Challenges Remain for Gene Therapies Targeting Hemoglobinopathies

Joachim Kunz, MD

Although gene therapy for sickle cell disease and transfusion-dependent thalassemia offers promise for those unresponsive to standard care, there still remain great challenges in advancing this relatively novel treatment domain.

A new review co-authored by Joachim Kunz, MD, and Andreas Kulozik, MD, PhD, of the Department of Pediatric Oncology, University of Heidelberg, Germany, laid out the potential for gene therapy, such as gene editing and addition. They also commented on the current roadblocks for making such practices available worldwide.

As a result of large migration from areas of high sickle cell disease and ß-thalassemia prevalence, such pathological mutations have become the most common genetic disorders globally. Thus, the authors noted that shifting demographics in countries with once low prevalence of hemoglobinopathies have led to a rising in patient numbers.

The current standard of care for these disorders, then, includes disease-modifying treatment with red blood cell transfusions, iron chelation, and pharmacologic induction of fetal hemoglobin (HbF), which require a combining with treatment of symptoms and complications.

Nonetheless, a gene therapy option for transfusion-dependent thalassemia has emerged in the past few years.

In 2019, the European Medicine Agency (EMA) conditionally licensed gene addition therapy (Zynteglo) for the European Union, based on data showing lentiviral transduction of hematopoietic stems cells.

The licensing was supported by the HGB-204 and HGB-205 trials run by bluebird bio, which found that 12 of 13 evaluable patients with a non-ß⁰/ß⁰ genotype became independent from red blood cell transfusions (HGB-204 median duration, 38 months).

The treatment is indicated for patients with transfusion dependent non-ß° thalassemia major, aged ≥12 years old and who have a non-ß⁰/ß⁰ genotype. Additionally, these patients must have no available HLA-matched sibling as a stem donor.

Kunz and Kulozik referenced various other clinical trials aimed at providing gene therapy in patients with sickle cell disease.

“In [sickle cell disease], successful gene therapy must reduce the frequency and severity of vasoocclusive complications such as pain crises or acute chest syndrome and ultimately prevent or even reverse end organ damage,” they wrote.

After optimization of therapy protocols, the study investigators were able to use gene addition to reduce the frequency of vasocclusive complications.

The review also acknowledged current advanced preclinical studies focused on gene editing and repair. However, such clinical experience with these techniques is limited in its availability. 

Despite the various techniques being developed under the umbrella of gene therapy, the authors suggested that a combination of strategies might be necessary to optimize patient outcomes.

And finally, there are still 2 major obstacles that they noted must be addressed before use of gene therapy can become widespread.

The first is that current protocols still require myeloablative conditioning. Even if the cumulative dose of chemotherapy is reduced, especially in comparison to allogeneic stem cell transplantation, there remains the risk of infertility and secondary neoplasms.

Furthermore, the sophisticated logistics and high cost of therapy can certainly pose a challenge in countries and healthcare systems with limited resources and a high prevalence of hemoglobinopathies.

“Obviously, the development of conditioning regimens with reduced toxicity and lowering the costs of gene therapy are the most important steps required to bring this treatment option to more than a small number of selected patients,” Kunz and Kulozik concluded.

The review, “Gene Therapy of the Hemoglobinopathies,” was published online in HemaSphere.