Recent trends in the gene therapy of β-thalassemia.
The β-thalassemias are a group of hereditary hematological diseases caused by over 300 mutations of the adult β-globin gene. Together with sickle cell anemia, thalassemia syndromes are among the most impactful diseases in developing countries, in which the lack of genetic counseling and prenatal diagnosis have contributed to the maintenance of a very high frequency of these genetic diseases in the population. Gene therapy for β-thalassemia has recently seen steadily accelerating progress and has reached a crossroads in its development. Presently, data from past and ongoing clinical trials guide the design of further clinical and preclinical studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene-therapy approaches. Moreover, human erythropoietic stem cells from β-thalassemia patients have been the cellular targets of choice to date whereas future gene-therapy studies might increasingly draw on induced pluripotent stem cells. Herein, we summarize the most significant developments in β-thalassemia gene therapy over the last decade, with a strong emphasis on the most recent findings, for β-thalassemia model systems; for β-, γ-, and anti-sickling β-globin gene addition and combinatorial approaches including the latest results of clinical trials; and for novel approaches, such as transgene-mediated activation of γ-globin and genome editing using designer nucleases.
Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy ; Associazione Veneta per la Lotta alla Talassemia, Rovigo, Italy ; Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy.
Alessia
A
Finotti
Department of Pediatrics, Division of Haematology/Oncology, Weill Cornell Medical College, New York, NY, USA.
Laura
L
Breda
Department of Molecular Genetics Thalassaemia, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus ; Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Carsten W
CW
Lederer
Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy ; Associazione Veneta per la Lotta alla Talassemia, Rovigo, Italy ; Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy.
Nicoletta
N
Bianchi
Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy ; Associazione Veneta per la Lotta alla Talassemia, Rovigo, Italy ; Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy.
Cristina
C
Zuccato
Department of Molecular Genetics Thalassaemia, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus ; Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Marina
M
Kleanthous
Department of Pediatrics, Division of Haematology/Oncology, Weill Cornell Medical College, New York, NY, USA ; Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY, USA.
Stefano
S
Rivella
Laboratory for the Development of Gene and Pharmacogenomic Therapy of Thalassaemia, Biotechnology Centre of Ferrara University, Ferrara, Italy ; Associazione Veneta per la Lotta alla Talassemia, Rovigo, Italy ; Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, Ferrara University, Ferrara, Italy.
Roberto
R
Gambari
CRISPR; HbF induction; TALEN; Thalassemia; ZFN; gene therapy; genome editing; induced pluripotent stem cells; transcription factors