Scientists at the University of Manchester in the United Kingdom have used stem cell gene therapy to treat a fatal genetic brain disease in mice. Sanfilippo is a fatal, inherited condition that causes progressive dementia in children. This particular treatment strategy could also be used to treat other types of neurological, inherited diseases. The Manchester team hopes to bring this strategy to a clinical trial within two years.
Sanfilippo afects one in 89,000 children in the United Kingdom and is an untreatable “mucopolysaccharide disease ” or MPS disease. MPS diseases involve an abnormal storage of mucopolysaccharides. This abnormal storage results from the absence of a specific enzyme. Without the enzyme, the breakdown process of mucopolysaccharides is incomplete. Partially broken down mucopolysaccharides accumulate in the body’s cells causing progressive damage. The storage process can affect appearance, development, and the function of various organs of the body. Each MPS disease is caused by the deficiency of a specific enzyme.
Patients with Sanfilippo are unable to degrade heparan sulfate. There are four different types of Sanfilippo, which is also called MPS type III. MPS type IIIA results from a deficiency in the enzyme N-sulfoglucosamine sulfohydrolase, MPS type IIIB lacks N-Acetylglucosaminidase, MPS type IIIC has an absence in Acetyl-CoA:alpha-glucosaminide-acetyltransferase, and MPS type IIID lacks N-acetylglucosamine 6-sulphatase. In all four forms of MPS III, excessive heparan sulphate storage occurs in the brain, leading to its progressive deterioration; the amount of heparan sulphate storage in other tissues influences the extent of physical symptoms. Children eventually lose the ability to walk and swallow.
Brian Bigger from the University of Manchester’s Institute of Human Development led this research into therapies for MPS type IIIA. According to Bigger, bone marrow transplants have been used to treat similar diseases (e.g., Hurler syndrome). In this case, gene therapy was used to introduce the missing enzyme into the transplanted cells. Unfortunately, this did not work terribly well because the white blood cells from the bone marrow did not make enough of the enzyme to treat the disease.
A fraction of the white blood cells made bone marrow are called monocytes, and some of the monocytes traffic to the brain to become microglia. Since microglia are made by hematopoietic stem cells (HSCs) in the bone marrow, genetic engineering of cultured HSCs should increase expression of the missing enzyme in microglia. In previous experiments, HSCs were engineered with viruses to express the missing enzyme, but this expression was poor in microglia.
To fix this problem, Bigger and his team increased enzyme expression in the engineered HSCs in bone marrow. They used a gene control region from the “pyruvate kinase” gene, which is a very highly expressed gene. This increased expression of the missing enzyme to five times the normal levels and to 11% of normal levels in the microglia cells in the brain. The enzyme
This type of treatment corrects the inflammation in the brain and completely corrects the hyperactivity behavior in mice with Sanfilippo. Bigger adds, “We now hope to work to a clinical trial in Manchester in 2015.”
Bigger and his colleagues are manufacturing a viral vector to deliver genetic material into cells for use in humans and they hope to use this in a clinical trial with patients at Central Manchester University Hospital NHS Foundation Trust by 2015.
This stem cell gene therapy approach was recently shown by Italian scientists to improve conditions in patients with a similar disease that affects the brain called metachromatic leukodystrophy. Bigger refined the vector used bythe Italian group.
According to Bigger, this approach might have the potential to treat several neurological genetic diseases.