Therapy Type: DNA-based
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Voyager Therapeutics
VY-AADC is a gene therapy. It aims to restore the treatment benefit of oral levodopa for people with advanced Parkinson's disease, whose treatment response has started fluctuating. VY-AADC attempts to supply transgenic L-amino acid decarboxylase (AADC), the enzyme that converts levodopa to dopamine, directly into the putamen area of the brain. As dopaminergic neurons in the brain's substantia nigra degenerate in PD, dopamine levels decrease in their projection area, the striatum encompassing the putamen, where medium spiny neurons survive and maintain expression of dopamine receptors long into PD progression (Braak et al., 2004). The treatment rationale is that local expression of transgenic AADC will boost dopamine levels in the putamen, reducing motor "off" time and prolonging "on" time for the patient.
VY-AADC uses the adeno-associated virus 2 capsid as a vector encoding AADC; expression is driven by a cytomegalovirus promoter. This renewed attempt at CNS gene therapy employs MRI-guided cannula placement to the putamen, convection-enhanced infusion of larger volumes of transgene solution to increase exposure, and 18F-DOPA PET to quantify local transgene expression and activity. The goal is to achieve long-term expression with a single treatment. Proof of concept, as well as safety and tolerability of this delivery mode, were reported in non-human primates (Su et al., 2010; Hadaczek et al., 2010; San Sebastien et al., 2012; San Sebastian et al., 2014).
In 2013, Voyager started enrolling 15 people who had had PD for at least five years and were on levodopa therapy into an open-label trial. It compared three ascending doses of VY-AADC, delivered once by neurosurgical infusion into the putamen on both sides of the brain. The primary outcome, being assessed over a three-year period, is safety and tolerability; secondary outcomes include PD symptoms as recorded in participant diaries and assessed by a neurologist, as well as quality of life surveys, changes to Parkinson's medications, and PET scanning six months after gene transfer. Conducted at the University of California, San Francisco, and the University of Pittsburgh, the trial is set to run through 2019.
Interim results were reported in December 2016, September 2017, and March 2018. Injection of up to 900 microliters of VU-AADC into the putamen was well-tolerated, achieved better coverage of the putamen than previous gene therapies, and was correlated with increased F-DOPA PET signal. The higher-dose cohort had higher putamen coverage, as well dose-dependent changes in imaging, responsiveness to levodopa, and clinical measures. Thus far, the trial shows a 2.1-hour lengthening in patient-reported diary on-time without dyskinesia from baseline to three years for patients in Cohort 1; 3.5 hours more on-time from baseline to 18 months in Cohort 2, and 1.5 hours more up to 12 months in Cohort 3. Participants needed less oral levodopa, and VY-AADC still appeared safe at three years out. One patient had a pulmonary embolism from a venous thrombosis during the procedure, which resolved (Chadwick et al., 2017; company release 9 March 2018).
In May 2017, a second open-label trial started enrolling 16 people with advanced PD who had a fluctuating levodopa response with a defined minimum of time spent in the "off" state. These participants received 9.4 x 1012 vector genomes of VY-AADC01, twice the highest dose than in the first trial, also infused once directly into the putamen. This trial evaluates delivery via an occipital, i.e. posterior, trajectory, along the long axis of the putamen, to see if that increases coverage of the putamen relative to the frontal trajectory used in the first trial. Primary outcomes include adverse events, brain abnormalities on MRI scans, routine physical exams and labs, as well as change on the Columbia-Suicide Severity Rating Scale—all recorded for up to three years after gene transfer. Secondary outcomes will monitor changes in PD medications, motor function using both participant diaries and neurologist assessment, changes in dyskenesia, as well as changes in transgene expression, sleep, compulsive behavior, cognition, quality of life, and other parameters. This trial is being conducted at four U.S. sites, and expected to run through 2021.
For all trials, see clinicaltrials.gov.
Clinical Trial Timeline
Last Updated: 25 May 2018
- Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 2004 Oct;318(1):121-34. Epub 2004 Aug 24 PubMed.
- Su X, Kells AP, Salegio EA, Salegio EA, Richardson RM, Hadaczek P, Beyer J, Bringas J, Pivirotto P, Forsayeth J, Bankiewicz KS. Real-time MR imaging with Gadoteridol predicts distribution of transgenes after convection-enhanced delivery of AAV2 vectors. Mol Ther. 2010 Aug;18(8):1490-5. Epub 2010 Jun 15 PubMed.
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- San Sebastian W, Richardson RM, Kells AP, Lamarre C, Bringas J, Pivirotto P, Salegio EA, Dearmond SJ, Forsayeth J, Bankiewicz KS. Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum. Hum Gene Ther. 2012 Feb;23(2):210-7. Epub 2012 Jan 26 PubMed.
- San Sebastian W, Kells AP, Bringas J, Samaranch L, Hadaczek P, Ciesielska A, Macayan M, Pivirotto PJ, Forsayeth J, Osborne S, Wright JF, Green F, Heller G, Bankiewicz KS. SAFETY AND TOLERABILITY OF MRI-GUIDED INFUSION OF AAV2-hAADC INTO THE MID-BRAIN OF NON-HUMAN PRIMATE. Mol Ther Methods Clin Dev. 2014 Oct 15;3 PubMed.
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