Gene therapies for Parkinson’s disease (PD) aim to produce therapeutic proteins in diseased brain regions to promote neuron survival. Overexpression of these proteins in wrong brain areas can cause detrimental effects, though. One unique characteristic in the diseased brain regions in PD patients is the higher levels of both iron and hydrogen peroxide (oxidative stress), which together could generate reactive oxygen species to damage neurons. A gene therapy method that allow cells to produce desired proteins only when triggered by the presence of these unique disease signals should deliver precise therapeutic effects and reduce unwanted side effects.
There are chemical compounds that can be used to artificially induce the expression of introduced genes. This project will chemically modify one inducer [abscisic acid (ABA)] to convert it into an iron-responsive inducer for gene expression. Researchers will first synthesize and screen a collection of modified ABAs to select promising iron-responsive inducers. They will then investigate their reactivity towards iron, their chemical and cellular stability, and their specificity towards other cellular signals. These studies will help to design and further optimize these inducers.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This new strategy may enable the production of therapeutic proteins for Parkinson’s disease — such as glial cell line-derived neurotrophic factor (GDNF) or aromatic amino acid decarboxylase (AADC) — precisely only in diseased neurons. It will have direct and significant contributions in the current clinical development of the gene and cell therapies for Parkinson’s disease.
The researchers expect to characterize ABA-based iron-responsive inducers to control gene expression and obtain the information that will allow them to optimize and tune the reactivity, specificity and stability of the inducers. Combined with a separate hydrogen peroxide-responsive compound based on other chemical inducers, they may be able to construct a cellular computing device that will allow neurons to produce desired therapeutic proteins only in response to unique PD signals.