Hurler Syndrome and treatment using stem cells
By Wideacademy - 10.01.2018
What is Hurler Syndrome?
Hurler Syndrome is an inherited condition which causes gradual mental and physical deterioration. It is related to the structure and function of a component within every cell in our bodies, called a lysosome.
Every lysosome within every cell of our bodies contains complex enzymes, the function of which is to break down and recycle carbohydrates the body can no-longer use.
These carbohydrates are chains of sugar called mucopolysaccharide molecules, or glycosaminoglycans (GAGs), that help to build bone, cartilage and other connective tissue.
When mucopolysaccharides cannot be broken down by the body, as is the case with Hurler Syndrome, they remain inside the cells where they cause progressive damage.
Physical effects can be noticeable soon after birth but increase in severity as the mucopolysaccharides build up within cells.
Hurler Syndrome results from an enzyme deficiency caused by a mutation in the IDUA gene, which is situated on chromosome 4. The disease is autosomal recessive, which means that a child with Hurler Syndrome must have inherited a copy of the gene from each parent in order for the disease to be present.
Hurler Syndrome is the most severe of three variants of Mucopolysaccharidosis type I, along with the milder Scheie syndrome, where children have normal intelligence and may live to be adults, and Hurler-Scheie syndrome, where children have reduced symptoms, but a reduced life expectancy .
Symptoms can include:
- growth problems
- abnormal spine
- hepatosplenomegaly (an enlarged liver and spleen)
- distinctive facial features
- progressive neurological impairment
- premature death
- respiratory infections or cardiac problems
- patients stop developing between ages 2-4
- enlarged tongue
- carpal tunnel syndrome
Overall, the symptoms are similar to Hunter Syndrome, though Hurler Syndrome is more severe and harder to diagnose.
How can stem cells help?
There is no known cure for Hurler syndrome.
It can be treated using enzyme replacement therapy which can alleviate some of the physical symptoms. However, such treatments don’t appear to improve a child’s neurological condition.
A haemopoietic stem cell transplant (HSCT) has been shown to be effective in treating Hurler syndrome since 1980.
More than 500 patients with Hurler Syndrome have undergone HSCTs, which is the highest number for a metabolic disease of its type. This means that in many ways it provides an indicator for HSCT in other lysosomal storage diseases, of which there are 50.
The positive effects of HSCT can include long-term survival. A transplant can also stop neurological deterioration (although it cannot reverse damage already done) and improve some of the physical symptoms, such as cardiac and respiratory problems.
However, as many children with Hurler Syndrome have heart disease, they can be unable to withstand the chemotherapy that forms part of the transplant.
There are other risks and complications involved in undergoing an HSCT for those with Hurler Syndrome. There is a relatively low success and survival rate due to engraftment failure (where the body rejects the donor stem cells) following HSCT.
Several factors must be considered before undergoing a transplant, including:
- the stage of the disease at the time of the transplant
- the likelihood of it improving bodily functions or neurological degeneration
- the likelihood of survival post-transplant
Improving transplant techniques with a view to promoting better engraftment is an on-going area of research.
A study comparing 146 patients with Hurler syndrome transplanted in Europe between 1994 and 2004 examined conditioning regimens, donor types and cell sources to identify the contributing factors to graft failure following a stem cell transplant.
There was no significant difference in engraftment between the use of cord blood, bone marrow or peripheral blood stem cells. However, transplants using cord blood appeared moderately more successful in terms of engraftment, and all patients transplanted with cord blood achieved normal enzyme levels. However, this could be because cord blood transplants were done more recently than the others and therefore transplantation techniques have improved.
Gene therapy may provide a valid alternative when a donor match can’t be found or a stem cell transplant is not possible.
The technique targets the root cause of a genetic disease, fixing the mutation that causes it by:
- replacing a mutated copy of a gene with the corrected one
- knocking out a faulty gene that isn’t 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.
However, gene therapy that uses haemopoietic stem cells, corrected with the normal gene, may have a positive effect on blood cell production and function.
Lysosomal and metabolic disorders such as Hurler Syndrome are considered to be particularly promising candidates for this approach.
A study carried out in 2014 by the Cincinnati Children’s Hospital Medical Center and the NINDS used genetically engineered blood platelets and bone marrow cells to deliver the corrected copy of the IDUA gene to Hurler syndrome in mice.
It showed that the treatment completely corrected the disease in the mice, meaning that the engineered blood platelets and megakaryocytes (cells in the bone marrow which produce platelets) were capable of creating and storing fully functioning lysosomal enzymes and could carry them to where they were needed.
This is an exciting proof of concept, but such successes in animal trials do not always translate when applied to humans. However, Sangamo Therapeutics is starting a phase 1 trial for patients with MPS 1.
The aim is to correct the gene mutation that causes Hurler syndrome, by using Zinc Finger Nuclease (ZFN) gene editing technology. ZFNs are molecular scissors that can cut out a specific strand of DNA to remove the mutated gene and replace it with a correct version.
The treatment is administered intravenously and acts specifically on the DNA of the liver cells, where it provides the correct copy of the alpha-L -iduronidase gene. This should enable a person with Hurler Syndrome’s liver to produce the enzyme alpha –L-iduronidase for the rest of their life.
A further objective of the study is to improve the clinical outcome of enzyme replacement therapy and HSCT in patients with Mucopolysaccharidosis I.
Sangamo Therapeutics also recently announced that they have used experimental gene therapy to treat a patient with Hunter syndrome. Brian Madeux of California underwent the SB-913 ZFN gene-editing therapy in November 2017. The results, when they arrive, in a few months’ time will be a good barometer of how effective the same approach will be for Hurler syndrome.