the BBB to hire, because no academic neuroscience program in the US emphasizes BBB transport biology, much less BBB drug targeting."

Moreover, Dr Pardridge notes that clinical trial failures are attributed to the test drug rather than the obvious fact the drug might not even be getting through to the brain. Further development on the drug - and even all CNS drug development - is abandoned. We all suffer.

(The absurd alternative is "trans-cranial brain drug delivery," a euphemism for invasive brain surgery to deposit the wonder drug.)

Dopamine is a small molecule, but its chemical structure prevents it from crossing the BBB. Its precursor, L-DOPA, however can literally hitch a ride on a certain type of amino acid transporter and sneak through the BBB Trojan Horse style.

"Preparation of Trojan Horse liposomes for gene transfer across the blood-brain barrier," reads a 2010 article authored by Dr Partridge.

Dr Pardridge and his team have been working on encasing genes in fatty spheres called liposomes, which are coated with a special polymer, to which certain antibodies are attached. The antibodies trick the brain-capillary receptors into letting the liposomes pass, where they can deliver their payload to brain cells.

In one set of experiments that induced Parkinson's symptoms in rats, Dr Pardridge's team injected the rats with liposomes containing a gene that boosts production of the enzyme tyrosine hydroxylase, which is a building block of dopamine. Three days later, the rats' abnormal movements were reduced by 70 percent.

Another set of experiments doubled the lifespans of rats with brain tumors. Weekly injections resulted in the successful delivery of antisense RNA, which blocked production of a malignant growth factor.

Ah! Right back where we started, with antisense therapy!

In a 2005 article in NeuroRX, Dr Pardridge discusses the possibilities of all manner of antisense and peptide molecular Trojan Horses aimed at various targets. But with mental illness, there is a major catch, namely - where are those targets? Consider: We know for instance that amyloid plaque is associated with Alzheimers, and that Alzheimers research is directed at busting up these plaques.
But where is the equivalent of amyloid plaque for depression or mania or anxiety?

Hopefully, Alzheimers and brain tumors and other conditions with clearly identifiable targets (and thus foreseeable treatments) will vastly increase funding for research into BBB drug technology. That is certainly Dr Pardridge's wish. And dare we hope? Imagine, for instance, a ready-made molecular Trojan Horse that could be customized to deliver an antisense agent capable of shutting down an over-reactive stress response before it happens.

Maybe we're just dreaming. But, oh, the possibilities ...

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