Bioengineering and Specialized Therapies Yield Results for Rare and Challenging Blood Diseases
Advances in gene therapy, stem cell engineering, and targeted drugs show persistence pays off
(Atlanta, December 9, 2017) — In four studies being presented today during the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta, researchers announce promising findings on innovative tools and therapies for hard-to-treat blood disorders including sickle cell disease (SCD), beta thalassemia, and X-linked severe combined immunodeficiency (X-SCID). The studies employ unique therapeutic approaches and advanced engineering technologies such as the gene-editing platform CRISPR/Cas9, reflecting the fruits of many years of research dedication and innovation.
“Achievements like these represent an enormous amount of determination on the part of physician-scientists to create treatments and cures for these patients,” said press briefing moderator Jonathan G. Hoggatt, PhD, principal faculty member of the Harvard Stem Cell Institute and Assistant Professor of Medicine at Harvard Medical School. “Making these tools and treatments a reality doesn’t happen overnight or in five years; it requires a great deal of perseverance both in the lab and in the clinic.”
This press conference will take place on Saturday, December 9, at 10:00 a.m. EST in Room A315 of the Georgia World Congress Center.
Gene Therapy Restores All Immune Cell Types in Infants with X-linked Severe Combined Immunodeficiency
Interim Results from a Phase I/II Clinical Gene Therapy Study for Newly Diagnosed Infants with X-Linked Severe Combined Immunodeficiency Using a Safety-Modified Lentiviral Vector and Targeted Reduced Exposure to Busulfan 
Infants with the devastating genetic condition X-SCID were able to produce all three major immune cell types with no major side effects after receiving an investigational gene therapy in a Phase I/II trial. The preliminary results suggest a substantial breakthrough for a therapeutic area that has encountered significant safety hurdles in the past, according to investigators.
X-SCID is an inherited condition in which the body cannot produce the cells responsible for defending against infection: T-cells, B-cells, and natural killer (NK) cells. The disease is rare, but devastating. Without treatment, babies born with SCID succumb to infections and die by age two. Of those who receive a stem cell transplant, the best-available treatment, approximately 30 percent die by age 10. Previous experimental gene therapies for X-SCID have only been able to restore T-cell function, and in some cases have caused treated infants to develop leukemia.
In developing this new gene therapy, researchers at St. Jude Children’s Research Hospital and the University of California, San Francisco used an inactivated form of HIV as a vector to introduce genetic modifications into the patients’ bone marrow cells. HIV was chosen as the delivery vehicle given the virus’ ability to better infiltrate cells compared to previously-used gene therapy vectors. The team used low doses of chemotherapy to prepare the patients’ bone marrow to receive this therapy.
To date, the researchers have tested their new gene therapy in seven infants, tracking outcomes for up to 12 months. Preliminary results reveal evidence of T-cell, B-cell, and NK cell production in some of the treated infants, with no major side effects. Unprecedentedly high levels of the vector were seen in all types of blood cells, and in some cases, more than 60 percent of all bone marrow stem cells contained the corrective gene for X-SCID. All of the treated babies have so far appeared to benefit from the therapy.
“It is very exciting that we observed restoration of all three very important cell types in the immune system,” said lead study author Ewelina Mamcarz, MD, assistant professor in the bone marrow transplant department at St. Jude Children’s Research Hospital. “This is something that’s never been done in infants and a huge advantage over prior trials. The initial results also suggest our approach is fundamentally safer than previous attempts.”
The researchers are continuing to track the infants’ immune activity and their ability to respond to vaccination, which will take more time to establish.
The current standard of care for SCID is a stem cell transplant from a matched sibling donor, but that treatment is only possible for about 20 percent of patients. The remaining 80 percent of patients typically receive a stem cell transplant from a parental donor, but continue to suffer from life-threatening infections and require monthly immunoglobulin infusions. If gene therapy proves successful and safe for SCID, it could potentially cure many more patients, reduce dependency on immunoglobulin, and avoid the serious risks associated with stem cell transplantation, such as graft-versus-host disease.
Several genetic mutations can cause SCID. The new therapy is designed for those with a type known as X-linked SCID, which comes from a mutation in the IL2RG gene found on the X chromosome. Researchers say the same approach could be adapted for any type of SCID, and indeed many other genetic disorders, as well.
This study was supported by The Assisi Foundation of Memphis, Inc. and the California Institute of Regenerative Medicine (CIRM).
Ewelina Mamcarz, MD, of St. Jude Children’s Research Hospital, will present this study during an oral presentation on Sunday, December 10, at 4:30 p.m. EST in Auditorium C101 of the Georgia World Congress Center.
First Intra-Bone Gene Therapy Reduces Transfusions for Patients with Rare Blood Disorder
Gene Therapy for Beta Thalassemia: Preliminary Results from the PHASE I/II Tiget-Bthal Trial of Autologous Hematopoietic Stem Cells Genetically Modified with GLOBE Lentiviral Vector 
In a Phase I/II trial, researchers report patients with transfusion-dependent beta thalassemia had a significantly reduced need for blood transfusions after a single infusion of cells carrying corrected genes. The results suggest gene therapy could offer a viable alternative to stem cell transplantation — currently the only curative therapy for this condition — for patients who do not meet the criteria for a stem cell transplant or cannot find a matched stem cell donor.
Beta thalassemia syndromes are a group of inherited anemias affecting hundreds of thousands of people worldwide; about 56,000 babies with the most severe forms of the disorder are born each year. Beta thalassemia causes malfunctions in red blood cells and can lead to severe anemia and other complications. More than 200 genetic variations have been associated with the disease, with severity of symptoms varying by a patient’s specific genetic mutation. Many with the disorder require frequent blood transfusions for the rest of their lives.
This investigational gene therapy aims to deliver corrected genes directly into the bone marrow to allow a patient’s body to manufacture red blood cells that produce normal hemoglobin. To test the approach, researchers extracted stem cells from seven patients (three adults and four children, all of whom required regular blood transfusions due to disease severity) and then infected the cells with a non-pathogenic virus carrying the correct gene. After conditioning each patient with chemotherapy to make space for new stem cells to proliferate, or graft, into the bone marrow, the stem cells carrying the correct genetic material were infused into the patients’ bone marrow.
This research follows several other clinical trials of beta thalassemia gene therapies, some of which also have had promising results; however, this approach varies from previous gene therapies in that it involves a different design of the viral vector, uses a different conditioning regimen for the patient, and is the first beta thalassemia stem cell gene therapy to be delivered directly into the bone marrow, where blood cells are made.
After a median of 16 months of follow-up, five of the seven patients showed a marked reduction in the number of blood transfusions needed. Three pediatric patients required no blood transfusions beginning one month after receiving the gene therapy.
“Our study suggests that gene therapy can correct the disease, resulting in transfusion independence,” said lead study author Sarah Marktel, MD, of San Raffaele Hospital and SR-Tiget (San Raffaele Telethon Institute for Gene Therapy) in Milan, Italy. “Although the number of patients is small, our preliminary results also suggest the benefit could be greater in children than in adults. Our hypothesis is that younger stem cells in pediatric patients may be more favorably corrected by gene therapy and in general may lead to better engraftment and performance.”
Compared to previous trials in which the genetically modified stem cells were introduced into the bloodstream via intravenous infusion, the patients in this trial began showing evidence of successful engraftment sooner after receiving the therapy, suggesting that infusing the cells directly into the patients’ bone marrow can make a difference.
The results also reveal an encouraging safety profile, with no gene therapy-related adverse reactions apart from the side effects typically associated with the chemotherapy used for conditioning, such as infection. The researchers are now in the process of administering the gene therapy to three additional pediatric patients.
This study was supported by Telethon Foundation. The therapy has been licensed by GSK.
Sarah Marktel, MD, San Raffaele Scientific Institute and SR-Tiget, Milan, Italy, will present this study during an oral presentation on Sunday, December 10, at 9:30 a.m. in Room B213 of the Georgia World Congress Center.
First Drug Designed Specifically for Sickle Cell Disease Shows Benefits in Adolescents
Initial Results from a Cohort in a Phase 2a Study (GBT440-007) Evaluating Adolescents with Sickle Cell Disease Treated with Multiple Doses of GBT440, a HbS Polymerization Inhibitor 
Preliminary results from a new trial of the investigational drug voxelotor (previously GBT440) suggest the drug is safe and effective in older children and adolescents with sickle cell disease (SCD). Voxelotor has previously been tested only in adults. Designed to prevent the abnormal curving, or “sickling,” of red blood cells with defective hemoglobin, the drug aims to reduce the frequent pain, inflammation, and long-term tissue damage associated with the accumulation of sickled cells in blood vessels.
The results suggest voxelotor can offer benefits above and beyond those of hydroxyurea, a chemotherapy drug that has long been considered the standard of care for SCD.
“What sets this drug apart is that it was designed specifically for sickle cell disease,” said lead study author Carolyn C. Hoppe, MD, associate hematologist at UCSF Benioff Children’s Hospital Oakland. “This is one of the first drugs that intentionally targets the fundamental mechanism of sickle cell disease — the polymerization, or clumping together of sickle cell hemoglobin. This prevents cells from sickling early on, eliminating all the downstream consequences of sickling.”
People with SCD have a genetic mutation in hemoglobin, the protein in red blood cells responsible for binding oxygen. This causes red blood cells to become rigid and misshapen, building up in blood vessels and impeding the delivery of oxygen to tissues. Administered orally, voxelotor binds to the defective hemoglobin, preventing the red cells from forming the characteristic sickled shape and thereby reducing the risk of life-threatening sickle cell crises.
This trial is being conducted in 24 teens (ages 12 to 17) with SCD. A preliminary analysis of results from the first 12 patients treated for 16 weeks reveals that voxelotor increased hemoglobin, reduced anemia, and helped participants’ red blood cells live longer. These results mirror the findings from previous trials conducted in adults. In addition, the researchers noted evidence of reductions in pain and possibly the risk of stroke. The treatment was not associated with any serious adverse effects.
Because most of the study participants also took hydroxyurea before and during the voxelotor trial, the improvements seen in the trial suggest the two drugs could provide additive effects. The researchers are continuing to assess outcomes in the enrolled patients and to experiment with different dosing regimens.
This study was supported by Global Blood Therapeutics, Inc.
Carolyn C. Hoppe, MD, UCSF Benioff Children’s Hospital Oakland, will present this study during an oral presentation on Monday,December 11, at 2:45 PM EST in Room B308–B309 of the Georgia World Congress Center.
Engineered Stem Cells Could Facilitate Safer Blood Transfusions for Patients with Sickle Cell Disease
Customized Induced Pluripotent Stem Cell-Derived Red Cell Reagents 
Researchers are announcing one of the first applications of induced pluripotent stem cells (iPSCs) poised to improve day-to-day clinical care of people with SCD. They report using the gene-editing platform CRISPR/Cas9 to engineer a panel of stem cell-derived red blood cells to guide rapid identification of antibodies common among people with SCD to allow for quicker, more efficient matching of blood for transfusions.
People with SCD frequently require blood transfusions, but the formation of uncommon antibodies in their blood often makes it challenging to find donor blood that is safe to use for these patients. By helping patients with SCD quickly find matched donor blood, the new screening panel represents a groundbreaking achievement in the use of stem cells and genetic engineering.
“It has been more than 10 years since iPSCs have been available, but we have yet to see applications for blood diseases that improve how we care for our patients,” said lead study author Stella T. Chou, MD, assistant professor of pediatrics at Children’s Hospital of Philadelphia (CHOP). “Using this panel, we would be able to more quickly identify what antibodies the patient has made, informing us what kind of blood we have to give them. It means we’ll be able to improve their ability to be transfused safely and reduce delays in their care.”
The work centers around a group of antibodies associated with the Rh blood group system. Individuals with SCD often have variations or mutations in the RH gene, which alters the Rh proteins on their red cells. Despite patients receiving blood that is “Rh-matched” by standard blood bank tests for Rh, having these variant proteins increases their risk of forming Rh antibodies with transfusions. If a person with Rh antibodies receives a blood transfusion that is not matched correctly, the recipient’s immune system treats the donated blood as foreign and destroys the transfused red cells.
While RH variants occur in only one to two percent of the general population, they are much more common in people with SCD. Dr. Chou said they are found in more than half of the children with SCD treated at CHOP. This is largely because of the increased prevalence of RH variants in people of African descent, who make up the majority of people living with SCD.
For patients dependent upon donor blood with perfectly matched Rh, transfusable blood is often hard to come by. Routinely RH genotyping all donated blood to better match eventual patients is extremely costly, and testing blood in the donor pool to find an appropriate candidate can take days. To address these problems, the researchers used iPSCs, which can become any cell in the body, to create an array of blood cells with rare red cell antigen combinations that could be used to quickly test for Rh antibodies. To reflect clinically important Rh variations, the researchers used blood from donors with rare RH variants and also genetically altered some iPSCs using CRISPR/Cas9 to create blood cells with specific combinations of antigens.
With further refinement of this technique, the researchers from CHOP and New York Blood Center hope to develop a simple, cost-effective screening tool that could be used at local blood banks across the country to help doctors quickly find Rh-matched blood for people with SCD.
This study was supported by the National Institutes of Health/National Heart Lung and Blood Institute.
Stella T. Chou, MD, The Children’s Hospital of Philadelphia, will present this study during an oral presentation on Sunday, December 10, at 2:00 p.m. EST in Hall C2 of the Georgia World Congress Center.