Stories about: Therapeutics

Two-drug approach halts lung tumors by starving them metabolically

(Illustration: Fawn Gracey)

Non-small-cell lung cancer is the leading cause of cancer death in the U.S. Roughly 1 in 4 cases are driven by the mutant KRAS oncogene. Though scientists have tried for more than three decades to target KRAS with drugs, they’ve had little success.

In a new study led by Nada Kalaany, PhD, and colleagues at Boston Children’s Hospital took a different approach, looking at what these deadly lung tumors need metabolically to live and grow. Reporting in the Proceedings of the National Academy of Sciences (PNAS), they show that a combination of two existing drugs can effectively starve tumors in a mouse model.

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Zeroing in on the fetal-to-adult hemoglobin switch and a new way to combat sickle cell disease

Normal red blood cell vs. sickle-shaped blood cell, which is found in sickle cell disease
Normal red blood cell vs. sickle-shaped blood cell.

It’s been known for more than 40 years that in rare individuals, lingering production of the fetal form of hemoglobin — the oxygen-transporting protein found in red blood cells — can reduce the severity of certain inherited blood disorders, most notably sickle cell disease and thalassemia. Typically, however, a protein called BCL11A switches off fetal hemoglobin production past infancy, but exactly how this happens has not been well understood until now.

In a new paper in Cell, researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center have revealed how BCL11A controls the switch in the body’s production of fetal hemoglobin to adult hemoglobin. It does so by binding to a DNA sequence — made up of the bases T-G-A-C-C-A — that lies just in front of the fetal hemoglobin genes.

Another approach to curing sickle cell disease is already being evaluated in a new clinical trial at Dana-Farber/Boston Children’s. The novel gene therapy restores fetal hemoglobin production by genetically suppressing BCL11A, which prevents it from blocking fetal hemoglobin production. Learn more.

“Genetically modifying this TGACCA segment could be another possible strategy to cure sickle cell disease by blocking BCL11A’s ability to bind to this DNA site and switch off fetal hemoglobin production,” says Stuart Orkin, MD, senior author on the study.

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Why does bariatric surgery ease diabetes?

diabetes gastric bypass

Many people who have Roux-en-Y gastric bypass surgery for obesity experience a striking but welcome side effect. In up to 80 percent of patients who also have type 2 diabetes, the diabetes abates even before they lose weight. A new study helps explain why, and suggests possible ways to combat diabetes (and obesity) without having to actually perform bariatric surgery.

“Our aim is to ‘reverse engineer’ the surgery, to find how it works and apply the mechanisms to new, less invasive treatments,” said study lead author Margaret Stefater, MD, PhD, a fellow in the lab of Nicholas Stylopoulos, MD, in a press release.

The Stylopoulos Lab, in Boston Children’s Hospital’s Division of Endocrinology, previously showed in a seminal 2013 paper that the bypass operation causes the small intestine to ramp up its sugar intake. In rodents, this appeared to account for resolution of their diabetes. Stylopoulos, together with collaborator Anita Courcoulas, MD, MPH of the University of Pittsburgh, then started an NIH-funded observational study of people undergoing Roux-en-Y gastric bypass surgery.

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The softer the nanoparticle, the better the drug delivery to tumors

Nanolipogels, pictured here, are a promising drug delivery system
Nanolipogels of different stiffness, as seen through a transmission electron microscope. Credit: Moses lab/Boston Children’s Hospital.

For the first time, scientists have shown that the elasticity of nanoparticles can affect how cells take them up in ways that can significantly improve drug delivery to tumors.

A team of Boston Children’s Hospital researchers led by Marsha A. Moses, PhD, who directs the Vascular Biology Program, created a novel nanolipogel-based drug delivery system that allowed the team to investigate the exclusive role of nanoparticle elasticity on the mechanisms of cell entry.

Their findings — that softer nanolipogels more efficiently enter cells using a different internalization pathway than their stiffer counterparts — were recently published in Nature Communications.

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Could poop transplants treat peanut allergy? A clinical trial begins

FMT peanut allergy

Increasing evidence supports the idea that the bacteria living in our intestines early in life help shape our immune systems. Factors like cesarean birth, early antibiotics, having pets, number of siblings and formula feeding (rather than breastfeeding) may affect our microbial makeup, or microbiota, and may also affect our likelihood of developing allergies.

Could giving an allergic person the microbiota of a non-allergic person prevent allergic reactions? In a new clinical trial, a team led by Rima Rachid, MD, of Boston Children’s Division of Allergy and Immunology, is testing this idea in adults with severe peanut allergies. The microbiota will be delivered through fecal transplants — in the form of frozen, encapsulated poop pills.

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Prescriptions for accelerating neuroscience translation: Q&A with Mustafa Sahin, MD, PhD

Mustafa Sahin Translational Neuroscience CenterMustafa Sahin, MD, PhD, a neurologist at Boston Children’s Hospital, directs the Translational Neuroscience Center, which he founded several years ago to accelerate neuroscience research to the clinic. He also directs the hospital’s Translational Research Program. In this interview with Boston Children’s Technology and Innovation Development Office (TIDO), Sahin talks about his motivations as a clinician-scientist and how he works with industry partners to move discoveries forward.

What drives you as a scientist? 

What drives me as a scientist has changed over the course of my career. It was my fascination with experimentation that first got me interested in biology. In high school, I took vials of fruit flies to a radiation oncology department and tested the effects of radiation on the mutation rate. When I came to the U.S. to study biochemistry in college, I was drawn to the mysteries of the brain. While my PhD and postdoctoral work continued on very fundamental questions about how neurons connect to each other, advances in genetics and neuroscience allowed me to bring rigorous basic science approaches to clinical questions. So more and more, my science is driven by a need to bring treatments to the patients I see in the clinic. Fortunately, this is no longer a long-term, aspirational goal, but something within reach in my career.

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A breakthrough in our understanding of how red blood cells develop

Artist's rendering of red blood cells
Red blood cells.

By taking a deep dive into the molecular underpinnings of Diamond-Blackfan anemia, scientists have made a new discovery about what drives the development of mature red blood cells from the earliest form of blood cells, called hematopoietic (blood-forming) stem cells.

For the first time, cellular machines called ribosomes — which create proteins in every cell of the body — have been linked to blood stem cell differentiation. The findings, published today in Cell, have revealed a potential new therapeutic pathway to treat Diamond-Blackfan anemia. They also cap off a research effort at Boston Children’s Hospital spanning nearly 80 years and several generations of scientists.

Diamond-Blackfan anemia — a severe, rare, congenital blood disorder — was first described in 1938 by Louis Diamond, MD, and Kenneth Blackfan, MD, of Boston Children’s. The disorder impairs red blood cell production, impacting delivery of oxygen throughout the body and causing anemia. Forty years ago, David Nathan, MD, of Boston Children’s determined that the disorder specifically affects the way blood stem cells become mature red blood cells.

Then, nearly 30 years ago, Stuart Orkin, MD, also of Boston Children’s, identified a protein called GATA1 as being a key factor in the production of hemoglobin, the essential protein in red blood cells that is responsible for transporting oxygen. Interestingly, in more recent years, genetic analysis has revealed that some patients with Diamond-Blackfan have mutations that block normal GATA1 production.

Now, the final pieces of the puzzle — what causes Diamond-Blackfan anemia on a molecular level and how exactly ribosomes and GATA1 are involved — have finally been solved by another member of the Boston Children’s scientific community, Vijay Sankaran, MD, PhD, senior author of the new Cell paper.

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News Note: Modeling sepsis better to find a cure faster

In this SEM image, E. coli (green) bacteria, a common instigator of sepsis, is captured by bioengineered magnetic beads.
New assessment criteria for monitoring sepsis in pig models could help clinical researchers more accurately evaluate potential sepsis treatments in preclinical experiments. In this SEM image, E. coli (green) bacteria, a common instigator of sepsis, is captured by bioengineered magnetic beads. Credit: Wyss Institute at Harvard University

Sepsis, or blood poisoning, occurs when the body’s response to infection damages its own tissues, leading to organ failure. It is the most common cause of death in people who have been hospitalized, yet no new therapies have been developed in the last 30 years. Many treatments that have prevented death in animal experiments have failed in clinical trials, indicating that a more clinically-relevant sepsis model is needed for therapeutic development.

To bridge this gap, a team of scientists from the Wyss Institute at Harvard University and Boston Children’s Hospital think a better experimental model of sepsis in pigs could help weed out the therapies most likely to succeed in humans. Their method, a scoring criteria to evaluate sepsis in pigs that closely mirrors standard human clinical assessment, is reported in Advances in Critical Care Medicine.

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A new tactic for eczema? A newly identified brake on the allergic attack

baby with eczema
(Arkady Chubykin/Adobe Stock)

Eczema affects about 17 percent of children in developed countries. Often, it’s a gateway to food allergy and asthma, initiating an “atopic march” toward broader allergic sensitization. There are treatments – steroid creams and a recently approved biologic – but they are expensive or have side effects. A new study in Science Immunology suggests a different approach to eczema, one that stimulates a natural brake on the allergic attack.

The skin inflammation of eczema is known to be driven by “type 2” immune responses. These are led by activated T helper 2 (TH2) cells and type 2 innate lymphoid cells (ILC2s), together known as effector cells. Another group of T cells, known as regulatory T cells or Tregs, are known to temper type 2 responses, thereby suppressing the allergic response.

Yet, if you examine an eczema lesion, the numbers of Tregs are unchanged. Interestingly, Tregs comprise only about 5 percent of the body’s T cells, but up to 50 percent of T cells in the skin.

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Snaps from the lab: From gene discovery to gene therapy for one rare disease

Will Ward’s birthday falls on Rare Disease Day (Feb. 28). That’s an interesting coincidence because he has a rare disease: X-linked myotubular myopathy (MTM), a rare, muscle-weakening disease that affects only boys. Originally on Snapchat, this video captures the Ward family’s recent visit to the lab of Alan Beggs, PhD to learn more about MTM research.

Beggs, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, has known Will since he was a newborn in intensive care. In this lab walk-though you’ll see a freezer filled with muscle samples, stored in liquid nitrogen; muscle tissue under a microscope; gene sequencing to identify mutations causing MTM and other congenital myopathies and a testing station to measure muscle function in samples taken from animal models.

Beggs’s work, which began more than 20 years ago, led to pivotal studies in male Labrador retrievers who happen to have the same mutation and are born with a canine form of MTM. By adding back a healthy copy of the gene, Beggs’s collaborators got the dogs back on their feet running around again. (Read about Nibs, a female MTM carrier whose descendants took part in these studies.)

Based on the canine results, a clinical trial is now testing gene therapy in boys under the age of 5 with MTM. The phase I/II trial aims to enroll 12 boys and measure their respiratory and motor function and muscle structure after being dosed with a vector carrying a corrected MTM gene. In the meantime, observational and retrospective studies are characterizing the natural history of boys with MTM.

Learn more about the Manton Center for Orphan Disease Research.

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