Background

AAV-GAD is a gene therapy for Parkinson’s disease. It delivers the glutamic acid decarboxylase (GAD) gene to the subthalamic nucleus, where this enzyme then increases production of the inhibitory neurotransmitter γ-amino-butyric acid (GABA). In people with Parkinson’s disease, increased activity of subthalamic nucleus neurons due to loss of inhibitory input contributes to movement problems such as tremor, rigidity, and difficulty walking. The goal of GAD gene therapy is to boost levels of GABA and normalize activity of these neurons. This is a similar mechanism to subthalamic deep brain stimulation, an approved surgical treatment for Parkinson’s symptoms.

The therapy, originally developed at Neurologix Inc., consists of a 1:1 mixture of two adenovirus vectors encoding the GAD-65 and GAD-67 enzyme isoforms, under regulation of cytomegalovirus enhancer–chicken β-actin promoter and woodchuck posttranscriptional regulatory elements. It is a given as a one-time injection, utilizing a surgical procedure similar to the implantation of deep brain stimulation (DBS) electrodes.

In preclinical work in rats, AAV-GAD injection into the subthalamic nucleus on one side led to robust GAD expression on the injected side five months later, but not on the uninjected side. In a toxin-induced Parkinson’s model, AAV-GAD-treated animals maintained significantly higher levels of GABA, better movement, and more dopamine neurons (Luo et al., 2002). An independent group showed efficacy of an AAV-GAD65 vector in Parkinson’s rats (Kim et al., 2008). The gene therapy was safe and improved some motor symptoms in a rhesus monkey model of Parkinson’s (Emborg et al., 2007). In a safety study performed in rats, AAV-GAD was not detected in blood or CSF after subthalamic injection. The vector did not disseminate to any organs outside the brain in most animals, or cause changes in general health or behavior (Fitzsimons et al., 2010).

Findings

In August 2003, Neurologix Inc. began a first-in-human study in 12 Parkinson’s patients, who received one of three doses of AAV-GAD into the subthalamic nucleus on one side of the brain. The surgical infusions caused no complications or adverse effects. The patients improved on the Unified Parkinson’s Disease Rating Scale (UPDRS) for motor function starting three months after surgery. Improvement was predominantly on one side, and persisted out to the one-year follow-up. FDG-PET imaging revealed reduced glucose utilization in the thalamus on the treated side one year after surgery (Kaplitt et al., 2007). Additional analysis of FDG-PET data showed that treatment caused normalization of metabolic activity in a motor-related brain network involving the subthalamic region and motor cortex, that correlated with clinical improvements (Feigin et al., 2007).

Phase 2 began in August 2008, with a placebo-controlled study in 44 advanced PD patients. Treatment consisted of bilateral virus injections, or control saline infusion. The primary outcome was listed as change in UPDRS scores. A long-term follow-up was to run for five years, but the study was terminated in December 2010 for financial reasons.

Results of this trial are published. Six months after treatment, motor scores while off dopamine medication improved in the treatment group by 23.1 percent, compared to just 12.7 percent improvement in the placebo group. While a positive result, the improvement was less than typically achieved with deep-brain stimulation. Adverse events were mild or moderate, with the most common being headache and nausea, likely related to surgery (LeWitt et al., 2011). At one-year post-surgery, motor scores were still better in treated patients compared to placebo. Treatment reduced the daily duration of levodopa-induced dyskinesias. FDG-PET showed glucose uptake declining in the thalamus, striatum, and cortical regions, suggesting an attenuation of hyperactivity in the subthalamic nucleus (Niethammer et al., 2017).

In early 2012, Neurologix cancelled a planned Phase 3 trial and declared bankruptcy.

In 2018, the publication of more FDG-PET data from the Phase 2 study revived interest in AAV-GAD, which had been acquired by MeiraGTx (press release). The gene therapy appeared to stimulate new functional connections in the brain, and these new circuits correlated with clinical efficacy (Niethammer et al., 2018). These changes were not seen in control or DBS-treated patients.

In October 2022, MeiraGTx restarted development with a Phase 1/2 placebo-controlled study in 14 people with Parkinson’s disease. Treatment will be a single bilateral infusion of two different doses of AAV-GAD or sham surgery, against a primary outcome of adverse events. The trial will also measure symptoms on the MDS-UPDRS motor function scale in the off-medication state at three and six months after surgery. The trial, at four sites in the U.S., will run until March 2024.

AAV-GAD has Fast Track designation from the U.S. FDA.

For details on AAV-GAD trials, see clinicaltrials.gov.