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Strategy for a multicenter phase I clinical trial to evaluate globin gene transfer in β‐thalassemia
Author(s) -
Sadelain Michel,
Rivière Isabelle,
Wang Xiuyan,
Boulad Farid,
Prockop Susan,
Giardina Patricia,
Maggio Aurelio,
Galanello Renzo,
Locatelli Franco,
Yannaki Evangelia
Publication year - 2010
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2010.05597.x
Subject(s) - genetic enhancement , viral vector , thalassemia , clinical trial , cd34 , vector (molecular biology) , medicine , stem cell , globin , regimen , hematopoietic stem cell , haematopoiesis , oncology , immunology , biology , hemoglobin , gene , genetics , recombinant dna
Globin gene transfer in autologous hematopoietic stem cells offers a potentially curative treatment option for patients suffering from β‐thalassemia major who lack an HLA‐matched hematopoietic stem cell donor. Based on extensive preclinical investigation, we are initiating a phase I clinical trial using G‐CSF mobilized, autologous CD34 + cells transduced with a vector similar to the original TNS9 vector. Our first mobilizations in adult β‐thalassemic subjects have been well tolerated and yielded the required CD34 + cell dose. To minimize toxicity to enrolled subjects, and in the absence of a demonstrated requirement for myeloablative conditioning, our trial will use a reduced intensity conditioning regimen. Because low vector titers may adversely affect efficacy and safety, we have focused on vector manufacturing processes. We are now in a position to transfer our globin lentiviral vectors in a clinically relevant dosage (averaging 0.8 vector copy per cell in bulk CD34 + cells) and to supply clinical grade vector to collaborating centers in the U.S.A. and in Europe. We anticipate that the first U.S. trial of globin gene transfer will start in 2010.