Two papers published online in advance in Science this week point to the potential of lentiviral hematopoietic stem cell gene therapy for debilitating inherited conditions.
The first chronicles researchers’ use of a lentiviral vector encoding a functional version of the gene encoding WASP, a cytoskeleton-regulating protein implicated in the inherited immunodeficiency Wiskott-Aldrich syndrome. San Raffaele Scientific Institute’s Luigi Naldini, M.D., Ph.D., and his colleagues applied such a vector to genetically correct hematopoietic stem/progenitor cells (HPSCs) from three Wiskott-Aldrich syndrome patients, which they then reinfused.
“All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score,” Dr. Naldini et al. report. They add vector integration analyses indicated that gene-corrected HSPCs resulted in highly polyclonal and multilineage hematopoiesis. Importantly, the researchers note that “lentiviral gene therapy did not induce selection of integrations near oncogenes,” and that they did not observe aberrant clonal expansion 20 to 32 months post-therapy.
“Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS [Wiskott-Aldrich syndrome],” the researchers conclude.
In a separate study, Dr. Naldini and his colleagues took a similar approach to transfer a functional arylsulfatase A (ARSA) gene into hematopoietic stem cells (HSCs) from three presymptomatic patients who showed genetic, biochemical, and neurophysiological evidence of late infantile metachromatic leukodystrophy, an inherited lysosomal storage disease.
The researchers found that the patients showed extensive and stable ARSA gene replacement after reinfusion of the gene-corrected HSCs. As with the first study, vector integration analyses showed no evidence of aberrant clonal behavior, Dr. Naldini et al. report.
“Notably, the disease did not manifest or progress in the three patients seven to 21 months beyond the predicted age of symptom onset,” the researchers write. “These findings indicate that extensive genetic engineering of human hematopoiesis can be achieved with lentiviral vectors and that this approach may offer therapeutic benefit for MLD [metachromatic leukodystrophy] patients.”
“Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome” and “Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy” appeared online in Science July 11.