Gene Therapy is a Cure for Sickle Cell Disease

Gene therapy can cure sickle cell disease. We have patients who are symptoms-free, fully enjoying their lives. The question is how to make the treatment accessible to the millions of people who need it

Yes. Gene Therapy Can Cure Sickle Cell Anemia

As of today, at least 10 patients have received gene therapy treatment for sickle cell disease.

The first patient was a 13 year old boy treated in October 2014 at Necker Children’s Hospital in Paris. The boy had had a history of numerous pain crises, as well as several health issues resulting from sickle cell disease.

More than 15 months after the treatment, this patient had no more pain crises, discontinued taking all medications, and reported full participation in normal academic and physical activities. (1).

Even to the most critical eye, the Paris boy case looks like a cure.

Jenelle Stephenson, featured on CBS News, was treated as a part of a different clinical trial at the National Institutes of Health in December 2017. Jenelle went from having repeated crises of acute “beyond level 10” pain to being able to run and practice martial arts. Jenelle’s blood looks perfectly normal under the microscope, with no sickle cells in sight. 

Seven other people were treated in the same clinical trial at the NIH, all of them are now showing signs of recovery (2).

Victoria Gray is a sickle cell patient participating in yet another clinical trial conducted by CRISPR Therapeutics. In June 2019 Victoria received a CRISPR-based treatment at the Sarah Cannon Research Center in Nashville. 

Following the treatment Victoria returned to her family. She is now waiting to see if the treatment is working (3).

Genetics of Sickle Cell Disease

Genetic root cause of sickle cell disease is a fault in the hemoglobin gene.

Hemoglobin is a protein responsible for binding and releasing oxygen. Red blood cells are like bean bags packed with hemoglobin molecules. They soak in the oxygen in our lungs and then release it in all the organs that they travel to.

Genetic defect leading to sickle cell anemia is tiny. 

It is an A – T substitution in DNA nucleotide sequence of hemoglobin beta chain. The protein that comes from defective DNA code has amino acid glutamine at position 6 replaced with amino acid valine (4).

Such amino acid substitution leads to different protein folding. Instead of being free floating globules, hemoglobin molecules link with each other, forming strands.

When hemoglobin strands accumulate inside red blood cells, the cells change their shapes from “bags” to “sickles”. Sickles get stuck in blood vessels, blocking blood supply and causing pain crises.

Sickle cell disease has been a prime candidate for gene therapy because fixing just one gene could cure a patient.

How it Works: Gene Therapy Applied to Hematopoietic Stem Cells

Sickle cell disease can be treated with a bone marrow transplant.

Bone marrow contains hematopoietic stem cells, which divide and differentiate into red blood cells. In the process of bone marrow transplant, the patient’s own hematopoietic stem cells are killed by chemotherapy, and then replaced by hematopoietic stem cells from a matching donor.

The problem with bone marrow transplants is that less than one-third of people with sickle cell disease can find a matching donor. Another problem is that the transplant can be rejected by a patient’s body, leading to severe complications or even death (4).

During gene therapy, bone marrow is extracted from a sickle cell patient, genetically modified in a lab, and then injected back. 

While the genetic modification is taking place, the patient goes through chemotherapy to remove their faulty hematopoietic stem cells. When the new stem cells arrive, they start producing healthy red blood cells, curing the patient from sickle cell disease.

There is no problem with trying to find a matching donor, and there is no conflict between donor and recipient cells.

There is only a challenge of applying gene therapy “magic” to patient’s bone marrow.

Insertion of Hemoglobin Gene into Hematopoietic Stem Cells

A cornerstone of gene therapy are gene delivery vehicles, also known as vectors. 

The vector used in the Paris clinical trial was LentiGlobin BB305, a modified lentivirus. The vector used in the NIH clinical trial involving Jenelle Stephenson was a modified HIV virus. 

Viruses have naturally evolved the ability to penetrate cell barriers and insert their genetic material into host cells. In order to a create gene therapy vector, infectious components of viral nucleic acid are removed, and then replaced with a gene of interest, for example functional beta globin.

The lab procedure done to the patient’s bone marrow involves treatment with a viral vector that delivers a functional gene to the patient’s own hematopoietic stem cells.

Once injected back into the patient, modified stem cells start producing healthy red blood cells that are no longer prone to sickling.

CRISPR Gene Therapy for Sickle Cell Disease

Gene therapy used to treat Victoria Gray relies on a different genetic mechanism.

In the human fetus and in newborn babies the function of beta globin is performed by another protein molecule, called gamma globin. Six months after birth levels of gamma globin start to decline. Gamma globin is replaced by the “adult” globin version, the beta globin.

Sickle cell babies do not develop disease symptoms while the gamma globin is produced. Gamma globin blocks mutated beta globin molecules from doing their sickling harm to red blood cells.

A gene responsible for reducing levels of gamma globin has been tracked down. It is called BCL11A. 

CRISPR technology allows to selectively disable BCL11A gene in hematopoietic stem cells in a patient’s bone marrow.

Once the bone marrow is extracted from the patient, it is genetically modified by the CRISPR/Cas9 system that knocks out BCL11A and boosts the production of gamma globin.

The hope for Victoria Grey is that increased levels of beta globin in her red blood cells will save them from sickling, the way it happens in newborn babies.

Are you eligible? Current clinical trials

At the moment, the only way to gain access to sickle cell gene therapy is to participate in a clinical trial. The good news is that there are several clinical trials going on, and many are actively recruiting patients.

NCT02140554 is a major clinical trial sponsored by bluebird bio, the same company that did the very first sickle cell gene therapy trial in Paris. NCT02140554 is done at nine sites across the United States, and it is intended to include 50 participants. The recruitment for this study is closed.

NCT03745287 is another major clinical trial with an estimated enrollment of 45 participants. Study sites are spread around the United States, Canada, and Europe. This study is sponsored by CRISPR Therapeutics, and it is using the same CRISPR gene editing technology used for Victoria Grey. By the way, the fact that this clinical trial is announced, means that Victoria must be doing well after her treatment.

There are also five other gene therapy clinical trials for sickle cell disease that are recruiting groups of three to ten patients. The latest clinical trial information can be accessed on ClinicalTrials.gov website (5).

The Future of Sickle Cell Gene Therapy

Gene therapy treatment for sickle cell disease is working. Yet it is a very long road from here to making this treatment available to millions of people suffering from the condition.

The first step involves monitoring the patients who already received the therapy, and conducting trials on larger groups. Phase 2 and Phase 3 clinical trials will take several years. Their main objective is to eliminate unknown risks, and prove that the treatment is truly effective and safe.

Then the issue of treatment cost will kick in.

According to Nick Leschly from bluebird bio, it takes hundreds of millions of dollars to develop a gene therapy (6). That’s why prices for already approved gene therapies are flying in the range of hundreds of thousands of dollars per treatment.

We could speculate that even in the United States, one of the most prosperous countries in the world, sickle cell gene therapy will be prohibitively expensive for most patients. 

There are also 4 million people living with sickle cell disease worldwide, most of them in Subsaharan Africa (7). Delivering modern medicine to them will require an effort that is currently hard to imagine.

Gene therapy potential for creating positive change in the world is huge. The question is how to make it accessible.

References

1. New England Journal of Medicine. Gene Therapy in a Patient with Sickle Cell Disease
2. CBS News. Could Gene Therapy Cure Sickle Cell Anemia? 2019
3. NPR. A Patient Hopes Gene-Editing Can Help With Pain of Sickle Cell Disease
4. NIH National Heart, Lung, and Blood Institute. Sickle Cell Disease
5. ClinicalTrials.gov. Search results for Sickle Cell Disease gene therapy
6. Gene Therapy — The time is now: Nick Leschly at TEDxBoston
7. The Lancet. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015