Hunter Syndrome and the future of stem cell treatment for mucopolysaccharidoses
By Wideacademy - 10.01.2018
What is Hunter Syndrome?
Hunter Syndrome is an inherited metabolic disorder affecting males. In Europe, one in approximately 150,000 babies is born with the disease.
The disease takes its name from Charles Hunter, from Manitoba, Canada, who first described two brothers with the disorder in 1917.
It is caused by a deficiency of the enzyme iduronate sulphatase, which is essential for breaking down the long molecular chains of sugar used by the body in the building of connective tissues like bone, cartilage and tendons, known as mucopolysaccharides.
Mucopolysaccharides are also known as Glycosaminoglycans or GAGs — but we’ll refer to them here as mucopolysaccharides.
If the mucopolysaccharides aren’t broken down by your body, then they remain inside your cells, where they cause progressive damage. A child might reach normal developmental milestones in infancy, before gradually losing cognitive and physical abilities as more and more cells become damaged by the accumulation of mucopolysaccharides.
Hunter Syndrome is one of several lysosomal storage diseases. The iduronate sulphatase deficiency is caused by a mutation in the IDS gene, which is situated on the X chromosome — which is why the disease affects boys.
The disease can manifest in either severe or mild form.
In severe cases, Hunter Syndrome will usually be diagnosed in babyhood and can lead to profound learning disability from neurological impairment, deafness and somatic dysfunction, such as restrictive stiffness in the joints and pelvis.
Features of the condition include a progressive changing of facial features, shortness in stature, macrocephaly (a larger than average head circumference), a thickening of the tongue, skin lesions and a prominent forehead.
Milder cases may not be noticed until late childhood or adulthood. Some of the physical features may be similar to the severe form, but neurological impairment will be far less pronounced and sufferers are expected to live longer.
There is no cure for Hunter Syndrome.
Enzyme replacement therapy can be used to alleviate some physical symptoms of the disease, but doesn’t appear to have any benefits in improving neurological function.
How can stem cells help?
Haemopoietic (blood-forming) stem cell transplants have been effective in treating a few enzyme deficiency disorders, notably Hurler syndrome. However, they have not been as effective in treating Hunter Syndrome because they do not appear to stop – or reverse — the progression of the disease.
There are also considerable risks to stem cell transplants because engraftment success and survival rate for patients with Hunter Syndrome is relatively low.
A trial assessing donor (allogeneic) blood stem cells from umbilical cords run by Duke University Medical Centre is seeking to improve the engraftment rate for patients with inherited metabolic diseases, like Hunter Syndrome. It intends to accelerate the delivery of stem cells to the central nervous system, by introducing them into the spinal cord, with the aim of prompting brain re-myelination. Myelin plays an essential part in the health and function of nerve cells, the brain and the nervous system. The hope is that this will help stop the deterioration of the central nervous system in these patients and therefore improve the engraftment potential.
Similarly, the Children’s Hospital of Pittsburgh is studying a factor that could improve engraftment and with it patient survival rate. It is comparing the effects of reduced intensity conditioning (which uses less chemotherapy) before a haematopoietic stem cell transplant, to the standard course of chemotherapy.
As Hunter Syndrome affects brain function, and often from a young age, getting patients involved in deciding what treatment course they should take is not always feasible.
For doctors, assessing the risks of engraftment, versus the potential benefit of a stem cell transplant in a disease that has such varying symptoms progression rate, is complicated. Should they wait until the patient is older and therefore capable of understanding the implications? Or by delaying, will the disease progress so much that engraftment is more likely to fail?
As Hunter Syndrome is such a rare disease, there is little long-term data that could shed light on this conundrum. As the worldwide database grows, hopefully, these decisions will become easier.
Gene therapy may provide a valid alternative for patients who are unable to find a donor and to whom a stem cell transplant is unavailable. Gene therapy is an experimental technique that targets the root cause of a genetic disease, by fixing the mutation that causes it. This can work by:
replacing a mutated copy of a gene with the corrected one knocking out a faulty gene that is not working properly introducing a new gene into the body to help fight disease
There is still much research to be done to ensure safety and efficacy in using it therapeutically.
Since the Human Genome Project, scientists know which genes are involved in many specific diseases. The Department of Medical Genetics at the Uppsala University Biomedical Center Studies is trying to map the genes associated with Hunter Syndrome. Gene therapy trials are ongoing but no results have been reported.
However, in November 2017, Brian Madeux became the first man to have gene-editing done inside his body, in an attempt to correct the gene responsible for Hunter Syndrome.
The process was achieved through zinc finger nucleases, molecular scissors that can target and cut out a specific strand of DNA and enable the corrected gene to be inserted in its place. It will take three months before they will know if it has been a success. If it has, it will mean that Madeux’s body will be able to make iduronate sulfatase on its own.