For the first time, Cincinnati Children's Hospital Medical Center researchers have shown how developing red blood cells could be used to produce lysosomal enzymes.
Researchers transplanted genetically modified hematopoietic stem cells into mice so that their developing red blood cells produce a critical lysosomal enzyme, preventing or reducing organ and central nervous system damage from the often-fatal genetic disorder Hurler's syndrome.
Dr. Dao Pan, the study's principal author, said that the study suggests a new approach to molecular gene therapy and a much-needed improved treatment option for children with Hurler's syndrome.
"The idea behind this is gene insertion so that after one treatment a person would be cured. In the mouse models receiving this treatment, the pathology of the peripheral organs tested was completely normalized. And although not as complete, we also saw significantly improved neurological function and brain pathology," said Pan.
Hurler's syndrome is the severe form of MPS type1, or mucopolysaccharidoses.
MPS type1 and similar genetic disorders are known as lysosomal storage disease, which are caused by the body's inability to produce specific lysosomal enzymes.
The lysosomes in the cells of children with Hurler syndrome do not have a vital enzyme called IDUA (/a-/L-idunronidase), which causes their cells to accumulate too much of a class of biochemical known as mucopolysaccharides, in this instance dermatan sulfate and heparin sulfate.
This excess accumulation results in progressive tissue damage to organs and the central nervous system and typically results in early death.
Initially, the researchers experimented on the cells of patients with Hurler syndrome that were cultured in the laboratory.
They successfully used what is called a viral vector (in this case a lentivirus) to insert a healthy version of the IDUA gene into early stage red blood cell cultures, and a hybrid promoter gene, to prompt the cells to produce the IDUA enzyme.
This could allow the enzyme to be absorbed by a patient's other cells to correct functional defects in the lysosomes.
Encouraged by the initial cell experiments, the research team next cultured hematopoietic stem cells taken from mouse models of MPS I by using the same hybrid promoter gene from the earlier experiments to reprogram the stem cells to produce IDUA.
They then performed bone marrow transplantation on the MPS I mice with the reprogrammed cells.
The developing red blood cells in these mice produced large amounts of IDUA in the blood stream, which was absorbed by other cells that help make tissues for vital organs and the central nervous system.
The researchers said that IDUA could circulate blood to somehow bypass the blood brain barrier - normally a severe limitation in treating diseases that affect the central nervous system.
Besides Hurler syndrome, Pan said the study will have positive implications in the treatment of many other lysosomal storage diseases, which affect different parts of the body, depending on the specific enzyme deficiency.
She also said this particular approach to gene therapy carries considerably less risk of stimulating cancer genes, which has been a concern with some forms of gene therapy.
The study has been published in the early edition of Proceedings of the National Academy of Sciences.