Penetrating the brain

Penetrating the brain

Psychology Research class 481

Instructions for summarizing a chapter or article.

Assignment:

1.    Write down each chapter title of the book. This will serve as the topic for each segment of the book you are summarizing.

2.    Below each chapter title that you have listed, write down the main ideas corresponding to each chapter anything in bold or script. Try to be as simple and direct as possible. Avoid lengthy and complex sentences. Keep straight to the point. This will help you remove unnecessary words that are better left out.

3.    The chapter titles and their corresponding main ideas that you have just listed down will serve as the outline of your book summary. Try to pick things up from there and expand your sentences by elaborating the ideas.

•    DO NOT write whether the book is poorly written or excellently discusses the ideas. Remember, you are simply writing a summary and NOT a book review.

•    DO NOT write down irrelevant ideas. They only make your book summary a mess.

•    DO NOT make-up ideas that are not included in the book. Be as honest as possible. Write only what the author has said and not what was not stated.

•    Read the entire text, noting the key points and main ideas.

•    Summarize in your own words what the single main idea of the essay is.

•    Paraphrase important supporting points that come up in the essay.

•    Consider any words, phrases, or brief passages that you believe should be quoted directly.

The Title of the Article is Penetrating the Brain

trating the Brain I The Scientist Magazine@

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enetrating the Brain

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rricade in the body-the blood-brain barrier.

Megan Scudellari I November 1, 2013

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ING THROUGH THE BBB: Some researchers are

ineering bispecific antibodies (yellow and green

), with one arm serving to help the molecule

the blood-brain barrier (BBB) while the other arm

tes the drug’s function in the brain.

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successfully get into the brain to treat

zheimer’s, Watts and Dennis designed one arm

their antibody to sneak the drug into the brain

binding to the transferrin receptor on BBB

cells, which typically allows the

ssage of iron. Once inside the brain, the

tibody’s second arm binds and inhibits

3*1 O Link this Stumble Tweet this

t I t hen neuroscientist Ryan Watts talks about

W receptor-mediated transcytosis, he sounds

like an orchestra conductor describing his favorite

piece of music. To him, the passage of a molecule

through a cell membrane via a receptor-assisted

vesicle is an art form, and, more importantly, a

way into the brain.

In 2OO4, Watts formed the neuroscience unit at

pharmaceutical company Genentech. Right away,

he organized a program to develop antibodies

against the protein fragment amyloid beta, a

component of brain plaques associated with

Alzheimer’s disease. But as soon as he began,

Watts, like many before him, ran into a

wall-literally. His antibodies were being trapped

at the blood-brain barrier (BBB), a mesh of tight

junctions between specialized endothelial cells

lining brain capillaries that prevent foreign

particles from entering the brain.

Antibodies actually can get into the brain, just not

very efficiently. For every thousand antibodies

injected into the blood, only one will find its way

into the brain, likely by slipping unnoticed into

vesicles crossing the barrier. Unfortunately, that

dramatic concentration decrease prevents

researchers from developing effective drug

treatments, because using higher doses would

cause harmful effects in the rest of the body. “We

needed a way to get more antibodies into the

brain,” says Watts.

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e small, lipid-soluble drugs do cross the BBB simply by diffusion through the cell membrane, and

rs, like caffeine, enter successfully via specialized transporter proteins. Many larger molecules, such

antibodies and enzymes, however, can’t get through unless one uses a needle or catheter to puncture Current lssue

BBB with brute force. Not surprisingly, however, such methods often result in dangerous

mplications, such as infections and tissue damage. So Watts, along with Genentech biochemist Mark

nnis, devised a far more subtle solution to get antibodies to cross the BBB-receptor-mediated

nscytosis. Their success surprised neuroscientists and caught the attention of the rest of the pharma

ustry, which has become eager to identify new ways to breach the BBB.

wo years ago, if you talked about the blood-brain barrier, you’d hear,’Eh, okay, another failure.’

ple criticized all sorts of approaches, showing no interest,” says Jean-Paul Castaigne, CEO of

ioChem, a Montreal-based biotech company developing treatments for brain diseases. Today,

wever. “we are seeing a major shift,” he says. “As often happens, one starts and the others follow.”

entech’s early achievements breaching the BBB have opened the floodgates. These days crossing the

is in vogue, with numerous companies and academics devising diverse, creative, and sometimes

ht wacky ways to pry open a window into the brain. In doing so, they hope to deliver drugs that

ill treat Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, and many more brain illnesses that

currently intractable.

ki lift to the skull

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p

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retase (BACE1), an enzyme that processes

amyloid beta precursor, thereby cutting off

uction of the harmful protein fragment.

t the first antibody they designed to bind to the

sferrin receptor was not successful in crossing

barrier. The antibody was being trapped within

capillaries of the BBB, nearly reaching the

in, but unable to break free from the receptor

complete its therapeutic duties-as if a chairlift

ed passengers to the top of a ski slope, but

the passengers failed to jump off.

nity for the transferrin receptor might be the A WEB OF VESSELS: The brain is replete with blood

vessels-some 500 miles of them-but getting drugs

from the blood into brain tissue is limited by the bloodbrain

barrier (BBB), comprised of tight junctions

between the endothelial cells lining brain capillaries.

I r ar !litl

lem. What if, they thought, the antibody

nd the receptor more loosely, so that it could

let go and fall into the brain? They tested a

w of low-affinity antibodies and found that the

ltegy worked like a charm. This time, the

ibodies hopped off at the top of the ski lift.

day, Genentech, now a member of the Roche Group, is conducting primate studies with the two-armed

body, and Watts hopes to soon move the therapy to clinical trials. “It looks really interesting,” he

, with unrestrained glee in his voice. “That’s all I can say.”

in the hunt to cross the BBB is Angiochem, which has developed another approach based on

mediated trancytosis. Instead of targeting the transferrin receptor, however, AngioChem’s

hnology utilizes a receptor in the BBB called lipoprotein receptor-related protein, or LRP-1, a

miscuous protein that binds more than 40 ligands and can transport molecules up to 700 kilodaltons

lecular weight-about 4 times the size of an antibody-across the BBB. By analyzing several of LRPligands,

the company identified a 19-amino-acid sequence that, like a zip code, homes a package to

destination. Now, the company is adding that zip-code sequence to proteins and therapeutics to

them through the LRP-1 door into the brain. The company’s proof-of-concept drug-a treatment

brain cancer that combines paclitaxel, an oft-used drug for brain cancer, with the zip-code peptide-is

tly in Phase 2 trials.

Netherlands-based biotech company to-BBB takes yet another receptor approach: hiding drugs in

balls of lipids, called liposomes, then decorating those liposomes with molecules of glutathione

SH), a three-pronged peptide that is rapidly taken up into the brain through specialized transporters.

e identity of those transporters is currently unknown, says the company’s chief scientific officer, Pieter

lard, but they effectively transport the GSH-coated liposomes across the BBB. The company has one

for brain cancer based on the widely used chemotherapeutic drug doxorubicin that recently

tered Phase 2 trials, and is also actively pursuing treatments for multiple sclerosis and stroke. “There’s

limit of what you can get into a liposome,” says Gaillard. “We’ve gotten whole antibodies, enzymes,

other large molecules inside.”

around

a sinus surgery specialist at the Massachusetts

and Ear Infirmary and Harvard Medical School

Boston, Benjamin Bleier often assists colleagues

surgeries that go in through the nose to

brain tumors. To do so, he cuts a hole in

lining of the brain, through both the BBB’s

h of blood vessels and the protective

inal fluid barrier, just above the sinus

ty. “That part is easy. It’s always easy to

rroy tissue,” says Bleier, “The part that is

is to close the hole.” Over the past seven

ars, however, Bleier and colleagues have

timized a closing technique that uses a patient’s

nasal lining to cover the hole made by the

ion.

the same time, Bleier studies drug delivery

h the nose and has learned that the nasal

is highly permeable to drugs. Many topical

aerosol treatments are delivered to the

through the nose, including pain and

usea medications and even insulin.

e day, Bleier put two and two together. “On

hand, we had this very permeable barrier that

a lot of drugs through in a very efficient

er. And here we are putting this barrier

ly against the brain” to patch the holes we’d

de, he says. “We’d essentially created a large

in the blood-brain barrier. So could we

that to deliver drugs to the brain?”

a proof-of-concept study published this year,

and colleagues performed the nasal surgery

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trating the Brain I The Scientist Magazine@ Page 3 of 4

mice, then delivered molecules of up to 500

Itons in size-1,000 times larger than those

can cross an intact BBB-through the nasal

ing. They are now performing the same

ure in a mouse model of Parkinson’s

this time delivering an experimental

t for the motor neuron disorder.

challenge that creating a permanent hole

the BBB would expose the brain to the risk of

, but Bleier notes that the nasal lining is

with immune cells to defend against

such as bacteria and viruses, and that

lininn’c rall maml.r=nac >rli,ahr ^. ‘n^ ^.,1

ins that diffuse into the cells. “It’s a very active

rrier, not just a fence,” he says. Because of

is, the nasal-lining patch does not increase the

in’s risk of infection, Bleier argues. Indeed,

rgeons have been repairing surgical incisions

the brain with the nasal lining for several

ars, and patients do not get postoperative

itis or other brain infections, so the

nique has a strong safety track record.

rmeating the BBB

course, entering the brain through transplanted

al tissue is not the only option, Bleier’s method

just one of several creative techniques to cross

BBB emerging from academic labs. At

umbia University in New York City, bioengineer

Konofagou is also applying an established

ical technique to the BBB problem: the use of

trasound and microbubbles. Tiny bubbles, made

lipid shells and a gas core, are injected into the

dstream, then triggered to expand and

‘act using waves of sound. Quick ultrasound

can help researchers image an organ, such

the heart, while longer ultrasound pulses have

used to damage tumor tissue as a treatment

r cancer.

rre recently, however, it has been observed that

e force of the bubbles’ movement causes

thelial cells of the BBB to temporarily

rate, creating a momentarily permeable

rier. “It’s very safe,” she says. “With the right

of pulses and the right pressure, you can

a drug in and get the barrier to recover.” Last

, her lab used the method to deliver brainneurotrophic

factor (BDNF) to mice, which resulted in hippocampal neurons taking up the drug

activating downstream signaling pathways. Her team has also tested the technique in nonhuman

and hopes to move it into the clinic in the next two years.

t Johns Hopkins University, nanomedical researcher Rangaramanujam Kannan and collaborator Sujatha

nnan are also taking advantage of a compromised BBB. During neuroinflammatory illnesses, such as

bral palsy and Alzheimer’s, the BBB becomes impaired just enough for nanoparticles to slip through.

t designing a nanoparticle to penetrate the brain once it is past the BBB is easier said than done, he

tes. “There have been many studies reporting that when there is sufficient breakdown of the bloodain

barrier, nanoparticles can get in,” says Kannan. “The problem has been that once they cross the

-brain barrier, they don’t move into the brain tissue or get taken up by target cells.”

overcome this hurdle, Kannan and his colleagues developed tiny tree-like synthetic nanoparticles

led dendrimers, each only about 4 nanometers in size. For some unknown reason, these molecules

ve into the brain and travel to activated inflammatory cells. In a paper last year, the team attached

endrimers to an anti-inflammatory drug called N-acetyl-L-cysteine (NAC) to successfully treat rabbits

th cerebral palsy. The dendrimers delivered the NAC straight to rampant inflammatory astrocytes and

icroglia in the brain, and the rabbits responded with improvement in coordination and motor control,

rly reaching the motor skill level of healthy controls. The team also used the technique to arrest

al degeneration in rats.

techniques push, prod, and pressure the BBB to allow bigger and bigger drugs to enter the brain.

team at National Taiwan University recently showed that heparin, a common anticoagulant, used in

nction with focused ultrasound, enhances delivery of molecules across the barrier. At Cincinnati

ren’s Hospital Medical Center, a team is attaching pieces of the fatty protein apolipoprotein E (apoE)

bind to fat receptors on BBB endothelial cells to successfully deliver an enzyme into neurons of mice

ith a lysosomal storage disorder and quell their symptoms. And at Johns Hopkins School of Medicine in

timore, molecular biologists have demonstrated that a protein located on the surface of BBB

othelial cells, called frizzled-4, plays an important role in the arrangement of cerebral blood vessels

nd can be mutated to cause a leaky BBB without destroying the overall integrity of the barrier.

SPRINGING A LEAK: One strategy for allowing drugs to

penetrate brain tissue is to create a semipermeable

window into the brain by using nasal mucosa to patch a

surgically introduced hole in the BBB. Here, fluorescent

microscopic images of mouse brains demonstrate the

increase in area and intensity of uptake of a fluorescent

marker following the surgical procedure.

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list goes on. Which method is most successful will likely depend on what type of molecule one is

to get into the brain. “This is a growing field,” says Watts. “There are a lot of cool things that are

ppening, It’s fun to be a part of it.” tr

gs

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g development, cell

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