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blood-brain barrier

One Little Girl’s Story Highlights the Promise of Precision Medicine

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Photo of Dr. Yu taking a selfie with Mila and her mom
Caption: Mila with researcher Timothy Yu and her mother Julia Vitarello. Mila’s head is covered in gauze because she’s undergoing EEG monitoring to determine if her seizures are responding to treatment. Credit: Boston Children’s Hospital

Starting about the age of 3, Mila Makovec’s parents noticed that their young daughter was having a little trouble with words and one of her feet started turning inward. Much more alarmingly, she then began to lose vision and have frequent seizures. Doctors in Colorado diagnosed Mila with a form of Batten disease, a group of rare, rapidly progressive neurological disorders that are often fatal in childhood or the teenage years. Further testing in Boston revealed that Mila’s disease was caused by a genetic mutation that appears to be unique to her.

No treatment existed for Mila’s condition. So, in an effort to meet that urgent need, Timothy Yu and his colleagues at Boston Children’s Hospital set forth on a bold and unprecedented course of action. In less than a year, they designed a drug that targeted Mila’s unique mutation, started testing the tailor-made drug for efficacy and safety on cells derived from her skin, and then began giving Mila the drug in her own personal clinical trial.

The experimental drug, which has produced no adverse side effects to date, hasn’t proved to be a cure for Mila’s disease [1]. But it’s helped to reduce Mila’s seizures and also help her stand and walk with assistance, though she still has difficulty communicating. Still, the implications of this story extend far beyond one little girl: this work demonstrates the promise of precision medicine research for addressing the unique medical challenges faced by individuals with extremely rare diseases.

Mila’s form of Batten disease usually occurs when a child inherits a faulty copy of a gene called CLN7 from each parent. What surprised doctors is Mila seemed to have inherited just one bad copy of CLN7. Her mother reached out online in search of a lab willing to look deeper into her genome, and Yu’s lab answered the call.

Yu suspected Mila’s second mutation might lie buried in a noncoding portion of her DNA. The lab’s careful analysis determined that was indeed the case. The second mutation occurred in a stretch of the gene that normally doesn’t code for the CLN7 protein at all. Even more unusual, it consisted of a rogue snippet of DNA that had inserted itself into an intron (a spacer segment) of Mila’s CLN7 gene. As a result, her cells couldn’t properly process an RNA transcript that would produce the essential CLN7 protein.

What might have been the end of the story a few years ago was now just the beginning. In 2016, the Food and Drug Administration (FDA) approved a novel drug called nusinersen for a hereditary neurodegenerative disease called spinal muscular atrophy (SMA), caused by another faulty protein. As I’ve highlighted before, nusinersen isn’t a typical drug. It’s made up of a small, single-stranded snippet of synthetic RNA, also called an oligonucleotide. This drug is designed to bind to faulty RNA transcripts in just the right spot, “tricking” cells into producing a working version of the protein that’s missing in kids with SMA.

Yu’s team thought the same strategy might work to correct the error in Mila’s cells. They reasoned that an appropriately designed oligonucleotide could block the effect of the rogue snippet in her CLN7 gene, allowing her cells to restore production of working protein.

The team produced candidate oligonucleotides and tested them on Mila’s cells growing in a lab dish. They found three candidates that worked. The best, which they named milasen after Mila, was just 22-nucleotides long. They designed it to have some of the same structural attributes as nusinersen, given its established safety and efficacy in kids with SMA.

Further study suggested that milasen corrected abnormalities in Mila’s cells in a lab dish. The researchers then tested the drug in rats and found that it appeared to be safe.

A month later, with FDA approval, they delivered the drug to Mila, administered through a spinal tap (just like nusinersen). That’s because the blood-brain barrier would otherwise prevent the drug from reaching Mila’s brain. Beginning in January 2018, she received gradually escalating doses of milasen every two weeks for about three months. After that, she received a dose every two to three months to maintain the drug in her system.

When Mila received the first dose, her condition was rapidly deteriorating. But it has since stabilized. The number of seizures she suffers each day has declined from about 30 to 10 or less. Their duration has also declined from 1 or 2 minutes to just seconds.

Milasen remains an investigational drug. Because it was designed specifically for Mila’s unique mutation, it’s not a candidate for use in others with Batten disease. But the findings do show that it’s now possible to design, test, and deploy a novel therapeutic agent for an individual patient with an exceedingly rare condition on the basis of a thorough understanding of the underlying genetic cause. This is a sufficiently significant moment for the development of “n = 1 therapeutics” that senior leaders of the Food and Drug Administration (FDA) published an editorial to appear along with the clinical report [2].

Yu’s team suspects that a similar strategy might work in other cases of people with rare conditions. That tantalizing possibility raises many questions about how such individualized therapies should be developed, evaluated, and tested in the months and years ahead.

My own lab is engaged in testing a similar treatment strategy for kids with the very rare form of premature aging called Hutchinson-Gilford progeria, and we were heartened by this report. As we grapple with those challenges, we can all find hope and inspiration in Mila’s smile, her remarkable story, and what it portends for the future of precision medicine.

References:

[1] Patient-customized oligonucleotide therapy for a rare genetic disease. Kim J, Hu C, Moufawad El Achkar C, Black LE, Douville J, Larson A, Pendergast MK, Goldkind SF, Lee EA, Kuniholm A, Soucy A, Vaze J, Belur NR, Fredriksen K, Stojkovska I, Tsytsykova A, Armant M, DiDonato RL, Choi J, Cornelissen L, Pereira LM, Augustine EF, Genetti CA, Dies K, Barton B, Williams L, Goodlett BD, Riley BL, Pasternak A, Berry ER, Pflock KA, Chu S, Reed C, Tyndall K, Agrawal PB, Beggs AH, Grant PE, Urion DK, Snyder RO, Waisbren SE, Poduri A, Park PJ, Patterson A, Biffi A, Mazzulli JR, Bodamer O, Berde CB, Yu TW. N Engl J Med. 2019 Oct 9 [Epub ahead of print]

[2] Drug regulation in the era of individualized therapies. Woodcock J, Marks P. N Engl J Med. 2019 Oct 9 {Epub ahead of print]

Links:

Batten Disease Fact Sheet (National Institute of Neurological Disorders and Stroke/NIH)

Mila’s Miracle Foundation (Boulder, CO)

Timothy Yu (Boston Children’s Hospital, MA)

NIH Support: National Center for Advancing Translational Sciences


Making Personalized Blood-Brain Barriers in a Dish

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Credit: Vatine et al, Cell Stem Cell, 2019

The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.

But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.

To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.

While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.

The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.

Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.

The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!

As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.

In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.

Reference:

[1] Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, Wen N, Spivia WR, Chen Z, Van Eyk J, Svendsen CN. Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Stem Cell Information (NIH)

Svendsen Lab (Cedars-Sinai, Los Angeles)

NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences


Blast Off! Sending Human Tissue Chips into Space

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Tissue Chips in Space

Credit: Josh Valcarcel, NASA

A big challenge in unlocking the mysteries of aging is how long you need to study humans, or even human cells, to get answers. But, in partnership with NASA, NIH is hoping that space will help facilitate this important area of research.

It’s already known, from what’s been seen in astronauts, that the weightless conditions found in space can speed various processes associated with aging. So, might it be possible to use the space station as a lab to conduct aging experiments?


Exercise Releases Brain-Healthy Protein

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ExerciseWe all know that exercise is important for a strong and healthy body. Less appreciated is that exercise seems also to be important for a strong and healthy mind, boosting memory and learning, while possibly delaying age-related cognitive decline [1]. How is this so? Researchers have assembled a growing body of evidence that suggests skeletal muscle cells secrete proteins and other factors into the blood during exercise that have a regenerative effect on the brain.

Now, an NIH-supported study has identified a new biochemical candidate to help explore the muscle-brain connection: a protein secreted by skeletal muscle cells called cathepsin B. The study found that levels of this protein rise in the blood of people who exercise regularly, in this case running on a treadmill. In mice, brain cells treated with the protein also exhibited molecular changes associated with the production of new neurons. Interestingly, the researchers found that the memory boost normally provided by exercise is diminished in mice unable to produce cathepsin B.


Creative Minds: A New Chemistry for Aging Research?

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Tony Wyss-Coray

Tony Wyss-Coray / Credit: Stanford School of Medicine

Basic scientists have long studied aging by looking inside of cells. While this research has produced many important leads, they are now starting to look outside the cell for the wealth of biochemical clues contained in the bloodstream.

To introduce you to this exciting frontier in aging research, this blog highlighted a while back the work of Tony Wyss-Coray at Stanford School of Medicine, Palo Alto, CA. He and a colleague had just received a 2013 NIH Director’s Transformative Research Award to explore the effects of exercise on the brains of mice. Their work, in fact, produced one of Science Magazine’s Breakthrough Discoveries of 2014. Their team showed that by fusing the circulatory systems of old and young mice to create a shared blood supply, the young blood triggered new muscle and neural connections in the older mice, while also improving their memories.

As fascinating as this theoretical Fountain of Youth was, Wyss-Coray recognized a critical limitation. He had no way of knowing how factors secreted by the young mouse could actually cross the blood-brain barrier and rejuvenate neurons. To solve this unknown, Wyss-Coray recently received a 2015 NIH Director’s Pioneer Award to build a potentially game-changing tool to track the aging process in mice.