Non-invasive gene therapy for Parkinson disease: Improve delivery of AAV vectors by single Intravenous delivery combined with Focused UltraSound (FUS). – FAB

In animal models of Parkinson’s disease, we propose using focused ultrasound through the skull to transiently open the blood-brain barrier and precisely deliver a vector carrying a therapeutic gene. We will target two deep brain regions: the striatum and the substantia nigra.

Our goal is to establish the first proof of concept that a single intravenous injection of a gene therapy agent can effectively cross the blood-brain barrier when combined with targeted ultrasound application to a specific brain region.

One month after the induction of Parkinson’s disease in the animals, they exhibited impaired exploration and observational abilities, as well as altered social behavior.

We performed an opening of the blood-brain barrier using the system developed for the project by the coordinating partner. The blood-brain barrier opening was confirmed through specific MRI imaging, and the therapeutic agent was then administered intravenously.

One month after the gene therapy, the animals' exploration and observational abilities, as well as their social behavior, showed significant improvement and were nearly normalized. Additionally, PET imaging was conducted to assess Parkinson’s pathology. The images revealed a significant restoration of dopamine levels following the treatment.

The results are encouraging, and the scientific challenges have been successfully addressed. We are now seeking to translate these findings into human applications.

Recent results demonstrated that gene therapy is an efficient strategy to treat rare or complex diseases of the central nervous system (CNS). Delivering therapeutic genes to the CNS mostly relies on Adeno-Associated Viruses (AAVs) vectors that can efficiently, safely and stably transduce neurons following direct intraparenchymal injection. However, this invasive approach limits there use. AAV vectors have a limited capacity to cross the Blood-Brain Barrier (BBB) after intravenous (IV) administration, even improved serotypes. Our goal is to optimize and simplify the delivery of gene therapy products to the CNS to make gene therapy safe, feasible in multiple centers and accessible to a large number of patients with genetic or complex diseases like Parkinson disease (PD).
To this aim, we will demonstrate in Non-Human Primate (NHP) that transient opening of the Blood-Brain Barrier (BBB) with Focused UltraSounds (FUS) directed to specific brain area, combined to a single intravenous (IV) AAV injection allows efficient transduction of target region. This program will set the basis of gene therapy for Parkinson disease. We will 1) demonstrate that a single IV injection of AAV driving our therapeutic gene (validated in mouse models) combined to FUS allows efficient targeting of the Substantia Nigra; 2) evaluate therapeutic efficiency of our approach in NHP model of PD (mut a-synuclein). This ambitious program would pave the way for a phase I/II clinical trial in PD patients.
The feasibility of this transdisciplinary program relies on the complementary expertise of partners: MZ: gene therapy for brain diseases and therapeutic target; JFA and MS: brain FUS delivery; MB: PET imaging to follow up synucleopathy; JJL: NHP PD model with AAV delivery encoding mutated alphasynuclein in the substantia nigra.