Stories about: Therapeutics

2017 pediatric biomedical advances at Boston Children’s Hospital: Our top 10 picks

New tools and technologies fueled biomedicine to great heights in 2017. Here are just a few of our top picks. All are great examples of research informing better care for children (and adults).

1. Gene therapy arrives

(Katherine C. Cohen)

In 2017, gene therapy solidly shed the stigma of Jesse Gelsinger’s 1999 death with the development of safer protocols and delivery vectors. Though each disease must navigate its own technical and regulatory path to gene therapy, the number of clinical trials is mounting worldwide, with seven gene therapy trials now recruiting at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. In August, the first gene therapy won FDA approval: CAR T-cell therapy for pediatric acute lymphoblastic leukemia.

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One-time hydrocephalus operation, alternative to shunting, brings good outcomes for babies

infant hydrocephalus archival photos
(Flickr/Wikimedia Commons)

Hydrocephalus, literally “water on the brain,” is an abnormal build-up of cerebrospinal fluid in the brain cavities known as ventricles. In infants, it can be congenital (it often accompanies spina bifida, for example), or it can be caused by brain hemorrhage or infection. The usual treatment is surgery to implant a shunt, which drains the excess fluid into the abdomen, relieving pressure on the brain.

But over time, shunts nearly always fail, requiring emergency neurosurgery to repair or replace them. But emergency neurosurgery is not something that’s readily available outside of metropolitan areas. Untreated, hydrocephalus causes progressive brain damage and usually death.

What if a one-time operation could treat hydrocephalus permanently? In today’s New England Journal of Medicine, a randomized trial shows good results with a minimally invasive, relatively inexpensive shunt alternative called endoscopic third ventriculostomy with choroid plexus cauterization (ETV/CPC).

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Taking a sideswipe at high-risk neuroblastoma

Microscopy image of human neuroblastoma cells.
Human neuroblastoma cells.

Cancer and other diseases are now understood to spring from a complex interplay of biological factors rather than any one isolated origin. New research reveals that an equally-nuanced approach to treating high-risk neuroblastoma may be the most effective way to curb tumor growth.

One challenge in treating pediatric cancers like neuroblastoma is that they are not initiated from the same kinds of genetic mutations as adult cancers, which usually arise from mutations related to an accumulation of DNA replication errors or environmental factors. In contrast, childhood cancers more often stem from genetic duplications, deletions or translocations, the latter of which occurs when a gene sequence switches its location from one chromosome to another.

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Patients’ individual genomes may affect efficacy, safety of gene editing

gene editing - truck delivering code
Subtle genetic variants in or near the gene editing target site could cause reagents to miss an address or arrive at the wrong one, researchers say.

Gene editing has begun to be tested in clinical trials, using CRISPR-Cas9, zinc finger nucleases (ZFN) and other technologies to directly edit DNA inside people’s cells. Multiple trials are in the recruiting or planning stages. But a study in PNAS this week raises a note of caution, finding that person-to-person genetic differences may undercut the efficacy of the gene editing process or, in more rare cases, cause a potentially dangerous “off target” effect.

The study adds to evidence that gene editing may need to be adapted to each patient’s genome, to ensure there aren’t variants in DNA sequence in or near the target gene that would throw off the technology.

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Which bacteria in the gut microbiome are really influencing disease?

investigating the 'influencers' in the gut microbiome

Over the last decade, multiple studies have examined possible links between groups of microbes and the presence or absence of multiple diseases, including diabetes, multiple sclerosis, autism and inflammatory bowel disease. But on an individual basis, it’s been unclear which microbes are innocent bystanders, mere markers of disease, and which are active agents, causing harm or providing protection.

Scientists from Harvard Medical School and Boston Children’s Hospital have now designed and successfully used a method to tease out cause-and-effect relationships within the microbiome. Their work, conducted in mice, was described Dec. 6 in Nature.

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Routing gene therapy directly into the brain

Image of mouse brain that received a transplantation of hematopoietic stem cells. The image shows the transplanted cells (green) rapidly engrafted and gave rise to new cells (also green) that have widely distributed throughout the entire brain. 
Image of a mouse brain that received a direct transplantation of hematopoietic stem cells. The image reveals the transplanted cells (green) rapidly engrafted and gave rise to new cells (also green) that have widely distributed throughout the entire brain.

A therapeutic technique to transplant blood-forming (hematopoietic) stem cells directly into the brain could herald a revolution in our approach to treating central nervous system diseases and neurodegenerative disorders.

The technique, which could be used to transplant donor-matched hematopoietic stem cells (HSCs) or a patient’s own genetically-engineered HSCs into the brain, was reported in Science Advances today by researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the San Raffaele Telethon Institute for Gene Therapy.

In their study, the team tested the technique in a mouse model to treat lysosomal storage disorders, a group of severe metabolic disorders that affect the central nervous system.

The team’s findings are groundbreaking because, until now, it was thought that HSCs — from a healthy, matched donor or a patient’s own genetically-corrected cells — needed to be transplanted indirectly

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Bypassing a narrowed midaorta with a living, growing graft

Midaortic syndrome is marked by narrowing of the middle section of the aorta.

By the time he arrived at Boston Children’s Hospital, the 6-month-old boy was near death from midaortic syndrome — a rare but life-threatening condition marked by narrowing of the middle section of the aorta, the largest artery in the body. It had left him with severe hypertension, acute kidney injury and heart failure. As cardiologists worked to stabilize him, the surgical team weighed the options.

With diminished blood flow to the chest, abdomen and lower limbs, a significant number of people with untreated midaortic syndrome die from complications by age 40. The condition can be treated surgically, traditionally with a prosthetic graft made from synthetic material to perform an aortic bypass. But synthetic grafts can pose a number of challenges in children.

“Synthetic grafts don’t grow with the patient, which means that multiple surgeries may be necessary through the years to ensure appropriate graft size,” explains nephrologist Michael Ferguson, MD, who was a member of this patient’s care team. “Artificial grafts also carry a higher risk of thrombosis and infection.”

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Why evolution is the challenge — and the promise — in developing a vaccine against HIV

HIV surrounds and attacks a cell.
HIV surrounds and attacks a cell.

To fight HIV, the development of immunization strategies must keep up with how quickly the virus modifies itself. Now, Boston Children’s Hospital researchers are developing models to test HIV vaccines on a faster and broader scale than ever before with the support of the Bill & Melinda Gates Foundation.

“The field of HIV research has needed a better way to model the immune responses that happen in humans,” says Frederick Alt, PhD, director of the Boston Children’s Program in Cellular and Molecular Medicine, who is leading the HIV vaccine research supported by the Gates Foundation.

The researchers are racing against HIV’s sophisticated attack on the human immune system. HIV, the human immunodeficiency virus, mutates much faster than other pathogens. Within each infected patient, one virus can multiply by the billions.

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What’s trending in neurological drug development?

Advanced MRI scans of the brain showing neural network connections
Credit: Boston Children’s Hospital

Momentum has been growing in the field of neuroscience in our ability to understand and treat various disorders affecting the brain, central nervous system, neuromuscular network and more. So what are the key ways that researchers and drug industry collaborators are discovering new therapies for preventing or reversing neurological disease?

Experts weighed in recently to offer their insights.

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How do cells release IL-1? The answer packs a punch, and could enable better vaccines

In hyperactivated immune cells, gasdermin D punches holes in the cell membrane that let IL-1 out — without killing the cell.

Interleukin-1 (IL-1), first described in 1984, is the original, highly potent member of the large family of cellular signaling molecules called cytokines that regulate immune responses and inflammation. It’s a key part of our immune response to infections, and also plays a role in autoimmune and inflammatory diseases. Several widely used anti-inflammatory drugs, such as anakinra, block IL-1 to treat rheumatoid arthritis, systemic inflammatory diseases, gout and atherosclerosis. IL-1 is also a target of interest in Alzheimer’s disease.

Yet until now, no one knew how IL-1 gets released by our immune cells.

“Most proteins have a secretion signal that causes them to leave the cell,” says Jonathan Kagan, PhD, an immunology researcher in Boston Children’s Hospital’s Division of Gastroenterology. “IL-1 doesn’t have that signal. Many people have championed the idea that IL-1 is passively released from dead cells: you just die and dump everything outside.”

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