Gene Therapy: Where We Started and Where the Field Is Going

In the more than 20 years since the first successful gene transfer was performed in a human subject (Blaese, R.M. et al. Science 1995; 270, 475-480), the promise of gene therapy has been at once tantalizingly close and just out of reach. Today, gene-modified therapies are being used to treat a variety of diseases, and direct manipulation of the human genome for therapeutic effect is becoming a reality. While many advances in gene-based therapeutics have come in the oncology space, non-malignant hematologic and primary immune disorders remain important targets for these approaches. The ability to manipulate hematopoietic stem cells (HSCs) ex vivo and return the modified HSCs to the patient offers many potential advantages over allogeneic HSC transplantation. Additionally, the potential to introduce new genes with therapeutic potential, or to modify genes to modulate protein expression, may open new avenues for transformative therapies for genetic diseases. The progress of gene therapy for hemoglobinopathies - from the γ-retroviral vector technology that established the field, to the accumulating clinical experience with lentiviral vector-based gene therapy and the potential for gene editing-based approaches to address these diseases - provides insight into the development of genetic therapeutics. Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) result from pathogenic mutations in the β-globin gene, HBB . Addition of functional HBB genes into autologous hematopoietic stem cells has the potential to offer the long-term therapeutic benefits of allogeneic HSC transplantation without the complications of graft vs host disease. The first human proof of concept of this approach came in a study of the HPV569 lentiviral vector coding for therapeutic β-globin, which was successfully introduced into the HSCs of patients with TDT and resulted in sustained clinical benefit in some patients (Cavazzana-Calvo et al., Nature 2010; 467(7313):318-22). Beyond restoring normal β-globin production, studies with HPV569 and its improved variant BB305, have shown that it is possible to drive expression of a β-globin variant with a point mutation, T87Q, designed to mimic the anti-sickling effect of γ-globin. This innovation may have important implications for patients with SCD, where introduction of normal β-globin may be insufficient to ameliorate the red blood cell sickling and polymerization that can cause painful and damaging vaso-occlusive crises. It has taken more than 20 years for HSC gene addition to reach safety and efficacy thresholds that may allow it to be used routinely for patients with hemoglobinopathies, but this approach is now nearing maturity. Important refinements in LVV architecture and advances in HBB gene cassette design have yielded promising results in multiple clinical studies of TDT and SCD (e.g. Ribeil J.A. et al., N Engl J Med 2017; 376:848-855). There is also significant excitement about the potential for gene editing approaches to address the hemoglobinopathies even as these technologies are just beginning to transition from lab to clinic. Critical questions of both efficacy and safety remain regarding the path forward for nuclease-based editing technologies such as CRISPR, ZFN, and megaTALs. Key lessons from the development of clinical gene addition therapies in the hemoglobinopathies may help chart the path forward for gene editing technologies.