Author: Nancy Fliesler

A life-saving adjustment in IV nutrition cleared by the FDA

Fourteen years after Charles Rolfe received an experimental IV fish-oil solution, Omegaven has been approved by the FDA. (PHOTOS: WEBB CHAPPELL/ROLFE FAMILY)

In 2004, a surgeon and a hospital pharmacist went against the prevailing dogma. They began revising the IV nutrition formula being given to children unable to take food by mouth. In doing so, they saved many lives. Yet, it wasn’t until last month that their intervention, a new fat emulsion called Omegaven, gained formal approval from the Food and Drug Administration.

Children with intestinal failure due to gastroschisis, necrotizing enterocolitis or other diseases are typically placed on parenteral nutrition, an intravenous method of feeding. Without it, they would die. But prolonged use of IV nutrition — using the traditional formula — had a massive side effect: injury to the liver. The majority of children either died from liver failure or required a liver transplant.

By 2001, surgeon Mark Puder, MD, at Boston Children’s Hospital was tired of watching babies slowly die from liver disease that should be preventable. He suspected something needed to be adjusted in the IV nutrition formula — particularly the fat component, derived from soybean oil and known as Intralipid.

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Patients with epilepsy and inflammatory bowel disease to get DNA sequenced in study

3000 exomes study to sequence patients with epilepsy, IBD
ILLUSTRATION: ADOBE STOCK

Boston Children’s Hospital has embarked on a strategic initiative to accelerate and expand its research genomics gateway, with plans to sequence the DNA of 3,000 patients with epilepsy or inflammatory bowel disease and their family members. Patients will have access to enroll in this pilot study if their condition is of likely genetic origin but lack a diagnosis after initial clinical genetic testing.

Sequencing will cover the entire exome, containing all of a person’s protein-coding genes. The Epilepsy and IBD were chosen for the pilot because Ann Poduri, MD, MPH and Scott Snapper, MD, PhD, have already made huge inroads into the genetics of these respective disorders. Both have built large, well characterized patient databases for research purposes, have disease-specific genetic expertise and have begun using their findings to inform their patients’ care.

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Gene mutation in children with microcephaly reveals an essential ingredient for brain development

This electron microscope image shows two multivesicular bodies in the dendrites of neighboring neurons in the cerebellum of a normal mouse. Each contains vesicles bearing sonic hedgehog. (Michael Coulter/Boston Children’s Hospital)

In 2012, researchers in the Boston Children’s Hospital lab of Christopher Walsh, MD, PhD, reported a study of three unrelated families that had children with microcephaly. All had smaller-than-normal brains — both the cerebrum and the cerebellum were reduced in size— and all had mutations that knocked out the function of a gene called CHMP1A.

It was clear that CHMP1A is needed for the brain to grow to its proper dimensions. But the study stopped there.

“Then I came along, and my goal was to figure out what this gene is doing in brain during development, and why, when you lose it, you have a small brain,” says Michael Coulter, MD, PhD, who joined the Walsh lab as a student in 2012.

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A tissue engineered heart ventricle for studying rhythm disorders, cardiomyopathy

a tissue engineered heart ventricle
(Luke MacQueen and Michael Rosnach/Harvard University)

While engineered heart tissues can replicate muscle contraction and electrical activity in a dish, many aspects of heart disease can only adequately be captured in 3D. In a report published online yesterday by Nature Biomedical Engineering, researchers describe a scale model of a heart ventricle, built to replicate the chamber’s architecture, physiology and contractions. Cardiac researchers at Boston Children’s Hospital think it could help them find treatments for congenital heart diseases.

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Inhibiting inhibitory neurons gets mice with spinal cord injury to walk again

Boosting KCC2 expression as a treatment for spinal cord injury
Boosting KCC2 expression: A cross section of a mouse spinal cord, stained two different ways, showing increased expression of KCC2 in inhibitory neurons. This increased expression, induced genetically or with a small-molecule drug, correlated with improved motor function, including ankle movement and stepping. (Zhigang He Lab)

Most people with spinal cord injury are paralyzed from the injury site down, even when the cord isn’t completely severed. Why don’t the spared portions of the spinal cord keep working, allowing at least some movement? A new study just published online by Cell provides insight into why these nerve pathways remain quiet. Most intriguingly, it shows that injection with a small-molecule compound can revive these circuits in paralyzed mice — and get them walking again.

“We saw 80 percent of mice treated with this compound recover their stepping ability,” says Zhigang He, PhD, of Boston Children’s Hospital’s F.M. Kirby Neurobiology Center, the study’s senior investigator. “For this fairly severe type of spinal cord injury, this is the most significant functional recovery we know of.”

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Skewed T-cell pathway may help explain transplant rejection, autoimmune diseases

Th17 transplant rejection
Researchers discover a pathway that controls our T helper cell profiles (Fawn Gracey illustration)

Second in a two-part series on transplant tolerance. (See part one.)

Our immune system has two major kinds of T cells. T helper cells, also known as effector T cells, tend to rev up our immune responses, while T regulatory cells tend to suppress or downregulate them. Last week we reported that bolstering populations of T regulatory cells might help people tolerate organ transplants better. A new study turned its focus to T helper cells, and found that an imbalance of these cells causes an exaggerated immune response that may also contribute to transplant rejection.

The study also showed, in mice and in human cells in a dish, that the immune imbalance can be potentially reversed pharmacologically. Findings were published yesterday in the Journal of Clinical Investigation.

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Can we tip the immune system toward transplant tolerance?

Shifting the balance of T cells toward Tregs might promote transplant tolerance
Turning on the DEPTOR gene shifts the immune system balance toward regulatory T cells (Tregs). This might promote transplant tolerance and perhaps curb autoimmune disorders. (Illustration: Fawn Gracey)

First in a two-part series on transplant tolerance. Read part two.

Although organ transplant recipients take drugs to suppress the inflammatory immune response, almost all eventually lose their transplant. A new approach, perhaps added to standard immunosuppressant treatment, could greatly enhance people’s long-term transplant tolerance, report researchers at Boston Children’s Hospital.

The approach, which has only been tested in mice as of yet, works by maintaining a population of T cells that naturally temper immune responses. It does so by turning on a gene called DEPTOR, which itself acts as a genetic regulator. In a study published July 3 in the American Journal of Transplantation, boosting DEPTOR in T cells enabled heart transplants to survive in mice much longer than usual.

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Precision medicine: Focus turns toward data sharing, costs, access

Precision Medicine 2018 at Harvard Medical School
(Paul Avillach via Twitter)

Precision medicine is often equated with high-tech, exquisitely targeted, million-dollar drug treatments. But at Precision Medicine 2018, hosted by Harvard Medical School’s Department of Biomedical Informatics (DBMI) this week, many of the speakers and panelists were more concerned about improving health for everyone and making better use of what we already have: data.

“We’re not going to make major changes in 21st century medicine without embracing data-driven approaches,” said HMS dean George Q. Daley in his opening remarks.

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Phenylketonuria without the ‘phe’: Enzyme therapy offers chance at a better life

Kaylee Goodwin credits pegvaliase for changing her life — including her engagement.
Kaylee Goodwin credits pegvaliase for changing her life — including her engagement. “It’s to the point where I don’t even think I have PKU anymore,” she says.

Kaylee Goodwin, 29, has struggled her whole life to control her blood levels of “phe” — the amino acid known as phenylalanine. “I was told that if my levels were controlled, I would be able to think more clearly and feel better overall,” she says.

Goodwin was born with phenylketonuria (PKU), a genetic metabolic disorder affecting roughly 1 in 16,000 newborns. Her body can’t break down phe because of a genetic mutation disabling the necessary enzyme, phenylalanine hydroxylase (PAH).

If left untreated, phe accumulates in the brain, causing intellectual disability and seizures. But starting in the early 1960s, newborn screening programs have been able to test for PKU. Goodwin tested positive and was prescribed a special phe-free diet by Harvey Levy, MD, at Boston Children’s Hospital.

Through the diet, Goodwin has dodged serious brain damage and was able to attend college and start a career as a dancer and actress. But because phe is in nearly all naturally occurring proteins, she couldn’t eat meat, eggs, dairy products, legumes, most grains and many fruits and vegetables. Instead, she had to consume a foul-tasting amino acid formula.

“I spent my entire life carrying special foods and medical formula around with me, and weighing and measuring foods,” she says.

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Our intestinal microbiome influences metabolism — through the immune system

microbiome metabolism concept - in Drosophila. In absence of intestinal bacteria to modulate metabolism, flies develop fat droplets.

Research tells us that the “good” bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies shows one of the ways in which these commensal microbes keep us metabolically fit.

The findings, published today in Cell Metabolism, suggest that innate immune pathways, our first line of defense against bacterial infection, have a side job that’s equally important.

The intestine’s digestive cells use an innate immune pathway to respond to harmful bacteria by producing antimicrobial peptides. But other intestinal cells, enteroendocrine cells, use the same pathway, known as IMD, to respond to “good” bacteria — by fine-tuning body metabolism to diet and intestinal conditions.

“What’s most interesting to me is that some innate immune pathways aren’t just for innate immunity,” says Paula Watnick, MD, PhD, of the Division of Infectious Diseases at Boston Children’s Hospital. “Innate immune pathways are also listening to the ‘good’ bacteria – and responding metabolically.”

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