Neurological Diseases Could Be Treated Through Novel Molecular Therapy
A team of scientists from the Cincinnati Children’s Hospital Medical Center has created a novel molecular therapy which is able to cross the blood-brain barrier. The new therapy has been tested on laboratory mice and it was able to reverse the neurological lysosomal storage disease. The paper was published online in the journal Proceedings of the National Academy of Sciences of the United States of America in early February. Dao Pan, the main investigator in the study, says that his team managed to develop a non-invasive procedure that is able to deliver therapeutic agents through the blood-brain barrier, thus being able to treat the diseases that cause neurological lysosomal storage.
The investigations done by the research team allows for future therapy development for disorders such as Alzheimer’s or Parkinson’s. In order to by-pass the blood-brain barrier, the research team used apolipoprotein E (apoE – a fatty protein) and a-L-idurondase (a therapeutic lysosonal enzyme). The team created two compounds, named IDUAe1 and IDUAe2, and used them to treat type 1 mucopolysaccharidosis (type 1 MPS). This was done in a laboratory environment, on human culture cells. Further, the two compounds were tested on laboratory mouse models of the same disease. One of the most commonly encountered lysosomal storage disease, type 1 mucopolysaccharidosis, affects the central nervous system causing hydrocephalus and various other cognitive defects. Most of the patients will die before they reach the age of 10 if the disease is not correctly diagnosed and treated.
Lysosomes are cellular organelles that contain acid hydrolase enzymes which are able to break down waste materials and other cellular debris. Lysosomes are responsible for the digestion of excess or old organelles and food particles, whilst also playing an important role in the phagocytosis of viruses and bacteria. In type 1 MPS the enzymes contained by the lysosome that are responsible for dissolving the organelles and other debris are missing, causing the accumulation of debris in the cell. This leads to the cell’s malfunction.
The IDUA (a-L-idurondase) is the enzyme that’s missing in type 1 MPS. Due to this fact, glycosaminoglycans accumulate in various organs, but most importantly, in the brain. Through their newly discovered compound, researchers managed to deliver IDUA to the brain cells without having trouble with the blood-brain barrier. The research team used a set of components from the apoprotein E that bind to endothelial cells. They observed that if the IDUA enzyme was added to some of those components, it was able to cross the blood-brain barrier and reach the tissue of the brain. The tail veins of laboratory mice models that were suffering from type 1 MPS were injected with IDUAe1. Tests showed that the modified enzyme penetrates the blood-brain barrier in a dose-dependent way.
The research team reports among their findings that the injection of IDUAe1 in laboratory mice normalized both the levels of glycosaminoglycans and beta-hexosaminidase (a lysosomal enzyme). These normalized levels lasted throughout the whole 5-month follow-up period. More preclinical studies are already taking place in order to verify the positive and negative effects of the two compounds.