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Gene therapy for beta-thalassemia safe, effective up to 8 years, but concerns emerge

Nature Medicine
Reuters Health - 04/01/2022 - Lentiviral globin gene therapy with reduced-intensity conditioning (RIC) was safe and effective in beta-thalassemia in a 6-8-year follow-up, although cautious monitoring is still necessary, researchers say.

Beta-thalassemias are inherited anemias caused by the absent or insufficient production of the beta chain of hemoglobin.

"The overall data from this report and others support the hope that globin disorders can be treated genetically," Dr. Michel Sadelain of Memorial Sloan Kettering Cancer Center in New York City told Reuters Health by email. "We have entered an era where therapeutic efficacy is within reach using a variety of genetic approaches, from integrating vectors to gene editing (e.g., with CRISPR). Their differentiation, and ultimate relevance, will be determined by long-term safety. As this study shows, this assessment takes a long time to accomplish."

"Many in the field had anticipated that 'myeloablative conditioning' - i.e., complete destruction of bone marrow stem cells - was necessary to stably engraft genetically modified stem cells in the thalassemias," he said. "Our study shows that RIC, which is associated with lesser side effects and spares some of the patient's stem cell reservoir, affords stable, long-term engraftment."

"The appearance of 'clonal expansions,' sometimes years after the cell infusion, surprised us," he acknowledged. "These are so far benign and appear to reflect unanticipated activity of the vector in cells where the vector was expected to be 'silent.' This will require to reassess the design of globin vectors."

Clonal expansions are greater-than-normal proliferation of a few of the genetically modified cells.

As reported in Nature Medicine, Dr. Sadelain and colleagues reported the 6-8-year follow-up of four adult patients with transfusion-dependent beta-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after RIC in a phase 1 clinical trial (https://bit.ly/3FUItly).

The primary endpoint was safety and tolerability of the infusion product after RIC and efficacy - engraftment of genetically modified autologous CD34+ cells, expression of the transduced beta-globin gene and post-transplant transfusion requirements - was the secondary endpoint.

No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, though not achieving transfusion independence. "This highlights that a low copy number of the transferred vector is ineffective, implying that multiple insertions of the vector are necessary to achieve therapeutic efficacy," Dr. Sadelain noted.

Overall, the findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment, with a minimum CD34+ cell transduction requirement for effective therapy. However, Dr. Sadelain added, "The findings need confirmation in larger studies."

Because moderate clonal expansions were associated with integrations near cancer-related genes, patients should be "cautiously" monitored.

Summing up, Dr. Sadelain said, "Meticulous patient monitoring needs to continue; current globin vectors need to be scrutinized for leaky activity in all blood cell types; and several technologies that are applicable to globin disorders may reach efficacy - but it is their safety features that will identify the winners."

Dr. Hans-Peter Kiem, Director, Stem Cell and Gene Therapy Program, and Associate Head of Transplantation Biology and of the Hematological Malignancies Program at Fred Hutch in Seattle, called the study "highly important for the field of hematopoietic stem cell gene therapy for hemoglobinopathies."

"RIC with busulfan was well tolerated in these patients and resulted in less neutropenia and thrombocytopenia compared to historic myeloablative comparisons," he said by email. "Rapid hematopoietic recovery is important in patients with thalassemia to minimize infectious disease complications and hospitalization; these patients are also often refractory to platelet transfusions."

Because patients did not become transfusion-independent, he said, "improved gene modification efficiency will be required with this approach. Also, the authors report several integration sites in cancer-related genes and moderate clonal expansion, thus requiring close monitoring and follow-up to detect potential malignant clones early."

"It also appears that gonadal failure was still a problem, despite the non-myeloablative conditioning," he noted.

"It will be important to see the level of correction that can be obtained with this conditioning regimen when improved/optimized transduction conditions are being used," Dr. Kiem said. "As a next step, one can also envision hematopoietic stem cell gene therapy protocols using nongenotoxic conditioning regimens to further reduce any conditioning-related side effects."

SOURCE: https://go.nature.com/3zs1v0d Nature Medicine, online January 3, 2022.

By Marilynn Larkin

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