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Genes, Blood Type Tied to Risk of Severe COVID-19

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SARS-CoV-2 virus particles
Caption: Micrograph of SARS-CoV-2 virus particles isolated from a patient.
Credit: National Institute of Allergy and Infectious Diseases, NIH

Many people who contract COVID-19 have only a mild illness, or sometimes no symptoms at all. But others develop respiratory failure that requires oxygen support or even a ventilator to help them recover [1]. It’s clear that this happens more often in men than in women, as well as in people who are older or who have chronic health conditions. But why does respiratory failure also sometimes occur in people who are young and seemingly healthy?

A new study suggests that part of the answer to this question may be found in the genes that each one of us carries [2]. While more research is needed to pinpoint the precise underlying genes and mechanisms responsible, a recent genome-wide association (GWAS) study, just published in the New England Journal of Medicine, finds that gene variants in two regions of the human genome are associated with severe COVID-19 and correspondingly carry a greater risk of COVID-19-related death.

The two stretches of DNA implicated as harboring risks for severe COVID-19 are known to carry some intriguing genes, including one that determines blood type and others that play various roles in the immune system. In fact, the findings suggest that people with blood type A face a 50 percent greater risk of needing oxygen support or a ventilator should they become infected with the novel coronavirus. In contrast, people with blood type O appear to have about a 50 percent reduced risk of severe COVID-19.

These new findings—the first to identify statistically significant susceptibility genes for the severity of COVID-19—come from a large research effort led by Andre Franke, a scientist at Christian-Albrecht-University, Kiel, Germany, along with Tom Karlsen, Oslo University Hospital Rikshospitalet, Norway. Their study included 1,980 people undergoing treatment for severe COVID-19 and respiratory failure at seven medical centers in Italy and Spain.

In search of gene variants that might play a role in the severe illness, the team analyzed patient genome data for more than 8.5 million so-called single-nucleotide polymorphisms, or SNPs. The vast majority of these single “letter” nucleotide substitutions found all across the genome are of no health significance, but they can help to pinpoint the locations of gene variants that turn up more often in association with particular traits or conditions—in this case, COVID-19-related respiratory failure. To find them, the researchers compared SNPs in people with severe COVID-19 to those in more than 1,200 healthy blood donors from the same population groups.

The analysis identified two places that turned up significantly more often in the individuals with severe COVID-19 than in the healthy folks. One of them is found on chromosome 3 and covers a cluster of six genes with potentially relevant functions. For instance, this portion of the genome encodes a transporter protein known to interact with angiotensin converting enzyme 2 (ACE2), the surface receptor that allows the novel coronavirus that causes COVID-19, SARS-CoV-2, to bind to and infect human cells. It also encodes a collection of chemokine receptors, which play a role in the immune response in the airways of our lungs.

The other association signal popped up on chromosome 9, right over the area of the genome that determines blood type. Whether you are classified as an A, B, AB, or O blood type, depends on how your genes instruct your blood cells to produce (or not produce) a certain set of proteins. The researchers did find evidence suggesting a relationship between blood type and COVID-19 risk. They noted that this area also includes a genetic variant associated with increased levels of interleukin-6, which plays a role in inflammation and may have implications for COVID-19 as well.

These findings, completed in two months under very difficult clinical conditions, clearly warrant further study to understand the implications more fully. Indeed, Franke, Karlsen, and many of their colleagues are part of the COVID-19 Host Genetics Initiative, an ongoing international collaborative effort to learn the genetic determinants of COVID-19 susceptibility, severity, and outcomes. Some NIH research groups are taking part in the initiative, and they recently launched a study to look for informative gene variants in 5,000 COVID-19 patients in the United States and Canada.

The hope is that these and other findings yet to come will point the way to a more thorough understanding of the biology of COVID-19. They also suggest that a genetic test and a person’s blood type might provide useful tools for identifying those who may be at greater risk of serious illness.

References:

[1] Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. Wu Z, McGoogan JM, et. al. 2020 Feb 24. [published online ahead of print]

[2] Genomewide association study of severe Covid-19 with respiratory failure. Ellinghaus D, Degenhardt F, et. a. NEJM. June 17, 2020.

Links:

The COVID-19 Host Genetics Initiative

Andre Franke (Christian-Albrechts-University of Kiel, Germany)

Tom Karlsen (Oslo University Hospital Rikshospitalet, Norway)


Searching for Ways to Prevent Life-Threatening Blood Clots in COVID-19

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At Home with Gary Gibbons

Six months into the coronavirus disease 2019 (COVID-19) pandemic, researchers still have much to learn about the many ways in which COVID-19 can wreak devastation on the human body. Among the many mysteries is exactly how SARS-CoV-2, which is the novel coronavirus that causes COVID-19, triggers the formation of blood clots that can lead to strokes and other life-threatening complications, even in younger people.

Recently, I had a chance to talk with Dr. Gary Gibbons, Director of NIH’s Heart, Lung, and Blood Institute (NHLBI) about what research is being done to tackle this baffling complication of COVID-19. Our conversation took place via videoconference, with him connecting from his home in Washington, D.C., and me linking in from my home just up the road in Maryland. Here’s a condensed transcript of our chat:

Collins: I’m going to start by asking about the SARS-CoV-2-induced blood clotting not only in the lungs, but in other parts of the body. What do we know about the virus that would explain this?

Gibbons: It seems like every few weeks another page gets turned on COVID-19, and we learn even more about how this virus affects the body. Blood clots are one of the startling and, unfortunately, devastating complications that emerged as patients were cared for, particularly in New York City. It became apparent that certain individuals had difficulty getting enough oxygen into their system. The difficulty couldn’t be explained entirely by the extent of the pneumonia affecting the lungs’ ability to exchange oxygen.

It turned out that, in addition to the pneumonia, blood clots in the lungs were compromising oxygenation. But some patients also had clotting, or thrombotic, complications in their veins and arteries in other parts of the body. Quite puzzling. There were episodes of relatively young individuals in their 30s and 40s presenting with strokes related to blood clots affecting the arterial circulation to the brain.

We’re still trying to understand what promotes the clotting. One clue involves the endothelial cells that form the inner lining of our blood vessels. These cells have on their surface a protein called the angiotensin-converting enzyme 2 (ACE2) receptor, and this clue is important for two reasons. One, the virus attaches to the ACE2 receptor, using it as an entry point to infect cells. Two, endothelial-lined blood vessels extend to every organ in the body. Taken together, it seems that some COVID-19 complications relate to the virus attaching to endothelial cells, not only in the lungs, but in the heart and multiple organs.

Collins: So, starting in the respiratory tree, the virus somehow breaks through into a blood vessel and then gets spread around the body. There have been strange reports of people with COVID-19 who may not get really sick, but their toes look frostbitten. Is “COVID toes,” as some people call it, also part of this same syndrome?

Gibbons: We’re still in the early days of learning about this virus. But I think this offers a further clue that the virus not only affects large vessels but small vessels. In fact, clots have been reported at the capillary level, and that’s fairly unusual. It’s suggestive that an interaction is taking place between the platelets and the endothelial surface.

Normally, there’s a tightly regulated balance in the bloodstream between pro-coagulant and anticoagulant proteins to prevent clotting and keep the blood flowing. But when you cut your finger, for example, you get activation for blood clots in the form of a protein mesh. It looks like a fishing net that can help seal the injury. In addition, platelets in the blood stream help to plug the holes in that fishing net and create a real seal of a blood vessel.

Well, imagine it happening in those small vessels, which usually have a non-stick endothelial surface, almost like Teflon, that prevents clotting. Then the virus comes along and tips the balance toward promoting clot formation. This disturbs the Teflon-like property of the endothelial lining and makes it sticky. It’s incredible the tricks this virus has learned by binding onto one of these molecules in the endothelial lining.

Collins: Who are the COVID-19 patients most at risk for this clotting problem?

Gibbons: Unfortunately, it appears right now that older adults are among the most vulnerable. They have a lot of the risks for the formation of these blood clots. What’s notable is these thrombotic complications are also happening to relatively young adults or middle-aged individuals who don’t have a lot of other chronic conditions, or comorbidities, to put them at higher risk for severe disease. Again, it’s suggestive that this virus is doing something that is particular to the coagulation system.

Collins: We’d love to have a way of identifying in advance the people who are most likely to get into trouble with blood clotting. They might be the ones you’d want to start on an intervention, even before you have evidence that things are getting out of control. Do you have any kind of biomarker to tell you which patients might benefit from early intervention?

Gibbons: Biomarkers are being actively studied. What we do know from some earlier observations is that you can assess the balance of clotting and anticlotting factors in the blood by measuring a biomarker called D-dimer. It’s basically a protein fragment, a degradation product, from a prior clot. It tells you a bit about the system’s activity in forming and dissolving clots.
If there’s a lot of D-dimer activity, it suggests a coagulation cascade is jazzed up. In those patients, it’s probably a clue that this is a big trigger in terms of coagulation and thrombosis. So, D-dimer levels could maybe tell us which patients need really aggressive full anticoagulation.

Collins: Have people tried empirically using blood thinners for people who seem to be getting into trouble with this clotting problem?

Gibbons: There’s a paper out of the Mount Sinai in New York City that looked at thousands of patients being treated for COVID-19 [1]. Based on clinical practice and judgments, one of the striking findings is that those who were fully anticoagulated had better survival than those who were not. Now, this was not a randomized, controlled clinical trial, where some were given full anticoagulation and others were not. It was just an observational study that showed an association. But this study indicated indirectly that by giving the blood thinners, changing that thrombotic risk, maybe it’s possible to reduce morbidity and mortality. That’s why we need to do a randomized, controlled clinical trial to see if it can be used to reduce these case fatality rates.

Collins: You and your colleagues got together and came up with a design for such a clinical trial. Tell us about that.

Gibbons: My institute studies the heart, lung, and blood. The virus attacks all three. So, our community has a compelling need to lean in and study COVID-19. Recently, NIH helped to launch a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). As the name spells out, this initiative provides is a clinical platform to generate life-saving treatments as we wait for the development of a vaccine.

Through ACTIV, a protocol is now in the final stages of review for a clinical trial that will involve a network of hospitals and explore the question: is it sufficient to try a low-dose thrombo-prophylactic, or clot preventative, approach versus full anticoagulation? Some think patients ought to have full anticoagulation, but that’s not without risk. So, we want to put that question to the test. As part of that, we’ll also learn more about biomarkers and what could be predictive of individuals getting the greatest benefit.

If we find that fully anticoagulating patients prevents clots, then that’s great. But it begs the question: what happens when patients go home? Is it sufficient to just turn off the drip and let them go their merry way? Should they have a low dose thrombo-prophylactic regimen for a period of time? If so, how long? Or should they be fully anticoagulated with oral anticoagulation for a certain period of time? All these and other questions still remain.

Collins: This can make a huge difference. If you’re admitted to the hospital with COVID-19, that means you’re pretty sick and, based on the numbers that I’ve seen, your chance of dying is about 12 percent if nothing else happens. If we can find something like an anticoagulant that would reduce that risk substantially, we can have a huge impact on reducing deaths from COVID-19. How soon can we get this trial going, Gary?

Gibbons: We have a sense of urgency that clearly this pandemic is taking too many lives and time is of the essence. So, we’ve indeed had a very streamlined process. We’re leveraging the fact that we have clinical trial networks, where regardless of what they were planning to do, it’s all hands on deck. As a result, we’re able to move faster to align with that sense of urgency. We hope that we can be off to a quick launch within the next two to three weeks with the anticoagulation trials.

Collins: This is good because people are waiting on the vaccines, but realistically we won’t know whether the vaccines are working for several more months, and having them available for lots of people will be at the very end of this year or early 2021 at best. Meanwhile, people still are going to be getting sick with COVID-19. We want to be able to have as many therapeutic options as possible to offer to them. And this seems like a pretty exciting one to try and move forward as quickly as possible. You and your colleagues deserve a lot of credit for bringing this to everybody’s attention.

But before we sign off, I have to raise another issue of deep significance. Gary, I think both of us are struggling not only with the impact of COVID-19 on the world, but the profound sorrow, grief, frustration, and anger that surrounds the death of George Floyd. This brings into acute focus the far too numerous other circumstances where African Americans have been mistreated and subjected to tragic outcomes.

This troubling time also shines a light on the health disparities that affect our nation in so many ways. We can see what COVID-19 has done to certain underrepresented groups who have borne an undue share of the burden, and have suffered injustices at the hands of society. It’s been tough for many of us to admit that our country is far from treating everyone equally, but it’s a learning opportunity and a call to redouble our efforts to find solutions.

Gary, you’ve been a wonderful leader in that conversation for a long time. I want to thank you both for what you’re doing scientifically and for your willingness to speak the truth and stand up for what’s right and fair. It’s been great talking to you about all these issues.

Gibbons: Thank you. We appreciate this opportunity to fulfill NIH’s mission of turning scientific discovery into better health for all. If there’s any moment that our nation needs us, this is it.

Reference:

[1] Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. J Am Coll Cardiol. 2020 May 5;S0735-1097(20)35218-9.

Links:

Coronavirus (COVID-19) (NIH)

Rising to the Challenge of COVID-19: The NHLBI Community Response,” Director’s Messages, National Heart, Lung, and Blood Institute/NIH, April 29, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


Aging Research: Blood Proteins Show Your Age

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Blood Test for Aging
Credit: Adapted from iStock/jarun011

How can you tell how old someone is? Of course, you could scan their driver’s license or look for signs of facial wrinkles and gray hair. But, as researchers just found in a new study, you also could get pretty close to the answer by doing a blood test.

That may seem surprising. But in a recent study in Nature Medicine, an NIH-funded research team was able to gauge a person’s age quite reliably by analyzing a blood sample for levels of a few hundred proteins. The results offer important new insights into what happens as we age. For example, the team suggests that the biological aging process isn’t steady and appears to accelerate periodically—with the greatest bursts coming, on average, around ages 34, 60, and 78.

These findings indicate that it may be possible one day to devise a blood test to identify individuals who are aging faster biologically than others. Such folks might be at risk earlier in life for cardiovascular problems, Alzheimer’s disease, osteoarthritis, and other age-related health issues.

What’s more, this work raises hope for interventions that may slow down the “proteomic clock” and perhaps help to keep people biologically younger than their chronological age. Such a scenario might sound like pure fantasy, but this same group of researchers showed a few years ago that it’s indeed possible to rejuvenate an older mouse by infusing blood from a much younger mouse.

Those and other earlier findings from the lab of Tony Wyss-Coray, Stanford School of Medicine, Palo Alto, CA, raised the tantalizing possibility that certain substances in young blood can revitalize the aging brain and other parts of the body. In search of additional clues in the new study, the Wyss-Coray team tracked how the protein composition of blood changes as people age.

To find those clues, they isolated plasma from more than 4,200 healthy individuals between ages 18 and 95. The researchers then used data from more than half of the participants to assemble a “proteomic clock” of aging.  Within certain limits, the clock could accurately predict the chronological age of the study’s remaining 1,446 participants. The best predictions relied on just 373 of the clock’s almost 3,000 proteins.

As further validation, the clock also reliably predicted the correct chronological age of four groups of people not in the study. Interestingly, it was possible to make a decent age prediction based on just nine of the clock’s most informative proteins.

The findings show that telltale proteomic changes arise with age, and they likely have important and as-yet unknown health implications. After all, those proteins found circulating in the bloodstream come not just from blood cells but also from cells throughout the body. Intriguingly, the researchers report that people who appeared biologically younger than their actual chronological age based on their blood proteins also performed better on cognitive and physical tests.

Most of us view aging as a gradual, linear process. However, the protein evidence suggests that, biologically, aging follows a more complex pattern. Some proteins did gradually tick up or down over time in an almost linear fashion. But the levels of many other proteins rose or fell more markedly over time. For instance, one neural protein in the blood stayed constant until around age 60, when its levels spiked. Why that is so remains to be determined.

As noted, the researchers found evidence that the aging process includes a series of three bursts. Wyss-Coray said he found it especially interesting that the first burst happens in early mid-life, around age 34, well before common signs of aging and its associated health problems would manifest.

It’s also well known that men and women age differently, and this study adds to that evidence. About two-thirds of the proteins that changed with age also differed between the sexes. However, because the effect of aging on the most important proteins of the clock is much stronger than the differences in gender, the proteomic clock still could accurately predict the ages in all people.

Overall, the findings show that protein substances in blood can serve as a useful measure of a person’s chronological and biological age and—together with Wyss-Coray’s earlier studies—that substances in blood may play an active role in the aging process. Wyss-Coray reports that his team continues to dig deeper into its data, hoping to learn more about the origins of particular proteins in the bloodstream, what they mean for our health, and how to potentially turn back the proteomic clock.

Reference:

[1] Undulating changes in human plasma proteome profiles across the lifespan. Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, Moran Losada P, Berdnik D, Keller A, Verghese J, Sathyan S, Franceschi C, Milman S, Barzilai N, Wyss-Coray T. Nat Med. 2019 Dec;25(12):1843-1850. 

Links:

What Do We Know About Healthy Aging? (National Institute on Aging/NIH)

Cognitive Health (NIA)

Wyss-Coray Lab (Stanford University, Palo Alto, CA)

NIH Support: National Institute on Aging


Making Personalized Blood-Brain Barriers in a Dish

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Credit: Vatine et al, Cell Stem Cell, 2019

The blood-brain barrier, or BBB, is a dense sheet of cells that surrounds most of the brain’s blood vessels. The BBB’s tiny gaps let vital small molecules, such as oxygen and water, diffuse from the bloodstream into the brain while helping to keep out larger, impermeable foreign substances that don’t belong there.

But in people with certain neurological disorders—such as amyotrophic lateral sclerosis (ALS) and Huntington’s disease—abnormalities in this barrier may block the entry of biomolecules essential to healthy brain activity. The BBB also makes it difficult for needed therapies to reach their target in the brain.

To help look for solutions to these and other problems, researchers can now grow human blood-brain barriers on a chip like the one pictured above. The high-magnification image reveals some of the BBB’s cellular parts. There are endothelial-like cells (magenta), which are similar to those that line the small vessels surrounding the brain. In close association are supportive brain cells known as astrocytes (green), which help to regulate blood flow.

While similar organ chips have been created before, what sets apart this new BBB chip is its use of induced pluripotent stem cell (iPSC) technology combined with advanced chip engineering. The iPSCs, derived in this case from blood samples, make it possible to produce a living model of anyone’s unique BBB on demand.

The researchers, led by Clive Svendsen, Cedars-Sinai, Los Angeles, first use a biochemical recipe to coax a person’s white blood cells to become iPSCs. At this point, the iPSCs are capable of producing any other cell type. But the Svendsen team follows two different recipes to direct those iPSCs to differentiate into endothelial and neural cells needed to model the BBB.

Also making this BBB platform unique is its use of a sophisticated microfluidic chip, produced by Boston-based Emulate, Inc. The chip mimics conditions inside the human body, allowing the blood-brain barrier to function much as it would in a person.

The channels enable researchers to flow cerebral spinal fluid (CSF) through one side and blood through the other to create the fully functional model tissue. The BBB chips also show electrical resistance and permeability just as would be expected in a person. The model BBBs are even able to block the entry of certain drugs!

As described in Cell Stem Cell, the researchers have already created BBB chips using iPSCs from a person with Huntington’s disease and another from an individual with a rare congenital disorder called Allan-Herndon-Dudley syndrome, an inherited disorder of brain development.

In the near term, his team has plans to model ALS and Parkinson’s disease on the BBB chips. Because these chips hold the promise of modeling the human BBB more precisely than animal models, they may accelerate studies of potentially promising new drugs. Svendsen suggests that individuals with neurological conditions might one day have their own BBB chips made on demand to help in selecting the best-available therapeutic options for them. Now that’s a future we’d all like to see.

Reference:

[1] Human iPSC-Derived Blood-Brain Barrier Chips Enable Disease Modeling and Personalized Medicine Applications. Vatine GD, Barrile R, Workman MJ, Sances S, Barriga BK, Rahnama M, Barthakur S, Kasendra M, Lucchesi C, Kerns J, Wen N, Spivia WR, Chen Z, Van Eyk J, Svendsen CN. Cell Stem Cell. 2019 Jun 6;24(6):995-1005.e6.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

Stem Cell Information (NIH)

Svendsen Lab (Cedars-Sinai, Los Angeles)

NIH Support: National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences


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


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