Gene Therapy Treats Sickle Cell Disease in Teenager Using Lentiviral Vector

Ricki Lewis, PhD

March 01, 2017

Gene therapy that delivered an antisickling variant of hemoglobin in an autologous hematopoietic stem cell (HSC) transplant has ameliorated symptoms of severe sickle cell disease (SCD) in a 15-year-old boy, according to a report published in the March 2 issue of the New England Journal of Medicine.

SCD results from a point mutation at amino acid position 6 in the beta globin gene that causes polymerization of the protein and sickling of the erythrocytes that contain it, under low-oxygen conditions, obstructing microcirculation and damaging organs. Hemoglobin A (HbA) is the normal subunit; HbS is the one altered by the sickle cell mutation.

Hydroxyurea, which stimulates fetal hemoglobin production, is the only disease-modifying therapy for SCD; allogeneic hematopoietic stem cell transplant is curative. Fewer than 18% of people with severe SCD find transplant matches. For them, autologous transplant with a corrected beta globin gene — gene therapy — is a tantalizing chance at a possibly one-time treatment.

Jean-Antoine Ribeil, MD, PhD, from the Reference Centre for Sickle Cell Disease, Necker Children's Hospital, Paris, France, and colleagues introduced a lentiviral vector bearing an antisickling variant of HbA into a boy when he was 13 years old. The patient "had complete clinical remission with correction of hemolysis and biologic hallmarks of the disease," they write.

The boy had a severe presentation, including vaso-occlusive crises, acute chest syndrome, and bilateral hip osteonecrosis, and had had his spleen and gallbladder removed. Hydroxyurea treatment between ages 2 and 9 years was ineffective, and he had also received prophylactic red cell transfusions and iron chelation. The patient enrolled in the clinical trial in May 2014 and received the LentiGlobin (bluebird bio, Inc) gene therapy in October 2014.

The alteration in the beta globin gene creates an antisickling effect similar to that of gamma globin, the subunit of fetal hemoglobin. The altered hemoglobin dampens polymerization of HbS and is also distinguishable from other globin chains using reverse-phase high-performance liquid chromatography. The boy's bone marrow was conditioned with busulfan, which provides room for repopulation, and was enriched for CD34+ stem cells.

Red cell transfusions continued until the transplanted cells began to produce altered Hb, ceasing on day 88. By the ninth month posttransplant, levels of HbA were 5.5 g/dL (46%), increasing to 5.7 g/dL (48%) by the fifteenth month. By the 18-month mark, which the researchers reported at the American Hematology Society meeting in December 2016, HbA level had risen to 6.6 g/dL (53%). At the same time, levels of HbS fell.

At 12 months, the proportion of sickled cells in the patient and his oxygen saturation levels were similar to those of his mother, a heterozygote. Proportions of all blood cell types had normalized.

Adverse events were minimal, resolved quickly, and were entirely caused by the busulfan conditioning. Bilirubin, lactate dehydrogenase, and reticulocyte count all decreased to normal levels.

The researchers monitored viral integration sites and confirmed a polyclonal response to the replacement HSCs — measures taken to ensure that the viruses did not integrate into proto-oncogenes. Some of the investigators were part of the team linking retroviral vectors to insertional oncogenesis to treat severe combined immunodeficiency type X1. Lentivirus has not been associated with that risk.

The only limitation to the case report is that transfusion before the procedure interfered with conducting certain before and after comparisons. A second research group testing the same gene therapy reported findings at the American Hematology Society meeting. Their seven patients have shown more modest improvement than the French cohort, but have not been followed as long.

"HbAT87Q expression appears to be sufficient to suppress hemolysis, resulting in stable hemoglobin concentrations of 11 to 12 g per deciliter and major improvement in all measurable sickle cell disease–specific biologic markers and blocking sickle cell disease–related clinical events," the researchers conclude.

The benefits of the approach include lowered risk for rejection compared with allogeneic transplant, no need for a donor, and "one treatment that could result in a permanent, curative outcome," Steven J. Gray, PhD, from the Gene Therapy Center at the University of North Carolina, Chapel Hill, told Medscape Medical News. Dr Gray designed the viral vector for the giant axonal neuropathy gene therapy clinical trial and others.

"This is one of the classic genetic diseases everyone learns about in freshman biology. As someone who works in the area of gene therapy every day, the realistic prospect of curing sickle cell disease with gene therapy is simply astonishing. This provides hope that the next generation of students will read about the devastation of this disease in history books only," Dr Gray added.

bluebird bio, Inc, funded this work. Dr Ribeil reports personal fees from bluebird bio, Inc, during the conduct of the study; grant support from AddMedica; and nonfinancial support from Vitalaire and Novartis outside the submitted work. Coauthors report various support relationships with France's Agence Nationale de la Recherche; the French Alternative Energies and Atomic Energy Commission; bluebird bio, Inc; CRISPR Therapeutics; Novartis; and from Addmedica. The remaining coauthors and Dr Gray have disclosed no relevant financial relationships.

N Engl J Med. 2017;376:848-855.

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