NU 2021-039
INVENTORS D. James Surmeier* Michael Kaplitt Patricia Gonzalez Rodriguez
SHORT DESCRIPTION A simple neurological procedure to treat late-stage Parkinson’s Disease patients
BACKGROUND Approximately 60,000 Americans are diagnosed with Parkinson’s Disease (PD) each year. Although levodopa has been the gold-standard for symptomatic PD, late-stage PD patients become unresponsive to levodopa therapy, resulting in a deterioration in the quality of life. The lack of responsiveness is attributable to the degeneration of dopaminergic neurons that express aromatic acid decarboxylase (AADC), an enzyme that converts levodopa to dopamine in the brain. The current treatment for late-stage PD patients is deep brain stimulation, an expensive surgery requiring external stimulation. Thus, there is a need for less invasive therapies for late-stage PD patients.
ABSTRACT
A previous clinical trial attempting to elevate striatal expression of AADC using a viral gene delivery strategy failed because of the difficulties associated with transducing a large brain region. Recent work by a group of Northwestern inventors has demonstrated that a more surgically tractable target could be used to move this therapy into the clinic. In a recent high profile publication in Nature, the Northwestern team demonstrated that in a novel mouse PD model that faithfully recapitulates the staging of basal ganglia pathology seen in PD patients, selective loss of striatal dopaminergic signaling impaired motor learning and fine motor skills, but it did not cause parkinsonism. Rather, parkinsonism only emerged with the loss of dopaminergic signaling in the substantia nigra (SN) – a small nucleus at the interface of the basal ganglia with the rest of the brain. Using an adenoassociated virus (AAV) carrying an AADC expression construct, the inventors demonstrated that expressing AADC in either the striatum or the SN of late-stage PD mice effectively boosted the ability of systemic levodopa to alleviate motor disability. In contrast to the striatum, which is very large in humans and which requires multiple injections to transduce, the SN is accessible and much smaller, allowing it to be effectively covered with a single injection of virus. This change in targeting strategy provides effective symptomatic benefit, while limiting surgical time and risk.
APPLICATIONS
ADVANTAGES
IP STATUS Provisional application has been filed.
PUBLICATION González-Rodríguez P, Zampese E, Stout K, Guzman J, Ilijic E, Yang G, Tkatch T, Stavarache M, Wokosin D, Gao L, Kaplitt M, López-Barneo J, Schumacker P, Surmeier DJ (2021) Disruption of mitochondrial complex I induces progressive parkinsonism. Nature, 599: 650-656.
Locomotor activity test for late-stage PD mice injected with AAV2-GFP(black) or AAV2-GFP-AADC). A single injection was performed for the SN. Two injection strategies were tested for the straitum: a single injection or three injections.