Science Seen: To deliver things into cells, do as rotavirus does

rotavirus cell entry - lessons for drug delivery
Courtesy Stephen Harrison

Rotavirus, a major cause of early childhood diarrhea, could have a lot to tell drug developers about how to deliver their products into cells.

Rotavirus doesn’t have an outer membrane, so it’s had to evolve a special system to infect cells. “Viruses with a membrane, like flu or HIV, can simply fuse that membrane with the membrane of the target cell and dump their contents inside the cell,” says Stephen Harrison, PhD, chief of the Laboratory of Molecular Medicine at Boston Children’s Hospital.

Rotavirus does something different, Harrison’s lab has found. First, each virion attaches itself to the cell membrane and wraps itself inside it. Next, its outer proteins, VP4 (the red spikes above) and VP7 (in yellow), disrupt that membrane — and are stripped off in a matter of seconds.

“If you will, they’re the booster the rocket has to shed so the payload can continue,” says Harrison.

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Making breastfeeding a breeze: Cleft lip/palate and beyond

Breast Breeze
Breast Breeze developers Olivia Oppel (left) and Janet Conneely (Photos: Katherine C. Cohen)

Janet Conneely, BSN, RN, CPN, was visiting a new mother in the hospital who had just delivered a baby with a cleft palate to let her know about Boston Children’s Hospital’s Cleft Lip and Palate Program. The mother was trying, without success, to breastfeed, but because of cleft palate, her baby didn’t have an intact hard surface on the roof of her mouth, so couldn’t create enough suction to draw milk.

“I was new to seeing these moms,” Conneely recalls. “This mother was in tears, pleading for ‘some way to be able to breastfeed my baby!’” She adamantly did not want to be shown the specialty bottle typically used for babies with cleft palate.

Conneely tapped her colleague, Olivia Oppel, BSN, RN, CPN, CLC, and together, they reviewed existing breastfeeding products. The few that were available — nipple shields, bottle attachments and a sling that holds the bottle against the breast — were either awkward to use or didn’t really allow for skin-to-skin contact.

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Delivered through amniotic fluid, stem cells could treat a range of birth defects

Transamniotic stem cell therapy, or TRASCET, is like amniocentesis is reverse.
Amniotic fluid is routinely withdrawn for prenatal testing. It could also be a delivery route for fetal cell therapy to treat congenital anomalies, with broader applications than once thought.

The amniotic fluid surrounding babies in the womb contains fetal mesenchymal stem cells (MSCs) that can differentiate into many cell types and tissues. More than a decade ago, Dario Fauza, MD, PhD, a surgeon and researcher at Boston Children’s Hospital, proposed using these cells therapeutically. His lab has been exploring these cells’ healing properties ever since.

Replicated in great quantity in the lab and then reinfused into the amniotic fluid in animal models — a reverse amniocentesis if you will — MSCs derived from amniotic fluid have been shown to repair or mitigate congenital defects before birth. In spina bifida, they have induced skin to grow over the exposed spinal cord; in gastroschisis, they have reduced damage to the exposed bowel. Fauza calls this approach Trans-Amniotic Stem Cell Therapy, or TRASCET.

New research findings, reported this month in the Journal of Pediatric Surgery, could expand TRASCET’s therapeutic potential.

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Why do some people with cystic fibrosis live much longer than others?

Lung tissue, which can be compromised by the genetic disorder known as cystic fibrosis, is seen under microscopic view.
Lung tissue under microscope.

The answer may be hidden in their genes.

Cystic fibrosis is an inherited disorder caused by genetic mutations that disrupt the normal movement of chloride in and out of cells. Among other health problems, cystic fibrosis compromises the lungs’ ability to fight infection and breathe efficiently, making it the most lethal genetic disease in the Caucasian population. Patients have an average lifespan of just 30 to 40 years.

Despite this narrow average lifespan, there is a big range in how severely cystic fibrosis (CF) affects the lungs and other organs depending on an individual’s specific genetic variation, and even in how long patients sharing the same, most common genetic mutation are able to survive with CF.

This led researchers at Boston Children’s Hospital to wonder if other genetic mutations could be protective against CF’s effects. Recent findings published in the American Journal of Respiratory Cell and Molecular Biology suggest that may be the case.

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Teaching an old drug a new trick to treat an ultra-rare red-blood-cell disease

Failed sickle-cell drug learns a new trick: hereditary xerocytosis

The National Institutes of Health maintains a library of drugs, the Clinical Collection, that are safe for humans but failed in clinical trials or didn’t make it to the market for other reasons. These compounds, numbering 450 to date, are just sitting on the shelf, waiting for a researcher to identify a disease process they might treat.

Repurposing such drugs could potentially save the pharmaceutical industry time and money. Getting a new drug from R&D to market currently takes $2 to 3 billion and 13 to 15 years. In contrast, some estimate that repurposing a safe drug could cost just $300 million and take just 6.5 years.

Pfizer, one of the biggest pharma companies in the world, saw the appeal. It just launched SpringWorks Therapeutics, a mission-driven company dedicated to reviving shelved drugs to treat underserved diseases. In its pipeline are experimental therapies to treat four diseases that currently have no cure.

One of the earliest-stage candidates is senicapoc.

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Organs-on-chips reveal breathing’s critical role in lung cancer development

Image of lung cancer cells grown alongside human lung small airway cells inside an organ-on-a-chip
Inside view of a lung cancer chip: Lung adenocarcinoma cells are grown as a tumor cell colony (blue) next to normal human lung small airway cells (purple). Credit: Wyss Institute at Harvard University

One of the biggest challenges facing cancer researchers — and lots of other medical researchers, in fact — is that experimental models cannot perfectly replicate human diseases in the laboratory.

That’s why human Organs-on-Chips, small devices that mimic human organ environments in an affordable and lifelike manner, have quickly been taken up into use by scientists in academic and industry labs and are being tested by the U.S. Food and Drug Administration.

Now, the chips have helped discover an important link between breathing mechanics and lung cancer behavior.

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Can rare pain syndromes point the way to new analgesics?

analgesic drug discovery could reduce prescription opioid use
Boston Children’s Hospital and Amgen will collaborate to discover and accelerate non-addicting pain drugs.

As the opioid epidemic deepens and drug overdoses increase, effective non-addicting painkillers are desperately needed. Efforts to discover new pain pathways to target with new drugs have thus far had little success. Other promising research is investigating triggerable local delivery systems for non-opioid nerve blockers, but it’s still in the early stages.

A new collaboration between Boston Children’s Hospital and the biopharmaceutical company Amgen is aimed at accelerating new pain treatments. Announced yesterday, it will revolve around patients with rare, perplexing pain syndromes. The scientists hope that the genetic variants they find in these patients will shed new light on pain biology and lead to new ways of controlling pain. 

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MATCHing precision medicine to all kids with cancer

Image of human neuroblastoma tumor cells. A new nationwide clinical trial called pediatric MATCH will utilize genomic sequencing to match children with individualized, targeted drugs matched to their tumor profile.
Human neuroblastoma cells.

A multi-center clinical trial is now offering nationwide genetic profiling services to pediatric and young adult cancer patients across the U.S. The goal is to identify gene mutations that can be individually matched with targeted drugs.

“This is the first-ever nationwide precision medicine clinical trial for pediatric cancer,” says pediatric oncologist Katherine Janeway, MD, clinical director of the solid tumor center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

Sponsored by the National Institute of Cancer (NCI) and the Children’s Oncology Group (COG), the so-called NCI-COG Pediatric MATCH trial will screen patients’ tumors for more than 160 gene mutations related to cancer. Nearly 1,000 patients are expected to participate in the trial and it is estimated that 10 percent of those patients will be matched with a targeted therapy.

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Meeting an unmet need: A surgical implant that grows with a child

Depiction of a growth-accommodating implant expanding in sync with a child's growing heart.
Artist’s rendering showing how a braided, tubular implant could grow in sync with a child’s heart valve. Credit: Randal McKenzie

Medical implants can save lives by correcting structural defects in the heart and other organs. But until now, the use of medical implants in children has been complicated by the fact that fixed-size implants cannot expand in tune with a child’s natural growth.

To address this unmet surgical need, a team of researchers from Boston Children’s Hospital and Brigham and Women’s Hospital have developed a growth-accommodating implant designed for use in a cardiac surgical procedure called a valve annuloplasty, which repairs leaking mitral and tricuspid valves in the heart. The innovation was reported today in Nature Biomedical Engineering.

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What do hospitals want from prospective digital health partners?

how digital health startups can better approach hospitals
How digital health startups can better approach hospitals.

How can the growing number of digital health startups sell their products to large-scale healthcare enterprises? Earlier this year, Rock Health, a San Francisco-based venture fund dedicated to digital health, conducted 30-minute interviews with executives at multiple startups and a few large healthcare organizations. They identified several key sticking points: navigating the internal complexities of hospitals, finding the right buyer, identifying the product’s value proposition and relevance to the hospital and avoiding “death by pilot.”

Now, in a Rock Health podcast, John Brownstein, PhD, Chief Innovation Officer at Boston Children’s Hospital’s Innovation and Digital Health Accelerator and Adam Landman, MD, MS, MIS, MHS, Chief Information Officer at Brigham and Women’s Hospital and part of its Innovation Hub, offer further tips from the inside. They were hosted by Rock Health’s director of research, Megan Zweig.

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