LAY SUMMARY 
Non-Technical Abstract 
Gaucher disease is an inherited disease. Patients suffer from enlarged organs, 
bone deterioration with multiple fractures and in some patients, progressive neurological 
degeneration. Most patients suffer significant disability and, many, an early death. 
The symptoms of Gaucher disease are a consequence of the accumulation of a fatty 
substance within specialized house keeping cells called macrophages(M0) . Bone marrow 
transplantation (BMT) results in the replacement of sick M0 by normal ones. It has 
resulted in significant clinical improvement for some patients. Unfortunately the 
i therapy is not available for the majority of patients because they lack a suitable bone 
marrow donor. The development of macrophage targeted enzyme replacement therapy has 
provided treatment options, but is not a completely satisfactory solution. Although 
patients improve with enzyme treatment, the therapy is not permanent and is very 
expensive. The cost for an adult usually exceeds $250,000 per year per patient. 
Gene therapy is a novel approach to the treatment of genetic diseases. It involves 
the addition of a normal gene to the cells of a patient with an inherited defect in the 
corresponding gene. Bone marrow cells are an important target cell for gene transfer in 
Gaucher disease because M0 are derived from the bone marrow. In the proposed approach 
to treatment, cells that can make the bone marrow would be collected from the patient, 
genetically corrected by inserting the normal gene, and then re-colonized in the 
patient's bone marrow. This is called gene transfer and autologous BMT. It avoids the 
immunologic problems of graft rejection and graft-versus-host disease, which occur with 
high frequency in bone marrow transplantations from a donor. 
To be successful, gene therapy requires high efficiency gene transfer into cells, 
followed by the sustained activity of the transferred gene to do the job of making the 
enzyme. The most efficient way to transfer and express genes in mammalian cells is by 
the use of modified viruses acting as carriers of genes. These are called vectors. The 
most often used and most completely studied vectors are derived from retroviruses. 
Retroviral vectors use the natural ability of these life forms to infect cells and 
integrate their genetic material into the target cell's chromosomes. By this action, 
these vectors provide cells with potentially therapeutic genes. Retroviral vectors can 
be rendered unable to multiply themselves and still retain the ability to transfer genes 
into cells of many different types leading to stable, intact residence in the host cell 
DNA. 
Correction of the genetic defect in bone marrow producing cells could result in the 
life-long production of enzymatically competent M0. This should be therapeutic for 
patients with GD. 
We have isolated the gene for glucocerebrosidase(GC) and demonstrated that transfer 
i of the gene reversed the enzyme deficiency in the cells of patients with Gaucher disease. 
; We have shown in bone marrow transplantation studies in mice that a retroviral vector can 
efficiently transfer the GC gene to primitive cells in bone marrow. Moreover, the human 
gene produced the GC enzyme in macrophages for the life of the mice. Furthermore, we 
have shown that transfer of the GC gene to macrophages obtained from the blood of Gaucher 
patients completely corrected the deficiency of the enzyme (GC) in this important cell. 
We also have transferred the normal human GC gene to cells from human blood enriched for 
bone marrow producing cells (CD34 + ) capable of reconstituting the bone marrow. The 
transduced cells expressed 2-4 times the amount of GC enzyme normally present in these 
cells. Recent results reveal that the CD34 + cells from a Gaucher patient are also 
| corrected to 2-4 times the normal amount of enzyme. This is an important advance because 
the correction occurs in a cell which can re-establish the entire bone marrow including 
i macrophages. The success of these studies permit consideration of clinical trials of 
j gene therapy for patients with Gaucher disease. 
Recombinant DNA Research, Volume 17 
[749] 
