Author: Nancy Fliesler

BCL11A-based gene therapy for sickle cell disease passes key preclinical test

sickle cell gene therapy coming

Research going back to the 1980s has shown that sickle cell disease is milder in people whose red blood cells carry a fetal form of hemoglobin. The healthy fetal hemoglobin compensates for the mutated “adult” hemoglobin that makes red blood cells stiffen and assume the classic “sickle” shape.

Normally, fetal hemoglobin production tails off after birth, shut down by a gene called BCL11A. In 2008, researchers Stuart Orkin, MD, and Vijay Sankaran, MD, PhD, at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center showed that suppressing BCL11A could restart fetal hemoglobin production; in 2011, using this approach, they corrected sickle cell disease in mice.

Now, the decades-old discovery is finally nearly ready for human testing — in the form of gene therapy. Today in the Journal of Clinical Investigation, Dana-Farber/Boston Children’s researchers report that a precision-engineered gene therapy vector suppressing BCL11A production overcame a key technical hurdle.

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Could targeting specific neurons in the hypothalamus relieve anxiety?

anxiety hypothalamus
(Ichiban Yada/

Anxiety disorders are the most common mental illness in the U.S., but lack an ideal treatment. The current drugs, SSRIs and benzodiazepines, have many side effects. More recently developed treatments seek to block corticotropin-releasing hormone (CRH), the classic stress hormone that activates our “fight or flight” response; in people with anxiety, CRH gets activated at the wrong time or too intensely.

But in clinical trials, results have been disappointing: of the eight completed phase II and III trials of CRH antagonists for depression or anxiety, six have been published, with largely negative findings, says Joseph Majzoub, MD, of the Division of Endocrinology at Boston Children’s Hospital.

Rong Zhang, PhD, who works in Majzoub’s research lab, had a hunch that blocking CRH throughout the brain, as was done in these trials, isn’t the best approach. “Blocking CRH receptors all over the brain doesn’t work,” she says. “We think the effects work against each other somehow. It may be that CRH has different effects depending on where in the brain it is produced.”

Today in Molecular Psychiatry, Zhang, Majzoub and colleagues demonstrate that certain neurons in the hypothalamus play a central, previously unknown role in triggering anxiety. When they used genetic tricks to selectively remove the CRH gene from about 1,000 of these neurons in mice, the effect was startling — they erased the animals’ natural fears.

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Drug-eluting contact lens offers hope in glaucoma

Daniel Kohane drug-eluting contact lens
Contact lenses ringed with a drug-bearing polymer film provided gradual, sustained drug release in this preclinical study, potentially offering an alternative to eye drops.

Daily medicated eye drops are the first line of treatment for glaucoma, the leading cause of irreversible blindness. The drops relieve pressure in the eye, a significant risk factor for glaucoma. But they’re not ideal: their delivery is imprecise, they can cause stinging and burning and patients often struggle to administer them. Adherence is poor: in one study based on insurance claims data, nearly half of patients who had filled a glaucoma prescription stopped topical glaucoma therapy within six months.

Engineered contact lenses dispensing glaucoma medication gradually could vastly improve adherence, helping hang onto their eyesight longer. In a pre-clinical study of glaucoma published online this week in the journal Ophthalmology, slow-release lenses lowered eye pressure at least as well as daily eye drops containing the drug latanoprost — and, in a higher-dose form, possibly more so.

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Acetaminophen does not aggravate young children’s asthma

A head-to-head comparison with ibuprofen refutes a link between acetaminophen and asthma exacerbations.

Your toddler is screaming in pain. Her forehead is burning. You rush to your local drugstore. What do you get — Tylenol or Motrin? And by the way, she also has asthma.

Recently, many parents have been under the impression that acetaminophen (Tylenol, etc.) may do more harm than good in young children with asthma.

“There’s been a lot of ‘smoke’ about this, based on a lot of retrospective observational data,” says Wanda Phipatanakul, MD, MS, of Boston Children’s Hospital’s Division of Allergy and Immunology.

The studies in question concluded that the common over-the-counter remedy can cause asthma exacerbations. Reviewing these studies, one author concluded, “Until future studies document the safety of this drug, children with asthma or at risk for asthma should avoid the use of acetaminophen.”

The Acetaminophen Versus Ibuprofen in Children with Asthma (AVICA) trial, led by Phipatanakul for the National Heart, Lung and Blood Institute’s AsthmaNet now sets the record straight.

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More clinical trials in kids? Nearly half are unfinished or unpublished

pediatric trials clinical trials
Of 559 interventional trials in children, 19 percent were stopped early and 30 percent of completed trials remained unpublished several years later, finds a new study. (Vmenkov/Wikimedia Commons)

Recent laws like the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act are encouraging clinical trials in children. Yet, as with adult trials, these trials commonly stall out or, if completed, remain unpublished several years later, finds a study published online today in Pediatrics.

“Our findings may speak to how commonplace discontinuation and non-publication are in medical research in general,” says Natalie Pica, MD, PhD, a senior resident at Boston Children’s Hospital and the study’s coauthor. “We need to make sure that when children participate in clinical trials, their efforts are contributing to broader scientific knowledge.”

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Can asthma be nipped in the bud?

A multicenter randomized trial is testing omalizumab (Xolair) in wheezy toddlers. (FDA/Wikimedia Commons)

Worldwide, asthma affects an estimated 300 million people, and is expected to surpass 400 million by 2025, according to the World Health Organization. About 1 in 10 U.S. children have asthma, and research shows that the vast majority of them also have allergy. Could that provide a clue to its prevention?

Starting at 2 to 3 years of age, susceptible children start to become sensitized to pollens, mold spores and other airborne allergens. They begin to produce IgE antibodies, which not only trigger allergic reactions but also impair their anti-viral immune responses — potentially leading to more viral infections that can further hasten their progression to asthma.

A multicenter clinical trial, led by Wanda Phipatanakul, MD, MS, of the Division of Allergy & Immunology at Boston Children’s Hospital, now aims to test whether the anti-IgE drug omalizumab (Xolair) can short-circuit this process.

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Citizen science: Giving patients a voice in drug development

citizen science patient voice drug development

There’s a natural tension between wanting the FDA to ensure safety and efficacy before a drug enters the market and wanting to speed up what many view as a glacially slow approval process. The rare disease community tends to fall in the second camp, and has become increasingly vocal in calling for more clinical trials, more flexibility in their design and redefinition of what constitutes a benefit.

ALS advocates, for example, have called for a parallel track, “in which FDA provides an early approval based on limited data, and then continues the learning process in a confirmatory clinical trial and if needed, patient registries to collect additional data from patients receiving the drug outside the clinical trial…”

Recent legislation is encouraging patient engagement in drug development, especially for conditions with profound unmet medical needs. In its 2012 iteration, the Prescription Drug User Fees Act (PDUFA) introduced public meetings to get input from the patient community, captured in a series of informative white papers.

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The genetics of early-onset psychosis: Could it aid understanding of schizophrenia?

psychosis schizophrenia
(Thomas Zapata/Wikimedia Commons)

At age six, Matthew (not his real name) began hearing voices coming out of the walls and the school intercom, telling him to hurt himself and others. He saw ghosts, aliens in trees and color footprints. Joseph Gonzalez-Heydrich, MD, a psychiatrist at Boston Children’s Hospital, put Matthew, at age 9, on antipsychotic medications, and the hallucinations stopped.

It’s rare for children so young to have psychotic symptoms. Intrigued, Gonzalez-Heydrich referred Matthew for genetic testing.

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Another use for mTOR inhibitors: Preserving vanishing bones in Gorham-Stout syndrome

Gorham Stout rapamycin sirolimus
In Gorham-Stout, lymphatic vessels gone amok eat away at bone. Sirolimus appears to reverse this process.

The mTOR pathway is fundamental to nearly every cell in the body. It drives processes related to cell growth, protein production and metabolism, influencing everything from neurocognition to tumor growth. Because of this broad role, indications for drugs targeting the mTOR pathway are also remarkably broad.

Alexander Malloy, 14, is one of the first patients to benefit from a new use: curbing rapid bone loss in patients with a rare “vanishing bone disease,” or Gorham-Stout syndrome. It was discovered when Alex, who had mild scoliosis, started getting worse. To his parents’ shock, an MRI scan showed he was missing bones in his spine.

Gorham-Stout is actually the result of a rare vascular anomaly.

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Where science connects with care: A Q&A with Leonard Zon

Leonard Zon in the lab

Leonard Zon, MD, is founder and director of the Stem Cell Research Program at Boston Children’s Hospital and an investigator with the Howard Hughes Medical Institute and the Harvard Stem Cell Institute. His laboratory research focuses on stem cell therapies for patients with cancer and blood disorders, using a high-throughput, automated system for screening potential drugs in zebrafish. Zon was cofounder of Scholar Rock and Fate Therapeutics and founder and past president of the International Society for Stem Cell Research.

Your hospital just received a #1 ranking from U.S. News & World Report. What does this mean relative to your role there?

I’ve been at Boston Children’s Hospital for 25 years, and it’s really satisfying to be at the premier institution for clinical care. And we’re very lucky to have one of the premier stem cell programs in the world. I have a strong sense that my impact on society is as a physician-scientist, bringing basic discoveries to the clinic. We’re able to have a huge impact on finding new diagnoses and new therapies for our children.

What inspires you to do your job every day?

As a hematologist I take care of patients who have devastating diseases – a variety of blood diseases and cancer. When I see these children, I’m always wondering, could there be ways to treating them that haven’t been thought of before? Successfully treating a child gives them an entire lifetime of health.

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