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Prepublished online as a Blood First Edition Paper on August 15, 2002; DOI 10.1182/blood-2002-06-1869.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 104-111
GENE THERAPY
High-level expression of hemoglobin A in human thalassemic
erythroid progenitor cells following lentiviral vector delivery of an
antisense snRNA
Marla M. Vacek,
Hong Ma,
Federica Gemignani,
Giuseppina Lacerra,
Tal Kafri, and
Ryszard Kole
From the Curriculum in Genetics and Molecular Biology,
University of North Carolina Gene Therapy Center, Department of
Pharmacology and Lineberger Comprehensive Cancer Center, University of
North Carolina, Chapel Hill; International Agency for Research on
Cancer, Lyon, France; and Istituto di Genetica e Biofisica
Adriano Buzzati Traverso-Consiglio Nazionale delle Ricerche, Naples,
Italy.
Mutations at nucleotides 654, 705, or 745 in intron 2 of the human
 -globin gene activate aberrant 3' and 5' splice sites within the intron and prevent correct splicing of -globin pre-mRNA, resulting in inhibition of -globin synthesis and in consequence -thalassemia. Transfection of HeLa cells expressing the 3 thalassemic mutants with modified U7 snRNA (U7.623), containing a
sequence antisense to a region between the aberrant splice sites,
reduced the incorrect splicing of pre-mRNA and led to increased levels of the correctly spliced -globin mRNA and protein. A lentiviral vector carrying the U7.623 gene was effective in restoration of correct
splicing in the model cell lines for at least 6 months. Importantly,
the therapeutic value of this system was demonstrated in hematopoietic
stem cells and erythroid progenitor cells from a patient with
IVS2-745/IVS2-1 thalassemia. Twelve days after transduction of the
patient cells with the U7.623 lentiviral vector, the levels of
correctly spliced -globin mRNA and hemoglobin A were approximately
25-fold over background. These results should be regarded as a proof of
principle for lentiviral vector-based gene therapy for
-thalassemia.
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