1. LentiGlobin gene therapy resulted in sustained production of the modified anti-sickling hemoglobin, HbAT87Q.

2. LentiGlobin led to reduced hemolysis and resolved severe vaso-occlusion from sickle cell disease.

Evidence Rating Level: 2(Good)

Study Rundown: Sickle cell disease is caused by an abnormal β-globin, resulting in sickle hemoglobin and dysfunctional red blood cells prone to hemolysis and vaso-occlusion. This leads to chronic anemia, painful vaso-occlusions, and increased mortality. Hematopoietic stem and progenitor cell (HSPC) transplant is the only curative option, which is limited by limited compatibility and risk of complications. The LentiGlobin gene therapy utilizes a lentiviral vector to transduce autologous HSPCs with a functional β-globin gene, resulting in the production of the modified antisickling HbAT87Q and providing a potential alternative to curing the disease. The article provided an interim analysis of a study investigating the safety and efficacy of LentiGlobin in treating sickle cell patients. It was found that engraftment of the transduced HSPCs occurred in all patients, and HbAT87Q was found to contribute significantly to the total hemoglobin and red cell population. In evaluated patients, all had reduced hemolysis and complete resolution of severe vaso-occlusive event, while none developed severe adverse events or hematologic malignancies attributable to the treatment. These results that LentiGlobin was safe and efficacious in treating hemolysis and vaso-occlusion in sickle cell disease patients.

Click here to read the study in NEJM

Relevant Reading: Gene Therapy in a Patient with Sickle Cell Disease

In-Depth [prospective cohort study]: This study is an interim analysis of an ongoing Phase 1-2 nonrandomized, open-label, single-dose trial looking at the LentiGlobin gene therapy for treating sickle cell disease. By the time of reporting, 43 patients had been enrolled, 35 of whom received a LentiGlobin infusion. Eligibility criteria included age between 12 and 50, a diagnosis of sickle cell disease, appropriate performance status, failure of hydroxyurea therapy, and a minimum of 4 severe vaso-occlusive events in the 24 months preceding the treatment. Patients eligible for matched allogeneic HSPC transplantation were ineligible for this trial. Patients underwent HSPC collection from peripheral blood by plerixafor mobilization and apheresis. The collected HSPCs were transduced with LentiGlobin and infused to patients following myeloablation. The primary efficacy endpoint was complete resolution of severe vaso-occlusive events, measured between 6 and 18 months after the treatment. A severe vaso-occlusive event was defined as an acute pain episode due to vaso-occlusion that led to hospitalization, repeated emergency department visits, or extended priapism requiring medical intervention. The secondary endpoint included changes to hemoglobin level, markers of hemolysis, and expression levels of βA-T87Q and HbAT87Q. The median follow-up at the time of reporting was 17.3 months (range, 3.7 to 37.6). It was found that the transduced HSPCs were engrafted in all 35 patients. Median total hemoglobin production rose from 8.5g/dL to 11g/dL or higher, sustained from 6 months to 36 months following treatment. The modified HbAT78Q containing the transduced β-globin (βA-T87Q) was found to contribute to at least 40% of total hemoglobin and was distributed in 85±8% of red blood cells by 24 months in 10 patients with available data. Hemolysis markers were observed to be similar to normal levels in all patients. No severe vaso-occlusive events were observed in the 25 patients evaluated following at least 6 months after the infusion. 3 patients reported nonserious adverse events attributable to LentiGlobin, which resolved within 1 week. 2 patients with two α-globin gene deletions in the study subsequently developed anemia, the causes of which are being investigated. No hematologic malignancies, a documented risk of lentiviral gene insertion, were observed during this study. Overall, despite a small number of patients, limited follow-up, and the lack of a control group, this interim analysis showed one-time treatment of LentiGlobin resulted in sustained benefits for sickle cell disease and resolution of severe vaso-occlusive complications.

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