Stories about: Therapeutics

How the antidepressant ketamine rapidly awakens the brain, and why its effects vary more in women

(CREDIT: NATHALIE PICARD / BOSTON CHILDREN’S HOSPITAL)

In small doses, the anesthetic ketamine is a mildly hallucinogenic party drug known as “Special K.” In even smaller doses, ketamine relieves depression — abruptly and sometimes dramatically, steering some people away from suicidal thoughts. Studies indicate that ketamine works in 60 to 70 percent of people not helped by slower-acting SSRIs, the usual drugs for depression.

Two ketamine-like drugs are in the clinical pipeline, and, as of this week, one appears close to FDA approval. With no significant new antidepressant in more than 30 years, anticipation is high. Yet no one has pinned down how low-dose ketamine works. Studies have implicated various brain neurotransmitters and their receptors — serotonin, dopamine, glutamate, GABA receptors, opioid receptors — but findings have been contradictory.

“We felt it was time to figure this out once and for all,” says neuroscientist Takao Hensch, PhD.

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Blood stem cell transplants from any donor, without toxicity?

could stem cell transplants be made nontoxic?
(ADOBE STOCK)

Many blood disorders, immune disorders and metabolic disorders can be cured with a transplant of hematopoietic (blood-forming) stem cells, also known as bone marrow transplant. But patients must first receive high-dose, whole-body chemotherapy and/or radiation to deplete their own defective stem cells, providing space for the donor cells to engraft. These “conditioning” regimens are highly toxic: they wipe out the immune system, raising infection risk, and can cause anemia, infertility, other organ damage and cancers. And when the donor isn’t an exact match, patients’ immune systems must be suppressed for prolonged periods to prevent rejection.

As a result, most patients either don’t receive a transplant or must endure serious side effects. But if two new studies bear out in clinical trials, a far gentler conditioning treatment could enable stem-cell transplants for a much wider range of disorders, even possibly from unmatched donors.

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Can we mass-produce platelets in the lab?

Lab-grown platelets could someday be given to patients
Activated platelets (IMAGE: ADOBE STOCK)

Most of us have somewhere around a trillion tiny platelets zooming around our bloodstreams. Joseph Italiano, PhD, of Boston Children’s Hospital’s Vascular Biology Program, calls them the “Swiss Army knives of the blood.” In addition to their key role in clotting, platelets are important in immunity, wound healing, chemical delivery, blood vessel development and more.

At healthcare facilities, platelets are in constant demand for patients with blood diseases, or those receiving radiation or chemotherapy for cancer. But unlike other blood products, platelets can’t be stored for more than a few days. If there’s a snowstorm or other emergency preventing donors from giving platelets, a hospital can easily run out. So researchers have been trying to make platelets in a lab setting.

Two teams at Boston Children’s Hospital are tackling the problem in slightly different ways.

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Natural killer cells: A new angle on neuropathic pain

natural killer cells, peripheral nerve damage and neuropathic pain
Like an immune cleanup crew, natural killer cells (green) infiltrate a damaged axon. (IMAGE: ALEXANDER DAVIES / SEOUL NATIONAL UNIVERSITY AND UNIVERSITY OF OXFORD)

Scientists have known since the 1800s what happens to a totally crushed peripheral nerve in animals: the damaged axons are broken down in a process called Wallerian degeneration, allowing healthy ones to regrow. But humans rarely suffer complete axonal damage. Instead, axons tend to be partially damaged, causing neuropathic pain — a difficult-to-treat, chronic pain associated with nerve trauma, chemotherapy and diabetes.

The lab of Michael Costigan, PhD, in Boston Children’s Hospital’s F.M. Kirby Neurobiology Center is studying how the body’s immune system breaks down these damaged nerves. Their latest research, published today in Cell, may change our understanding of neuropathic pain and how to treat it.

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Drug repurposing and DNA mining: The hunt for new endometriosis treatments

endometriosis researchers Michael Rogers and Danielle Peterse
Michael Rogers and Daniëlle Peterse (PHOTO: MICHAEL GODERRE/BOSTON CHILDREN’S HOSPITAL)

Endometriosis is a common gynecological condition that may affect more than 1 in 10 reproductive-age women. Yet, there’s very little research into the disease and limited options for treatment. A team in the Vascular Biology Program at Boston Children’s Hospital is trying to change that.

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Overriding resistance to epigenetic inhibitors in neuroblastoma: Targeting PI3K

(IMAGE COURTESY NATIONAL CANCER INSTITUTE)

Children’s cancers pose unique challenges. They’re not caused by the same kinds of genetic mutations that cause adult cancers, and only a minority of their mutations can be targeted with drugs. In a recent study, Kimberly Stegmaier, MD, at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and her colleagues systematically deleted every gene in the genome in a number of childhood cancers. This led them to previously unknown — and targetable — genes that help drive tumor growth.

But Stegmaier is also interested in epigenetic regulators — proteins that help control the regulation of genes and contribute to many pediatric cancers. They’re a hot subject of research: Child cancers tend to arise in developing tissues, and epigenetic regulators are active during early development. Clinical trials are starting to test drugs that inhibit epigenetic cancer-promoting factors.

There’s a problem, though: Cancers often become resistant to targeted inhibitors, including epigenetic inhibitors. So, again using genome-wide approaches, Stegmaier set out to find ways to overcome this resistance.

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CRISPR-Cas9 screen opens new targets for Ewing sarcoma, other childhood cancers

Ewing sarcoma research by Kimberly Stegmaier, MD
The TP53 pathway normally helps pull the plug on cancerous cells. While the pathway is intact in most pediatric cancers, research finds that drugs targeting the pathway can curb tumor cell proliferation in Ewing sarcoma. Photo: Kimberly Stegmaier, MD (SAM OGDEN / DANA-FARBER CANCER INSTITUTE)

While the genetic mutations driving adult cancers can sometimes be targeted with drugs, most pediatric cancers lack good targets. That’s because their driving genetic alterations often create fusion proteins that aren’t easy for drugs to attack.

“This is one reason why it is notoriously hard to make targeted drugs against childhood cancers — their cancer-promoting proteins often lack good pockets for drugs to bind to,” says Kimberly Stegmaier, MD.

However, that’s beginning to change.

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After 80 years, genetic causes of Diamond-Blackfan anemia come into view

Vijay Sankaran, MD and a patient with Diamond-Blackfan anemia
Hematologist Vijay Sankaran with Jack Farwell (PHOTO: MICHAEL GODERRE / BOSTON CHILDREN’S HOSPITAL)

In 1938, Louis K. Diamond, MD, and Kenneth Blackfan, MD, at Boston Children’s Hospital described a severe congenital anemia that they termed “hypoplastic” (literally, “underdeveloped”) because of the bone marrow’s inability to produce mature, functioning red blood cells. Eighty years later, the multiple genetic origins of this highly rare disease, now known as Diamond-Blackfan anemia, or DBA, are finally coming into view.

The largest study to date, published recently in the American Journal of Human Genetics, raises as many questions as it answers. But in the meantime, it provides a genetic explanation for nearly 80 percent of patients.

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New angles for blocking Shiga and ricin toxins, and new light on an iconic biological process

Shiga toxin producing E. coli
Shiga-toxin-producing E. coli (IMAGE: JANICE HANEY CARR / USCDC)

Min Dong, PhD, and his lab are world experts in toxins and how to combat them. They’ve figured out how Clostridium difficile’s most potent toxin gets into cells and zeroed in on the first new botulinum toxin identified since 1969. Now, they’ve set their sights on Shiga and ricin toxins, and not only identified new potential lines of defense, but also shed new light on a fundamental part of cell biology: glycosylation.

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Reviving fetal hemoglobin in sickle cell disease: First patient is symptom-free

Manny Johnson of Boston, 21, previously required monthly blood transfusions to keep his severe sickle cell disease under control. After receiving a new gene therapy treatment, he’s been symptom-free for six months.

Researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reported Manny’s case Saturday at the American Society of Hematology meeting in San Diego. Manny is their first patient, and an ongoing clinical trial will treat additional patients between ages 3 and 40.

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