Fetal Gene Therapy in Mouse Model

This report in the latest issue of the Proceedings of the National Academy of Sciences highlights the progress being made, as well as the challenges involved with, developing a gene therapy for fatal forms of thalassemia.

What is thalassemia? Here is some info from the National Human Genome Research Institute:

What do we know about heredity and thalassemia?

Thalassemia is actually a group of inherited diseases of the blood that affect a person's ability to produce hemoglobin, resulting in anemia. Hemoglobin is a protein in red blood cells that carries oxygen and nutrients to cells in the body. About 100,000 babies worldwide are born with severe forms of thalassemia each year. Thalassemia occurs most frequently in people of Italian, Greek, Middle Eastern, Southern Asian and African Ancestry.

The two main types of thalassemia are called "alpha" and "beta," depending on which part of an oxygen-carrying protein in the red blood cells is lacking. Both types of thalassemia are inherited in the same manner. The disease is passed to children by parents who carry the mutated thalassemia gene. A child who inherits one mutated gene is a carrier, which is sometimes called "thalassemia trait." Most carriers lead completely normal, healthy lives.

A child who inherits two thalassemia trait genes - one from each parent - will have the disease. A child of two carriers has a 25 percent chance of receiving two trait genes and developing the disease, and a 50 percent chance of being a thalassemia trait carrier.

Most individuals with alpha thalassemia have milder forms of the disease, with varying degrees of anemia. The most severe form of alpha thalassemia, which affects mainly individuals of Southeast Asian, Chinese and Filipino ancestry, results in fetal or newborn death.

A child who inherits two copies of the mutated gene for beta thalassemia will have beta thalassemia disease. The child can have a mild form of the disease, known as thalassemia intermedia, which causes milder anemia that rarely requires transfusions.

Here is the abstract from the PNAS article:

Fetal gene therapy of α-thalassemia in a mouse model

Xiao-Dong Han, Chin Lin, Judy Chang, Michel Sadelain, and Y. W. Kan

Fetuses with homozygous α-thalassemia usually die at the third trimester of pregnancy or soon after birth. Hence, the disease could potentially be a target for fetal gene therapy. We have previously established a mouse model of α-thalassemia. These mice mimic the human -thalassemic conditions and can be used as preclinical models for fetal gene therapy. We tested a lentiviral vector containing the HS 2, 3, and 4 of the -LCR, a central polypurine tract element, and the -globin gene promoter directing either the EGFP or the human -globin gene. We showed that the GFP expression was erythroid-specific and detected in BFU-E colonies and the erythroid progenies of CFU-GEMM. For in utero gene delivery, we did yolk sac vessel injection at midgestation of mouse embryos. The recipient mice were analyzed after birth for human -globin gene expression. In the newborn, human -globin gene expression was detected in the liver, spleen, and peripheral blood. The human -globin gene expression was at the peak at 3–4 months, when it reached 20% in some recipients. However, the expression declined at 7 months. Colony-forming assays in these mice showed low abundance of the transduced human -globin gene in their BFU-E and CFU-GEMM and the lack of its transcript. Thus, lentiviral vectors can be an effective vehicle for delivering the human -globin gene into erythroid cells in utero, but, in the mouse model, delivery at late midgestation could not transduce hematopoietic stem cells adequately to sustain gene expression.

Cheers,
Colin