Stories about: Therapeutics

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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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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Getting a grip on genetic loops

Chromatin is housed inside the nucleus. A new discovery about its physical arrangement could pave the way for new therapeutics.
Artist’s rendering of chromatin, which is housed inside the nuclei of mammalian cells. A new discovery about its physical arrangement could pave the way for new therapeutics.

A new discovery about the spatial orientation and physical interactions of our genes provides a promising step forward in our ability to design custom antibodies. This, in turn, could revolutionize the fields of vaccine development and infection control.

“We are beginning to understand the full biological impact that the physical structure and movement of our genes play in regulating health and development,” says Frederick Alt, PhD, director of the Boston Children’s Hospital Program in Cellular and Molecular Medicine (PCMM) and the senior author of the new study, published in the latest issue of Cell.

Recent years of research by Alt and others in the field of molecular biology have revealed that it’s not just our genes themselves that determine health and disease states. It’s also the three-dimensional arrangement of our genes that plays a role in keeping genetic harmony. Failure of these structures may trigger genetic mutations or genome rearrangements leading to catastrophe.

The importance of genetic loops

Crammed inside the nucleus, chromatin, the chains of DNA and proteins that make up our chromosomes, is arranged in extensive loop arrangements. These loop configurations physically confine segments of genes that ought to work together in a close proximity to one another, increasingly their ability to work in tandem.

“All the genes contained inside one loop have a greater than random chance of coming together,” says Suvi Jain, PhD, a postdoctoral researcher in Alt’s lab and a co-first author on the study.

Meanwhile, genes that ought to stay apart remain blocked from reaching each other, held physically apart inside our chromosomes by the loop structures of our chromatin.

But while many chromatin loops are hardwired into certain formations throughout all our cells, it turns out that some types of cells, such as certain immune cells, are more prone to re-arrangement of these loops.

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Hearts get a boost from mitochondrial transplantation

In this artistic rendering, mitochondria (enlarged at top left) are depicted inside heart muscle cells. Watch an animation about mitochondrial transplantation.

For decades, cardiac researcher James McCully, PhD, has been spellbound by the idea of using mitochondria, the “batteries” of the body’s cells, as a therapy to boost heart function. Finally, a clinical trial at Boston Children’s Hospital is bringing his vision — a therapy called mitochondrial transplantation — to life.

Mitochondria, small structures inside all of our cells, synthesize the essential energy that our cells need to function. In the field of cardiac surgery, a well-known condition called ischemia often damages mitochondria and its mitochondrial DNA inside the heart’s muscle cells, causing the heart to weaken and pump blood less efficiently. Ischemia, a condition of reduced or restricted blood flow, can be caused by congenital heart defects, coronary artery disease and cardiac arrest.

For the smallest and most vulnerable patients who are born with severe heart defects, a heart-lung bypass machine called extracorporeal membrane oxygenation (ECMO) can help restore blood flow and oxygenation to the heart. But even after blood flow has returned, the mitochondria and their DNA remain damaged.

“In the very young and the very old, especially, their hearts are not able to bounce back,” says McCully.

Ischemia can be fatal for the tiniest patients

After cardiac arrest, for instance, a child’s mortality rate jumps to above 40 percent because of ischemia’s effects on mitochondria. If a child’s heart is too weak to function without the support of ECMO, his or her risk of dying increases each additional day spent connected to the machine.

But what if healthy mitochondria could come to the rescue and replace the damaged ones?

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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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Vessel-lengthening technique offers game change for a rare vascular condition

TESLA concept for midaortic syndrome

Tissue expanders — small balloons that can be filled with saline solution or other fluids to grow skin — have long been used in plastic surgery, most commonly breast reconstruction. They’re based on the simple idea that the surrounding skin will stretch as the device expands over time. That extra skin can then help repair injuries or congenital anomalies or accommodate implants.

Now, a novel approach extends tissue expansion to blood vessels. It is transforming the way that surgeons treat a rare but serious condition called midaortic syndrome, report Heung Bae Kim, MD, Khashayar Vakili, MD and their colleagues at Boston Children’s Hospital.

Midaortic syndrome occurs when the middle section of the aorta is narrowed and typically affects children and young adults. It can cause severe hypertension and can be life-threatening if left untreated. The surgical approach to this condition would be to replace the damaged portion of the aorta with nearby healthy blood vessels. However, this usually isn’t possible because these vessels tend to be too short to adequately fill in.

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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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Putting patients first in the translational research pipeline

During a follow-up visit, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.
During a follow-up visit at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, pediatric hematologist/oncologist Sung-Yun Pai, MD, hugs a patient who received gene therapy for X-linked severe combined immunodeficiency.

This is part II of a two-part blog series recapping the 2018 BIO International Convention. Read part I: Forecasting the convergence of artificial intelligence and precision medicine.

The hope to improve people’s lives is what drives many members of industry and academia to bring new products and therapies to market. At the BIO International Convention last week in Boston, there was lots of discussion about how translational science intersects with patients’ needs and why the best therapeutic developmental pipelines are consistently putting patients first.

As a case in point, Mustafa Sahin, MD, PhD, of Boston Children’s discussed his work to improve testing and translation of new therapies for autism spectrum disorder (ASD). As a member of PACT (Preclinical Autism Consortium for Therapeutics) and director of Boston Children’s Translational Neuroscience Program, Sahin aims to bridge the gap between drug discovery and clinical translation.

“Our mission is to de-risk entry of new therapies in the ASD drug discovery and development space,” said Sahin, who is also a professor of neurology at Harvard Medical School.

One big challenge, says Sahin, is knowing how well — or how poorly — autism therapies are actually affecting people with ASD. Externally, ASD is recognized by its core symptoms of repetitive behaviors and social deficits.

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