Stories about: Therapeutics

Inhaled hydrogen could protect the brain during heart-lung bypass

hydrogen gas
ILLUSTRATION: ELENA HARTLEY / BOSTON CHILDREN’S HOSPITAL

Newborns with life-threatening congenital heart disease often undergo open-heart surgery with cardiopulmonary bypass, which carries a risk of damaging the brain. Critically ill newborns who are placed on ECMO are at even higher risk for brain injury.  Hypothermia, or cooling the body, can improve neurologic outcomes, but has limitations.

A new study in a large animal model suggests that adding a dash of hydrogen to the usual mix of respiratory gases could further protect babies’ brains.

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Protecting damaged hearts with microRNAs

microRNAs facilitate cardiac regeneration after a heart attack
New work advances the possibility of regenerating cardiac tissue after a heart attack. (PHOTO: ADOBE STOCK)

Once the heart is fully formed, the cells that make up heart muscle, known as cardiomyocytes, have very limited ability to reproduce themselves. After a heart attack, cardiomyocytes die off; unable to make new ones, the heart instead forms scar tissue. Over time, this can set people up for heart failure.

New work published last week in Nature Communications advances the possibility of reviving the heart’s regenerative capacities using microRNAs — small molecules that regulate gene function and are abundant in developing hearts.

In 2013, Da-Zhi Wang, PhD, a cardiology researcher at Boston Children’s Hospital and a professor of pediatrics of Harvard Medical School, identified a family of microRNAs called miR-17-92 that regulates proliferation of cardiomyocytes. In new work, his team shows two family members, miR-19a and miR-19b, to be particularly potent and potentially good candidates for treating heart attack.

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Probing the mystery of drug resistance: New hope for leukemia’s toughest cases

Alejandro Gutierrez, MD, was inspired by the deaths of three patients to figure out how leukemia cells become resistant to drugs.
Alejandro Gutierrez, MD
(PHOTO: MICHAEL GODERRE / BOSTON CHILDREN’S HOSPITAL)

Three children Alejandro Gutierrez, MD, treated for leukemia during his fellowship at Boston Children’s Hospital still haunt him more than a decade later. One 15-year-old boy died from the toxicity of the drugs he was given; the other two patients went through the whole treatment only to die when their leukemia came back. “That really prompted a deep frustration with the status quo,” Gutierrez recalls. “It’s motivated everything I’ve done in the lab since then.”

Gutierrez, now a researcher in the Division of Hematology/Oncology, has made it his mission to figure out why leukemia treatments cure some patients but not others. And in today’s issue of Cancer Cell, he and 15 colleagues report progress on two important fronts: They shed light on how leukemia cells become resistant to drugs, and they describe how two drugs used in combination may overcome that resistance, offering new hope to thousands of children and adults with leukemia.

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‘Nanobodies’ from alpacas could help bring CAR T-cell therapy to solid tumors

These alpacas produce the unusually small antibodies (nanobodies) used in a new form of CAR T-cell therapy
Like other alpacas, as well as camels and llamas, Bryson (left) and Sanchez produce unusually small antibodies that could have a role in cancer immunotherapy. (PHOTO COURTESY HIDDE PLOEGH / BOSTON CHILDREN’S HOSPITAL)

In 1989, two undergraduate students at the Free University of Brussels were asked to test frozen blood serum from camels, and stumbled on a previously unknown kind of antibody. It was a miniaturized version of a human antibody, made up only of two heavy protein chains, rather than two light and two heavy chains. As they eventually reported, the antibodies’ presence was confirmed not only in camels, but also in llamas and alpacas.

Fast forward 30 years. In the journal PNAS this week, researchers at Boston Children’s Hospital and MIT show that these mini-antibodies, shrunk further to create so-called nanobodies, may help solve a problem in the cancer field: making CAR T-cell therapies work in solid tumors.

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More efficient gene editing for blood stem cells could ease hemoglobin disorders

A new CRISPR strategy overcomes prior technical challenges. IMAGE: NANCY FLIESLER / ADOBE STOCK

The ability to edit genes in patients’ blood stem cells — which produce red blood cells, platelets, immune cells and more — offers the potential to cure many genetic blood disorders. If all goes well, the corrected cells engraft in the bone marrow and produce healthy, properly functioning blood cells… forever.

But scientists have had difficulty introducing edits into blood stem cells. The efficiency and specificity of the edits and their stability once the cells engraft in the bone marrow have been variable.

A new approach, described this week in Nature Medicine and in January in the journal Blood, overcomes prior technical challenges, improving the efficiency, targeting and durability of the edits. Researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the University of Massachusetts Medical School successfully applied the technique to two common blood diseases — sickle cell disease and beta thalassemia — involving mutations in the gene for beta globin protein.

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Mobilizing the immune system’s ‘natural killers’ against inflammatory bowel disease

Stripped of their STAT1 protein “shield,” the helper T cells that cause inflammatory
bowel disease are wiped out by the immune system’s “natural killer” (NK) cells.
(ILLUSTRATION: FAWN GRACEY)

The human immune system includes about a dozen major cell types with specialized roles in the body’s defenses. They serve as sentries, identify threats, mobilize troops, capture and transport invaders, interrogate and kill those deemed dangerous and clear the battlefield of casualties. This intricate command-and-control system is what enables us to fend off most of the dangerous bacteria and viruses that come our way.

But in patients who suffer from inflammatory bowel disease (IBD), the immune system itself becomes the enemy. Even when the body faces no threat, immune cells called “helper T cells” take up arms, resulting in a kind of perpetual warfare that — far from being helpful — causes collateral damage to the gut.

“The system goes into overdrive,” says Yu Hui Kang, an immunology graduate student at Harvard Medical School and a researcher at Boston Children’s Hospital. “These cells have gone too far, and they can’t stop.”

Now Kang and colleagues in the lab of Scott Snapper, MD, PhD, director of Boston Children’s Inflammatory Bowel Disease Center, may have found a way to turn the tables on the immune system by recruiting its own “natural killer” cells to wipe out the harmful T cells. Though clinical applications are years away, the work suggests new avenues for developing treatments for the debilitating disease.

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Dually-targeted liposomes curb triple-negative breast cancer, metastases in mice

dual targeting for triple-negative breast cancer
(IMAGE: ADOBE STOCK)

Some 15 to 20 percent of all breast cancers are triple-negative, meaning they lack receptors for estrogen, progesterone and human epidermal growth factor type 2. They have the worst prognosis of all breast cancers and very limited treatment options. Finding a treatment that distinguishes between cancer cells and normal cells has been especially challenging.

A novel precision medicine strategy described today in Science Advances offers an intriguing ray of hope. Researchers at Boston Children’s Hospital, with bioengineers at the City College of New York (CCNY), showed that dually-targeted, antibody-guided nanoparticles, loaded with an existing chemotherapy drug, markedly improved tumor targeting, decreased tumor and metastatic growth and dramatically improved survival in a mouse model of triple-negative breast cancer. There were no observable side effects.

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How celastrol sensitizes brains to leptin, curbing hunger and obesity

celastrol path of action
Celastrol increases numbers of IL1R1 receptors in the brain, allowing leptin to act. (ILLUSTRATION: ELLA MARU STUDIO)

Here’s what’s known about celastrol, widely hailed in 2015 for its potent anti-obesity effects. It’s derived from the roots of the thunder god vine. It increases the brain’s sensitivity to leptin, the hormone that signals we’ve had enough to eat. It has curbed food intake by nearly 80 percent in obese mice, producing up to a 45 percent weight loss. It’s now in Phase 1 clinical trials conducted by ERX Pharmaceuticals; phase 2 studies are slated to begin this year.

What hasn’t been known is how celastrol makes the brain more sensitive to leptin. A study in today’s Nature Medicine finally provides an answer.

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50-year-old mystery solved — with clues to making more red blood cells

why steroids boost red blood cell production
Red blood cells produced by a single progenitor cell (IMAGE COURTESY HOJUN LI / DANA-FARBER/BOSTON CHILDREN’S VIA CELL PRESS)

Back in the 1950s, doctors began using steroids to treat Diamond-Blackfan anemia, or DBA, a severe condition in which patients cannot make enough red blood cells. There was no real rationale for using steroids, but there was no other good option, aside from regular transfusions. At the time, steroids were being thrown at seemingly everything.

But steroids worked in most patients, at least for a time — at the expense of serious side effects such as weight gain, bone loss, hypertension, diabetes and an increased risk of infections. A new study published yesterday in Developmental Cell finally explains why steroids work — and could provide a foothold for developing safer and better treatments for DBA. It could even pave the way to treatments for other types of bone marrow failure.

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Light-activated nanoparticles could avoid painful eye injections for ‘wet’ macular degeneration

Could intravitreal injections become a thing of the past?
(PHOTO: ZKALILA1998 / WIKIMEDIA COMMONS)

There are two standard treatments for “wet” age-related macular degeneration (AMD), in which abnormal, leaky blood vessels in the back of the eye lead to fluid buildup and vision loss. The first, injection of medication directly into the eye, can be painful and can cause inflammation, infection and detachment of the retina. The second, ablation therapy, uses lasers to destroy the leaky blood vessels. It, too, is unpleasant to undergo, and the lasers can also destroy surrounding healthy tissue, causing further vision loss.

In today’s Nature Communications, the lab of Daniel Kohane, MD, PhD, provides proof-of-concept of a more tolerable alternative: tiny, drug-carrying nanoparticles that can be injected intravenously, but deliver medication only to the eye.

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