Cell and Gene Therapy of Blood Disorders

"... develop safe and effective cell and gene therapy for serious blood disorders that remain incurable to day"

Hematopoietic stem cells - targets for gene therapy

Hematopoietic stem cells remain among the most interesting target cells for gene therapy because they have the ability to differentiate into all blood cells and can also self-renew to create new stem cells. Successful, permanent gene delivery to these mother cells of the blood system is therefore expected to result in permanent presence of genetically modified stem cells in the body.

Stem cell gene therapy for blood disorders

Diseases of the blood system that would be strong candidates for stem cell gene therapy are various genetic diseases that disturb normal function of blood cells and malignant disorders of the blood, bone marrow and lymph nodes.

Gaucher disease, Diamond-Blackfan anemia, osteopetrosis and various immune defects are examples of genetic disorders that would be suitable candidates for stem cell gene therapy. Leukemias and lymphomas are examples of malignant disorders that could in the future become candidate disorders for stem cell gene therapy.

• Gaucher disease
• Diamond-Blackfan anemia
• Osteopetrosis

Viral vectors

Gammaretroviral vectors (Moloney Murine Leukemia Virus, MMLV and various derivatives) have traditionally been used in experimental model systems and in clinical trials to transfer genes to hematopoietic stem cells and more recently, lentiviral vectors and Foamy virus derived vectors have been used with increasing efficiency in experimental model systems. Successful clinical gene therapy of X-linked severe combined immunodeficiency, adenosine deaminase deficiency and chronic granulomatous disease by oncoretroviral gene delivery to hematopoietic stem cells has demonstrated efficacy of this therapeutic approach in principle (1-3).

Figure: Model of viral entry into hematopoietic stem cell.

Despite this recent success in the clinic, problems remain for the development of gene therapy for disorders in which high percentage of hematopoietic stem cells need to be corrected by gene transfer. Similarly, out of approximately 25 patients that have been treated by hematopoietic stem cell gene therapy, three have developed a malignant blood disorder which is, at least in part, caused by insertional mutagenesis (4). Therefore, safer vectors need to be developed to reduce the risks of gene therapy. For effective development of gene therapy, proper disease models are required to study the mechanisms of disease development and estimate the efficacy of cell and gene therapy.

For this purpose, we have generated animal models and used existing models in our effort to develop gene therapy for genetic blood disorders. Similarly, we use lentiviral- and gammaretroviral vectors to transfer genes into candidate human stem cells in xenograft models. We plan to use these model systems to develop safe and effective cell and gene therapy for serious blood disorders that remain incurable to day.

References:

1. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science . Apr 28 2000;288(5466):669-672.
2. Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science . Jun 28 2002;296(5577):2410-2413.
3. Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med . Apr 2006;12(4):401-409.
4. Baum C, von Kalle C, Staal FJ, et al. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther . Jan 2004;9(1):5-13.

Print version Tell a friend about this page