Study Rationale:
Hexosaminidase (HEX) is a protein that is stored inside lysosomes, tiny bubbles inside the cell responsible for getting rid of its waste. A lack of HEX is associated with Sandhoff disease, in which fatty substances build up in the body. Studying pre-clinical models of Sandhoff disease, we noticed hallmarks of Parkinson's disease (PD): an increase in alpha-synuclein clumps and a loss of dopamine-producing brain cells in the substantia nigra, a brain region implicated in PD. These findings suggest a similarity between the mechanisms of Parkinson's disease and Sandhoff disease.
Hypothesis:
In this study, we will use gene therapy, an approach based on making the cell produce a therapeutic protein as opposed to giving the protein in the form of a drug. We hypothesize that restoring the level of HEX through gene therapy will enhance the capacity of brain cells to manage changes in fatty substances and the function of lysosomes in Parkinson's disease as well as reduce the toxic effect of alpha-synuclein clumping.
Study Design:
In this study, we will test how gene therapy can reduce or otherwise influence cell death and other disease-related changes in the substantia nigra. This study will be conducted in pre-clinical models of Parkinson's with toxic alpha-synuclein in the substantia nigra. We will measure glycosphingolipids -- fatty substances that serve as indicators of lysosomal function -- inflammation and cell death in these models from two to five months after the start of gene therapy.
Impact on Diagnosis/Treatment of Parkinson's disease:
This study will test whether HEX can counteract the major PD-related changes in the brain. This therapeutic approach may be tailored to individual therapy recepients based on their body's ability to produce the protein.
Next Steps for Development:
This study would expand what recearchers and clinicans already know about therapeutic proteins like HEX and help determine the relevance of developing such therapies. Either gene therapy or drugs that activate HEX or other proteins could be useful in counteracting factors causing Parkinson's disease.