The ability to edit genes in patients’ blood
stem cells — which produce red blood cells, platelets, immune cells and more — offers
the potential to cure many genetic blood disorders. If all goes well, the
corrected cells engraft in the bone marrow and produce healthy, properly
functioning blood cells… forever.
But scientists have had difficulty introducing
edits into blood stem cells. The efficiency and specificity of the edits and
their stability once the cells engraft in the bone marrow have been variable.
A new approach, described this week in Nature Medicine and in January in the journal Blood, overcomes prior technical challenges, improving the efficiency, targeting and durability of the edits. Researchers at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and the University of Massachusetts Medical School successfully applied the technique to two common blood diseases — sickle cell disease and beta thalassemia — involving mutations in the gene for beta globin protein.
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
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. …
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.
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.
Our blood carries tiny amounts of DNA from broken-up cells. If we have cancer, some of that DNA comes from tumor cells. Studies performed with adult cancers have shown that this circulating tumor DNA (ctDNA) may offer crucial clues about tumor genetic mutations and how tumors respond to treatment.
Brian Crompton, MD, with colleagues at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and elsewhere, is now working to bring ctDNA “liquid biopsies” to pediatric solid tumors as well. The researchers hope that these blood tests will eventually improve early detection, choice of treatment and monitoring of young patients with these diseases without having to sample the tumor itself. …
The lab of Leonard Zon, MD, has long been interested in making blood stem cells in quantity for therapeutic purposes. To test for their presence in zebrafish, their go-to research model, they turned to the MYB gene, a marker of blood stem cells. To spot the cells, Joseph Mandelbaum, a PhD candidate in the lab, attached a fluorescent green tag to MYB that made it easily visible in transparent zebrafish embryos.
“It was a real workhorse line for us,” says Zon, who directs the Stem Cell Research Program at Boston Children’s Hospital.
In addition to being a marker of blood stem cells, MYB is an oncogene. About five years ago, Zon was having lunch at a cancer meeting and, serendipitously, sat next to Jeff Kaufman, who was also interested in MYB. Kaufman was excited to hear about Zon’s fluorescing MYB zebrafish, which can be studied at scale and are surprisingly similar to humans genetically.
“Have you ever heard of adenoid cystic carcinoma?” he asked Zon. …
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.
“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. …
For more than 15 years, pediatric neuro-oncologist Mariella Filbin, MD, PhD, has been on a scientific crusade to understand DIPG (diffuse intrinsic pontine glioma). She hopes to one day be able to cure a disease that has historically been thought of as an incurable type of childhood brain cancer.
“While I was in medical school, I met a young girl who was diagnosed with DIPG,” Filbin recalls. “When I heard that there was no treatment available, I couldn’t believe that was the case. It really made a huge impression on me and since then, I’ve dedicated all my research to fighting DIPG.”
Her mission brought her to Boston Children’s Hospital for her medical residency program and later, to do postdoctoral research at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Now, she’s starting her own research laboratory focused on DIPG — which has also been called diffuse midline glioma (DMG) in recent years — and continuing to treat children with brain tumors at the Dana-Farber/Boston Children’s pediatric brain tumor treatment center. She’s also a scientist affiliated with the Broad Institute Cancer Program.
This year, Filbin has made new impact in the field by leveraging the newest single-cell genetic sequencing technologies to analyze exactly how DIPG develops in the first place. Her latest research, published in Science, entailed profiling more than 3,300 individual brain cells from biopsies of six different patients.
Using what’s known as a single-cell RNA sequencing approach to interrogate the makeup of DIPG/DMG tumors, Filbin was able to identify a particularly problematic type of brain cell that acts forever young, constantly dividing over and over again in a manner similar to stem cells. …
Their plan is to optimize the ability for CAR T-cell therapies, which use a patient’s genetically modified T cells to combat cancer, to more specifically kill tumor cells without setting off an immune response “storm” known as cytokine release syndrome. The key ingredient is a unique small molecule that greatly enhances the specificity of the tumor targeting component of the therapy. …