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Accelerating Cures in the Genomic Age: The Sickle Cell Example

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Sickle Cell Disease Symbol
Credit: Jill George, NIH

Forty-five years ago, when I was a first-year medical student, a lecturer introduced me to a young man with sickle cell disease (SCD). Sickle cell disease is the first “molecular disease”, with its cause having been identified decades ago. That helped me see the connection between the abstract concepts of molecular genetics and their real-world human consequences in a way no textbook could. In fact, it inspired some of my earliest research on human hemoglobin disorders, which I conducted as a postdoctoral fellow.

Today, I’m heartened to report that, thanks to decades of biomedical advances, we stand on the verge of a cure for SCD. While at the American Society of Hematology meeting in San Diego last week, I was excited to be part of a discussion about how the tools and technologies arising from the Human Genome Project are accelerating the quest for cures.

The good news at the meeting included some promising, early results from human clinical trials of SCD gene therapies, including new data from the NIH Clinical Center. Researchers also presented very encouraging pre-clinical work on how gene-editing technologies, such as CRISPR, can be used in ways that may open the door to curing everyone with SCD. In fact, just days before the meeting, the first clinical trial for a CRISPR approach to SCD opened.

One important note: the gene editing research aimed at curing SCD is being done in non-reproductive (somatic) cells. The NIH does not support the use of gene editing technologies in human embryos (germline). I recently reiterated our opposition to germline gene editing, in response to an unethical experiment by a researcher in China who claims to have used CRISPR editing on embryos to produce twin girls resistant to HIV.

SCD affects approximately 100,000 people in the United States, and another 20 million worldwide, mostly in developing nations. This inherited, potentially life-threatening disorder is caused by a specific point mutation in a gene that codes for the beta chain of hemoglobin, a molecule found in red blood cells that deliver oxygen throughout the body. In people with SCD, the mutant hemoglobin forms insoluble aggregates when de-oxygenated. As a result the red cells assume a sickle shape, rather than the usual donut shape. These sickled cells clump together and stick in small blood vessels, resulting in severe pain, blood cell destruction, anemia, stroke, pulmonary hypertension, organ failure, and much too often, early death.

The need for a widespread cure for SCD is great. Since 1998, doctors have used a drug called hydroxyurea to reduce symptoms, but it can cause serious side effects and increase the risk of certain cancers. Blood transfusions can also ease symptoms in certain instances, but they too come with risks and complications. At the present time, the only way to cure SCD is a bone marrow transplant. However, transplants are not an option for many patients due to lack of matched marrow donors.

The good news is that novel genetic approaches have raised hopes of a widespread cure for SCD, possibly even within five to 10 years. So, in September, NIH’s National Heart, Lung, and Blood Institute launched the Cure Sickle Cell Initiative to accelerate development of the most promising of these next generation of therapies

At the ASH meeting, that first wave of this progress was evident. A team led by NHLBI’s John Tisdale, in collaboration with Bluebird bio, Cambridge, MA, was among the groups that presented impressive early results from human clinical trials testing novel gene replacement therapies for SCD. In the NIH trial, researchers removed blood precursor cells, called hematopoietic stem cells (HSCs), from a patient’s own bone marrow or bloodstream and used a harmless virus to insert a sickle-resistant hemoglobin gene. Then, after a chemotherapy infusion to condition the patient’s existing bone marrow, they returned the corrected cells to the patient.

So far, nine SCD patients have received the most advanced form of the experimental gene therapy, and Tisdale presented data on those who were farthest out from treatment [1,2]. His team found that in the four patients who were at least six months out, levels of gene therapy-derived hemoglobin were found to equal or exceed their levels of SCD hemoglobin.

Very cool science, but what does this mean for SCD patients’ health and well-being? Well, none of the gene therapy trial participants have required a blood transfusion during the follow-up period. In addition, improvements were seen in their hemoglobin levels and key markers of blood-cell destruction (total bilirubin concentration, lactate dehydrogenase, and reticulocyte counts) compared to baseline. Most importantly, in the years leading up to the clinical trial, all of the participants had experienced frequent painful sickle crises, in which sickled cells blocked their blood vessels. No such episodes were reported among the participants in the months after they received the gene therapy.

Researchers did report that one patient receiving this form of gene therapy developed myelodysplastic syndrome (MDS), a serious condition in which the blood-forming cells in the bone marrow become abnormal. However, there is no indication that the gene replacement technology itself caused the problem, and MDS has previously been linked to the chemotherapy drugs used in conditioning regimens before bone marrow transplants.

The NIH trial is just one of several clinical trials for SCD that are using viral vectors to deliver a variety of genes with therapeutic potential. Other trials actively recruiting are led by researchers at Boston Children’s Hospital, Cincinnati Children’s Hospital, and the University of California, Los Angeles.

While it’s hoped that genes inserted by viral vectors will provide long-lasting or curative treatment, other researchers are betting that new gene-editing technologies, such as CRISPR, will offer the best chance for developing a widespread cure for SCD. One strategy being eyed by these “gene editors” is to correct the SCD mutation, replacing it with a normal gene. Another strategy involves knocking out certain DNA sequences to reactivate production of fetal hemoglobin (HbF).

The HbF protein is produced in the developing fetus to give it better access to oxygen from the mother’s bloodstream. But shortly after birth, the production of fetal hemoglobin shuts down, and the adult form kicks in. Adults normally have very low levels of fetal hemoglobin, which makes sense. However, from genome-wide association studies of human genetic variation, we know that that actual levels of HbF are under genetic control.

A major factor has been mapped to the BCL11A gene, which has subsequently been found to be a master mediator for the fetal to adult hemoglobin switch. Specifically, variations in a red cell specific enhancer of BCL11A affect an adult’s level of HbF— levels of BCL11A protein lead to higher amounts of fetal hemoglobin. Furthermore, it’s been known for some time that rare individuals keep on producing relatively high levels of hemoglobin into adulthood. If people with SCD happen to have a rare mutation that keeps fetal hemoglobin production active in adulthood (the first of these was found as part of my postdoctoral research), their SCD symptoms are much less severe.

Currently, two groups—CRISPR Therapeutics/Vertex Pharmaceuticals and Sangamo Therapeutics/Bioverativ—are gearing up to begin the first U.S. human clinical trials of gene-editing for SCD within the next few months. While they employ different technologies, both approaches involve removing a patient’s HSCs, using gene editing to knock out the BCL11A red cell enhancer, and then returning the gene-edited cells to the patient. The hope is that the gene-edited cells will greatly boost fetal hemoglobin production, thereby offsetting the effects of SCD.

All of this is exciting news for the 100,000 people living in the United States who have SCD. But what about the 300,000 babies born with SCD every year in other parts of the world, mostly in low- and middle-income countries?

The complicated, high-tech procedures that I just described may not be practical for a very long time in places like sub-Saharan Africa. That’s one reason why NIH recently launched a new effort to speed the development of safe, effective genome-editing approaches that could be delivered directly into a patient’s body (in vivo), perhaps by infusion of the CRISPR gene editing apparatus. Recent preclinical experiments demonstrating the promise of in vivo gene editing for Duchenne muscular dystrophy make me optimistic that NIH’s Somatic Cell Genome Editing Program, which is hosting its first gathering of investigators this week, will be able to develop similar approaches for SCD and many other conditions.

While moving forward in this fast-paced field, it is important that we remain ethical, but also remain bold on behalf of the millions of patients with genetic diseases who are still waiting for a cure. We must continue to assess and address the very serious ethical concerns raised by germline gene editing of human embryos, which will irreversibly alter the DNA instruction book of future children and affect future generations. I continue to argue that we are not ready to undertake such experiments.

But the use of gene editing to treat, perhaps even to cure, children and adults with genetic diseases, by correcting the mutation in their relevant tissues (so-called somatic cell gene editing), without risk of passing those changes on to a future generation, holds enormous promise. Somatic cell gene editing is associated with ethical issues that are much more in line with decades of deep thinking about benefits and risks of therapeutic trials.

Finally, we must recognize that somatic cell gene editing is a profoundly promising approach not only for people with SCD, but for all who are struggling with the thousands of diseases that still have no treatments or cures. Real hope for cures has never been greater.

References:

[1] NIH researcher presents encouraging results for gene therapy for severe sickle cell disease. NIH News Release. December 4, 2018 

[2] Bluebird bio presents new data for LentiGlobin gene therapy in sickle cell disease at 60th annual meeting of the American Society of Hematology. Bluebird bio. December 3, 2018 

Links:

Sickle Cell Disease (National Heart, Lung, and Blood Institute/NIH)

Cure Sickle Cell Initiative (NHLBI)

John Tisdale (NHLBI)

Somatic Cell Genome Editing Program (Common Fund/NIH)

What are genome editing and CRISPR-Cas9? (National Library of Medicine/NIH)

ClinicalTrials.gov (NIH) 

NIH Support: National Heart, Lung, and Blood Institute; Common Fund


Zooming In on Meiosis

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Meiosis

Credit: Simone Köhler, Michal Wojcik, Ke Xu, and Abby Dernburg, University of California, Berkeley

Meiosis—the formation of egg and sperm cells—is a highly choreographed process that creates genetic diversity in all plants and animals, including humans, to make each of us unique. This kaleidoscopic image shows cells from a worm exchanging DNA during meiosis.

You can see a protein-based polymer tether (green) from what’s called the synaptonemal complex. The complex holds together partner chromosomes (magenta) to facilitate DNA exchange in nuclei (white). Moving from left to right are views of the molecular assembly that progressively zoom in on the DNA, revealing in exquisite detail (far right) the two paired partner chromosomes perfectly aligned. This is not just the familiar DNA double helix. This is a double helix made up of two double helices!


Blast Off! Sending Human Tissue Chips into Space

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Tissue Chips in Space

Credit: Josh Valcarcel, NASA

A big challenge in unlocking the mysteries of aging is how long you need to study humans, or even human cells, to get answers. But, in partnership with NASA, NIH is hoping that space will help facilitate this important area of research.

It’s already known, from what’s been seen in astronauts, that the weightless conditions found in space can speed various processes associated with aging. So, might it be possible to use the space station as a lab to conduct aging experiments?


Future Service Dogs

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NIH Director Francis Collins with puppies at NIH

I got to join in the four-legged fun with NIH’s “Puppycam” event on November 29, 2018 at the NIH Clinical Center. The event, which was live streamed for folks on Twitter, offered demonstrations from service dogs, therapy dogs, and puppies-in-training (including these adorable ones at rest). Credit: Stephanie Clipper


The Actin Superhighway

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Actin Superhighway

Credit: Andrew Lombardo and David Warshaw, University of Vermont, Burlington

What looks like a traffic grid filled with roundabouts is nothing of the sort: It’s actually a peek inside a tiny microchamber that models a complex system operating in many of our cells. The system is a molecular transportation network made of the protein actin, and researchers have reconstructed it in the lab to study its rules of the road and, when things go wrong, how it can lead to molecular traffic accidents.

This 3D super-resolution image shows the model’s silicone beads (circles) positioned in a tiny microfluidic-chamber. Suspended from the beads are actin filaments that form some of the main cytoskeletal roadways in our cells. Interestingly, a single dye creates the photo’s beautiful colors, which arise from the different vertical dimensions of a microscopic image: 300 nanometers below the focus (red), at focus (green), and 300 nanometers above the focus (blue). When a component spans multiple dimensions—such as the spherical beads—all the colors of the rainbow are visible. The technique is called 3D stochastic optical reconstruction microscopy, or STORM [1].


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