Curing Pompe Disease: a Gene Therapy Approach
What is Pompe disease?
Pompe disease is a genetic disorder that is caused by the buildup of glycogen in the body. Glycogen is a complex sugar, and its accumulation in muscles such as the heart and skeletal muscles, disable them from functioning normally. It’s an autosomal recessive disease, meaning both parents must be carriers for the abnormal gene for their child to express the disorder.
There are varying symptoms depending on when a person begins expressing the symptoms of Pompe disease. Early-onset Pompe disease, which affects babies from a few months to age 1, is characterized by difficulty eating, failure to gain weight, muscle weakness, lack of head control, respiratory difficulties, and enlargement of the heart. Many infants with Pompe disease don’t make it to their first birthday because of complications in their heart and with their breathing.
When Pompe disease begins from the ages of 10–60 years old, it’s called late onset Pompe disease. The first symptoms are muscle weakness and shortness of breath and later progresses to respiratory complications that lead to lung infections and respiratory failure after a few years. The heart normally isn’t affected. As the disease emerges later in life than early onset Pompe disease, it progresses more slowly.
What causes Pompe disease?
Pompe disease is an inherited disorder caused by a mutation in the GAA gene. There have been over 300 different mutations identified in the GAA gene that cause Pompe disease. Every case of Pompe disease differs, and different mutations can vary in terms of age of onset and severity of symptoms.
The GAA gene instructs cells in the body to produce the enzyme acid alpha-glucosidase or acid maltase. Acid maltase is a workhorse in cell compartments called lysosomes. Lysosomes are like a cell’s recycling centers, taking in cell materials, and either destroying them or putting them to good use. They use digestive enzymes like acid maltase to break complex molecules into simple ones that a cell can use. Acid maltase breaks the complex sugar, glycogen into a simple sugar called glucose. Glucose fuels cells and is the body’s main source of energy. A patient with Pompe disease has a mutation in the GAA gene, which impairs or completely disables the production of this crucial enzyme, acid maltase. Since glycogen cannot be broken down, it accumulates in every part of the body, but namely the heart and skeletal muscles are most severely affected.
How is Pompe disease treated?
The current gold-standard treatment for Pompe disease called Enzyme Replacement Treatment (ERT), is delivered by injection into the vein of the patient. Scientists found a way to genetically engineer a GAA enzyme, coined rhGAA, which acts like the naturally occurring acid maltase. By delivering this enzyme, they hope to ensure that glycogen is broken down and cells can clean out unnecessary accumulation.
This however, isn’t effective for all forms of Pompe. In early-onset Pompe, an infant’s immune system may identify rhGAA as a foreign substance, attack and neutralize it. Furthermore, this enzyme doesn’t circulate in the body for too long and varies in capacity to reach certain tissues. There has to be a better way.
What Research is Happening to Cure Pompe Disease?
Gene therapy was discovered to increase acid maltase enzyme in a mouse model, lessening Pompe disease symptoms and improving strength in muscles. Mice treated with gene therapy were compared to untreated mice and mice who received ERT, and the therapeutic quality of gene therapy won by a landslide. When the study was complete, the GAA enzyme was barely detected in mice treated with ERT, but was actively circulating in mice treated with gene therapy. GAA activity was also significantly higher in the brain and spinal cord of those treated with gene therapy than with ERT-treated mice and non-treated mice. The gene therapy treated mice also showed full normalization of glycogen levels in the heart, diaphragm and muscles, while those on ERT only had slight reduction of glycogen levels in the heart.
This sounds great, so what next? Spark Therapeutics, the organization investigating this therapy dubbed SPK-3006, has also tested this therapy on rhesus monkeys. The results were positive, with circulation of GAA detected in the heart, diaphragm, brain, muscles, and spinal cord. The therapy was also deemed to be safe through analysis of liver function and various lab tests. Currently, there is a clinical trial that hopes to determine whether or not SPK-3006 is a definite cure for Pompe disease.
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