Gene Therapy for Hemoglobinopathies

WHILE HEMOGLOBINOPATHIES are not necessarily common in the United States, with only approximately 100,000 adults and children affected, they are more often found in other areas of the world.¹ Approximately 7 percent of the world’s population are carriers, and hemoglobinopathies are the most common monogenic diseases, especially widespread in Asia, the Mediterranean and Africa.² Today, hemoglobinopathies are spread globally because of increased migration rates.³ They are also a major health concern, with roughly 330,000 children born with the diseases worldwide every year. In the United States, Hispanic-Americans and Black or African-American populations are more at risk for hemoglobinopathies, and they often carry the autosomal recessive disease (two inherited mutated genes, one from each parent).⁴ Patients living with hemoglobinopathies typically cope with a level of uncertainty or even grief because their lives are so deeply affected by the illnesses. They are often anxious, for example, about their constant need for comprehensive resources to ensure their effective and costly care. And, they are almost invariably concerned about their long-term prognosis.

What Are Hemoglobinopathies?

Hemoglobinopathies are a group of disorders passed down through families in which there is abnormal production or structure of the hemoglobin (the red protein responsible for transporting oxygen in the blood) molecule (Figure). The most common hemoglobinopathies are sickle cell disease (SCD) and thalassemia. SCD, an umbrella group of hemoglobinopathies that includes sickle cell anemia, is an inherited disorder caused by an abnormal form of a protein called beta-globin, which causes red blood cells to become sickle (crescent)-shaped and inflexible.

Thalassemia is an inherited blood disorder caused by a defect in the gene that helps control the production of hemoglobin. There are two main types of thalassemia: alpha and beta, which differ according to which protein is altered. In both cases, people with thalassemia have fewer healthy red blood cells. Two other rare hemoglobinopathies include congenital sideroblastic anemia and congenital dyserythropoietic anemia caused by low levels of functioning red blood cells and often high levels of iron in the body. All types rob the body of adequate blood and oxygen, which damages the kidneys, liver and spleen, among other organs, and can be fatal.⁴

Currently, the only cure for SCD is a blood and bone marrow transplant. Transplants come from a human leukocyte antigen-matched sibling; however, only a small number of people are able and eligible for this treatment. There are other somewhat successful treatments that can reduce symptoms and prolong life, which are relatively available for patients who cannot afford or otherwise access a transplant. Severe cases of thalassemia are sometimes managed by frequent blood transfusions, while milder cases are prescribed folic acid to help treat anemia, typically to augment other therapies. For patients who are unresponsive to such remedies and who are merely managing symptoms, life without an available cure can be devastating.⁴

Gene Therapy: A Cure for Hemoglobinopathies?

Today, gene therapy is providing a glimmer of optimism for hemoglobinopathy patients, with successful clinical trials pointing to a more accessible cure.

In simplified terms, gene therapy adds modified, functional copies of the beta-globin gene into a patient’s hemopoietic stem cells so the body can make functional hemoglobin molecules and, therefore, functional red blood cells. In several ongoing studies, patients with six or more months of follow-up after treatment for SCD had median sickle cell hemoglobin levels reduced to 50 percent or less of total hemoglobin without blood transfusions. And in thalassemia, studies found sufficient hemoglobin production to reduce or eliminate the need for transfusion support. As the first-ever gene therapy for either of the conditions, medical researchers are nearing approval to cure these diseases.⁴

According to the authors of one recent study, “Gene therapy for hemoglobinopathies is now founded on transplantation of autologous hematopoietic stem cells genetically modified with a lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Preclinical and early clinical studies showed the safety and potential efficacy of this therapeutic approach, as well as the hurdles still limiting its general application. In addition, for both beta-thalassemia and SCD, an altered bone marrow microenvironment reduces the efficiency of stem cell harvesting and engraftment. These hurdles still need to be addressed for gene therapy for hemoglobinopathies to become a clinical reality.”⁵

The New England Journal of Medicine has published the work of two groups of researchers who used different types of gene therapy techniques that target the transcription factor BCL11a involved with globin switching, which have improved clinical outcomes in patients with SCD and thalassemia. According to Mark Walters, MD, a researcher at the University of California’s Blood and Bone Marrow Transplant Program, “These trials herald a new generation of broadly applicable curative treatments for hemoglobinopathies.” In one clinical trial with two patients, one with thalassemia and the other with SCD, researchers administered CRISPR-Cas9 gene edited hematopoietic stem and progenitor cells (HSPCs) with reduced BCL11A expression in the erythroid lineage. The product, CTX001, had been shown in a preclinical study to restore Y-globulin synthesis and reactivate production of fetal hemoglobin. Both patients underwent busulfan-induced myeloablation prior to receiving the treatment. The researchers suggested the CRISPR-Cas9-based gene-edited product could change the paradigm for patients with these conditions if it is found to successfully and durably graft, produce no “off-target” editing products and, importantly, improve clinical course.⁶

In the second trial, which included six patients with SCD, researchers described results with infusion of gene-modified cells derived from lentivirus insertion of a gene that knocks down BCL11a by encoding an erythroid-specific, inhibitory short-hairpin RNA. They found that at median follow-up of 18 months, all patients had engraftment and a robust and stable HbF induction broadly distributed in red cells. And, clinical manifestations of SCD were reduced or absent during the follow-up period. “The field of autologous gene therapies for hemoglobinopathies is advancing rapidly,” lead researcher Erica Esrick, MD, and colleagues reported, “including lentiviral trials of gene addition in which the nonsickling hemoglobin is formed from an exogenous Y-globin or modified ß-globin gene.”⁶

Deepa Manwani, MD, director of pediatric hematology at Children’s Hospital and professor at Albert Einstein College of Medicine in New York City, maps out other major aspects of hemoglobinopathies in her American Society of Hematology presentation “Moving From Science Fiction to Clinical Reality.” In it, she answers key questions regarding the illnesses and their treatment. When asked about the rationale for beta-hemoglobinopathies and SCD, Dr. Manwani says, “These are very common hematologic disorders with a very high cost of care, as well as burden of disease, to the patients. There are limited options for treatment, and specifically for curative treatment. The only curative treatment that’s currently approved outside of genetic therapies, most of which are in clinical trials, is stem cell transplantation. [However], since these are genetic disorders, those treatments are available to a minority of patients. Less than 15 percent, for instance, of sickle cell patients will have a matched sibling donor who doesn’t have the disease since it’s genetic. That’s why it’s very important that these patients have access to newer therapies that can be accessed by many, many patients.”

With regard to recent advances in gene therapies, Dr. Manwani believes it is a “very, very exciting time. Three decades ago, when I decided I would focus my research on beta-hemoglobinopathies, we were talking about gene therapies being a reality in five years, and then we were talking about it every five years like it was going to happen, and it didn’t happen.” The problem was, she says, that “the gene that’s abnormal, the beta-globin gene, is very, very large, and that plagued scientists because they were not able to get it in and be expressed at the right levels. It was challenging technically.” But she also states that in the last five years, she and fellow researchers have seen “tremendous improvements,” and now the gene can be expressed “through a lentiviral vector.” The technology is now easier because the gene “gets into the right place, expressed at the right level, and these patients are actually on clinical trials doing extremely well. It gives me great hope, and I think that this provides great promise for our patients.”

Major challenges in clinical trials versus real world use, according to Dr. Manwani, include treatment expense and the length of treatment. “This is not a therapy that is inexpensive and quick,” she says. “It’s a commitment on the part of the patient, and it is also extremely expensive. So this is not a therapy that’s a pill that can be taken by, for instance, children in Africa where the largest burden of sickle cell disease is. So it will be again, at least initially, available to fewer patients in high-resource settings, but I think that this opens the window to these types of therapies, and this is how we will continue to advance and finally provide those therapies to a wider group of patients at a lower cost.

“One of the biggest problems with the current strategies is it requires what is known as an autologous bone marrow, or stem cell transplantation approach, where the patient’s stem cells are actually harvested and modified, but then the patient has to receive chemotherapy to wipe out their bone marrow before these modified stem cells can be given back to the patient, and that’s not trivial therapy,” explains Dr. Manwani. “For one, it results in infertility. So those types of very toxic, preparative regimens can be a huge problem, especially facing these very difficult decisions about whether to opt for this therapy or not. And I think that researchers are well aware of the urgent need for different ways of preparing the patient’s bone marrow to receive the modified stem cells back. There’s some very exciting research that’s ongoing. And [recently], we’ve heard about so many wonderful advances, it gives me great hope. I think that we’re finally in an era where we’re going to continue to move forward, and at a very fast pace. I think in the next five to 10 years, we’ll see better and better approaches to delivering this type of care with less toxicity.”

Of course, the high cost of this therapy must be overcome, which can be a reality since various organizations and agencies are funding the work. For instance, says Dr. Manwani, in the U.S., the National Heart, Lung and Blood Institute is partnering with the Bill and Melinda Gates Foundation to focus on funding research that will allow this therapy to be delivered more easily without the high cost. One change that might be required to accomplish that, she explains, is called in vivo gene therapy, where the gene therapy can be given as a single shot to correct the abnormal gene without requiring the stem cell transplantation. Given the initial reports with CRISPR/ Cas9 and other viral vectors, she believes that is not outside the realm of possibility.

“Even having the high-cost therapy in the high-resource settings is a huge step forward,” says Dr. Manwani. “When we talk to our patients, they tell us, ‘I know that as doctors and scientists you want everything to be perfect before you move forward, but we want the treatments that are possible now.’ I think that the shared decision-making that goes into actually preparing a patient for this type of therapy is going to be very important at this stage.”⁷

A Cure May Be Forthcoming

The innovations, medical insights and genetic problem-solving will certainly not end with these studies and advances. As gene therapy for all diseases is developed and honed, patients worldwide who have unbearable, chronic and even life-threatening conditions such as hemoglobinopathies may soon be free of their physical ailments and emotional medical concerns.