Injecting millions of viral particles deep into the brain may sound nefarious, but when the particles are relatively benign and carry the gene for the enzyme glutamic acid decarboxylase (GAD), then the strategy may have the makings of a therapy for Parkinson's disease (PD). As reported in the March 17 Lancet Neurology online, PD patients who received the viruses in a small Phase 2 clinical trial (see had better motor control six months later than patients who received surgery without the viral construct. “This is the first successful Phase 2 trial for a Parkinson’s disease gene therapy, in the sense that we met our primary endpoint,” said senior author Andrew Feigin from the Feinstein Institute for Medical Research, Manhasset, New York. Robert Hauser, University of South Florida, Tampa, told ARF that "the primary outcome was positive and the safety profile looked good, indicating there should be further trials of this approach. If it can be proven to be effective, it would be a real scientific advance, and it would prove that we can change the function of neurons with gene therapy," he added.

Hauser was not involved in the study but is one of the lead investigators for ADVANCE-PD, a Phase 3 trial of IPX066. This is an extended-release form of carbidopa-levodopa, a stalwart therapy for Parkinson's. Last Monday, top-line data released by Impax Laboratories, Inc., which sponsors the drug, suggested that patients on the extended release formulation have less "off" time, which is when the drug wears off and motor symptoms return (see company press release).

Though the two trials use very different approaches, both outcomes are promising. The gene therapy aims to correct an imbalance deep in the brain in the subthalamic nucleus (STN). In Parkinson’s disease, neurons in the STN are overactive (“disinhibited” is the technically correct term) because the dopaminergic neurons in the substantia nigra that die as the disease progresses normally help drive inhibitory neurons that calm the STN. That inhibition can be restored in PD patients by using dopaminergic agents, such as levodopa, or stimulating inhibitory neurons with electrodes planted deep into the brain (see ARF related news series). The gene therapy approach uses viruses to deliver the gene for glutamic acid decarboxylase. This enzyme catalyzes one of the rate-limiting steps in the production of γ-aminobutyric acid (GABA), the major inhibitor neurotransmitter in the STN.

A small pilot trial suggested that GAD gene therapy was safe and potentially effective (see ARF related news story on Kaplitt et al., 2007). For the Phase 2 trial, Feigin and colleagues randomized 22 PD patients to the therapy and 23 to serve as controls. Surgeons stereotactically implanted microelectrodes (as would be done for deep-brain stimulation) into the STN of all patients. After withdrawal of the electrodes, 34.5 μL containing about 34 billion viral particles were slowly pumped into the STN through a catheter inserted into the same bore hole. The control group were injected with a similar volume of saline.

“One caveat is that we limited our analysis to people who received only the full treatment,“ Feigin told ARF. They excluded people from the analysis if the infusion pumps didn’t work properly, or the catheter was not correctly targeted to the STN. This is unusual for clinical trials, which are mostly done on an “intent-to-treat” basis, meaning that people randomly assigned to a treatment are included in the final analysis even if they drop out at some point along the way. This is to ensure that the treatment is generalizable to the population as a whole. “Our view is that this is not what a Phase 2 trial is all about. You need a large Phase 3 trial to assess general effects, but because this was a small Phase 2 trial, we felt we needed to optimize our chances of seeing benefit,” said Feigin. Some PD researchers contacted by ARF wondered if the omission of certain patients in the analysis compromised the validity of the study. But Michael Hutchinson, New York University School of Medicine, called it a “prudent strategy,” in an accompanying Lancet Neurology commentary. He noted that in a previous gene therapy trial of glial-derived neurotrophic factor, “at least two of 17 patients in the treatment group had catheters in the wrong place, yet were included in the analysis.”

The patients in the GAD trial were followed for six months with the primary endpoint being motor function as assessed by the unified Parkinson’s disease rating scale (UPDRS) motor score. Parkinson’s disease is notoriously sensitive to placebo effects, especially for surgical treatments, but in this trial, treatment and control groups did have significantly different outcomes. Motor scores improved in the control group by about four points (or 12.7 percent) over six months, whereas the treatment group improved by eight points (23.1 percent) over the same period.

Questions still abound. Some researchers wondered if the small improvement was worth the risks associated with the surgery and a potential adverse immune reaction to the virus. Hutchinson noted that improvements after DBS are twice as large as seen in this GAD trial, and wondered if long-term effects might arise after introducing viruses into the brain. Hauser also noted that secondary outcomes, such as global ratings, activities of daily living, or other motor functions such as the number of finger taps per minute, did not confirm efficacy, though some trended in the right direction. This could be because the study was too small, he suggested, though he added that in DBS studies of the same size, he would expect to see improvements in some of the secondary measures as well.

One of the secondary measures that showed no difference between treatment and placebo groups in this Phase 2 study is hours in the off state. In contrast, the extended-release carbidopa-levodopa formulation reduced it by 1.2 hours in the Phase 3 ADVANCE-PD trial. “We believe anything greater than an hour is clinically relevant,” said Hauser. But, in addition, he believes one of the important benefits of the extended-release formulation is that patients only need to take it three times a day, as opposed to four, five, or more times a day for the current form. Patients’ compliance tends to go down when they have to take a drug that many times a day, partly because they find it difficult to reliably schedule the drug before or after meals or snacks. Then it becomes difficult for the physician to anticipate the patient’s response to the drug, Hauser told ARF. He believes that not only reducing off time, but also reducing the frequency of dosing, is an important advance for patients. Other measures that improved in patients taking IPX066 included the Clinician Global Impression of Change and Quality of Life Measures.

The GAD gene therapy may advance Phase 3 as well. Marc Panoff, Chief Financial Officer of Neurologix, Inc., which sponsors the therapy, told ARF the company had met with the Food and Drug Administration and hopes to file for a Phase 3 trial this year. Matthew During, Ohio State University, and Michael Kaplitt, Weill Cornell Medical College, New York, are coauthors on the Lancet Neurology paper and co-founders of Neurologix.

In other Parkinson’s developments, Ceregene, which is developing gene therapy for neurturin, a form of nerve growth factor, recently announced that it was moving forward with a Phase 2b trial in PD as well (see company news release). That therapy had failed to reach its endpoint in an earlier Phase 2 trial (see ARF related news story).—Tom Fagan


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News Citations

  1. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD
  2. Parkinson Disease—Potential Targets, Therapies
  3. PD Studies Highlight Deep Brain Stimulation, New Role for α-Synuclein

Paper Citations

  1. . Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet. 2007 Jun 23;369(9579):2097-105. PubMed.

External Citations

  2. Impax Laboratories, Inc.
  3. company press release
  4. Neurologix, Inc.
  5. Ceregene
  6. company news release

Further Reading

Primary Papers

  1. . AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial. Lancet Neurol. 2011 Apr;10(4):309-19. PubMed.
  2. . At last, a gene therapy for Parkinson's disease?. Lancet Neurol. 2011 Apr;10(4):290-1. PubMed.