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Gene Therapy to Restore Protein Imbalance in Parkinson's Disease

Study Rationale:
Parkinson's disease (PD) is characterized by impairment of motor control as a result from extensive neuron death. The primary mechanism responsible for the progressive neuronal loss in PD remains unknown; however, clues have been obtained from families who have a genetic form of PD that is accompanied by a mutation (change in genetic material, or DNA) in an important protein called alpha-synuclein. It has been suggested that changes in the function of an organelle (a part of the cell) called the endoplasmic reticulum (ER) may determine the pathological effects of PD. In this project, we aim to define the direct contribution of this pathway to PD using a pre-clinical model of idiopathic PD (cause of PD unknown). By employing a novel gene therapy approach with translational potential in the clinic, we will interfere with the capacity of neurons to repair changes in protein homeostasis (balance), one of the major targets of alpha-synuclein. This work will help validate a novel therapeutic target.

Enforcing the adaptive capacity of the cell against changes in protein homeostasis using a gene therapy approach delays disease onset and increases dopaminergic neuron survival and motor function in a model of idiopathic PD.

Study Design:
We propose using an idiopathic model of PD to address the impact of the Unfolded Protein Response (UPR) for the treatment of PD. Gene therapy using recombinant viruses is becoming an attractive strategy to deliver active UPR components to specific brain areas, avoiding the possible effects of systemic and chronic administration of ER stress-targeting compounds. Adeno-associated viruses (AAV) are the current choice to deliver therapeutic genes into the brain due to their safety profile, as demonstrated in multiple clinical trials. In this project, we plan to measure the potential of delivering a central transcription factor, known as XBP1, using the UPR that is responsible for repairing the proteome (protein network) under chronic damage.

Impact on Diagnosis/Treatment of Parkinson's Disease:
We plan to define, for the first time, the actual role of the main cellular pathway against protein misfolding, known as the UPR, in the development of PD. This research aims to determine if the UPR is a valid target to design therapeutic strategies against to treat those with PD. To pursue this aim, we will test the efficacy of a novel gene therapy that could be applied in the clinic in the future.

Next Steps for Development:
In this proposal, we will collaborate with Genzyme-Sanofi, which is currently equipped to produce AAVs for human use, to generated highly purified AAV to deliver XBP1s, and cross-validate the proposal results, putting us in an excellent position to move forward with the validation of this experimental therapy for PD.


  • Claudio Hetz Flores, PhD

    Santiago Chile

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