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In Open-Label Trial, Gene Therapy Found Safe and Well-Tolerated in Advanced Parkinson's



TWO-DIMENSIONAL FLAIR MRI (A) sequences done 1 month after surgery, showing increased signal within the postcommissural putamen corresponding to motor putamen injection sites (lower arrow), and no signal change in the non-injected caudate nucleus. (B, C) Binding potential parametric maps from11C-raclopride PET scans of patient 11 (cohort 3) done at baseline (B) and 6 months after ProSavin injection (C) within the putamen. Note a decrease in a binding potential index only in the left and right postcommissural putamen area (B, lower arrow), compared with no binding potential change on either side of the non-injected caudate nucleus (B, upper arrow).

For the first time, investigators reported they used a lentiviral vector to deliver gene therapy into patients with advanced Parkinson's disease, and they found the procedure was safe and well tolerated.

Scientists from France and the United Kingdom delivered a lentiviral-based gene therapy packed with three different genes into 15 patients with advanced Parkinson's disease (PD) and found that it was well tolerated and safe.

In the open-label phase 1/2 study, the 12-month follow-up showed improvement in motoric scores in all patients. The most improvement was observed in those who received the highest dose of the gene therapy, the investigators reported in the Jan. 10 online edition of The Lancet. The patients will continue to be followed for the rest of their lives.

In the study, Stéphane Palfi, MD, PhD — and his colleagues at Henri Mondor Hospital, University of Paris, the Commissariat à l'Energie Atomique, INSERM at the Institut de Recherche Biomédicale, Oxford BioMedica, and the John van Geest Centre for Brain Repair and Addenbrooke's Hospital in Cambridge — set out to test the safety of ProSavin, a gene therapy built on a lentiviral vector — an equine retrovirus — that can deliver genetic material into non-dividing brain cells and is less likely to stimulate a host immune reaction when compared with other viral vectors being tested to deliver genes into the human body.

This is the first attempt at delivering a lentiviral vector into the central nervous system in patients. The hope is that this technique could deliver a safe and steady source of dopamine to the brain, which would reduce the uneven control of abnormal motor symptoms associated with oral medications. Oxford BioMedica developed the gene therapy technique and is funding the current study.


The research team generated a lentiviral vector based on the equine infectious anemia virus encoding the rate-limited dopamine biosynthetic enzymes — tyrosine hydroxylase, cyclohydrolase 1, and amino acid decarboxylase (AADC). “Previous studies have shown that expression of these three enzymes in nondopaminergic cells, such as striatal neurons, is sufficient to enable these cells to manufacture dopamine,” the investigators wrote. The gene therapy technique does not repair the damaged dopamine neurons but reprograms other neurons to take over the manufacturing of dopamine.

The investigators injected the vector bilaterally into the putamen of 15 patients — who were 48 to 65 years old — with advanced PD. The patients had PD for at least five years, had motor fluctuations, and were still responding to oral dopaminergic therapy. Three different doses were studied.

Over the next year, the researchers assessed the number and severity of vector-related effects, and evaluated symptoms with the Unified Parkinson's Disease Rating Scale (UPDRS). At the one-year mark, there were 54 drug-related adverse events. Virtually all events were mild; three were considered moderate. The most common side effects were increased on-medication dyskinesias, but they resolved with a reduction in their oral medication. The researchers reported a significant improvement in the average UPDRS part III motor scores off-medication in all patients at six months and then again at one year.

“Patients reported improvements in rigidity and walking,” Dr. Palfi told Neurology Today. “There were fewer off-times and they were less severe. Brain scans using positron emission tomography showed a significant increase in dopamine, up to 10 percent at the highest dose. We are optimistic with the results.”

“This is a very different approach to gene therapy for Parkinson's,” Dr. Palfi said, adding that the scientists are now working on improving the lentiviral vector to increase the dose of dopamine release. They have plans to conduct a phase 2B double-blind trial using sham surgery as a control.


Several PD experts — some of whom have been involved with their own gene therapy studies — praised the innovative technique involving the lentivirus in the current study and the fact that there were no safety issues. But they noted that open-label studies are not reliable and the results need to be confirmed with a double-blind study.

“Since gene therapy for Parkinson's is in its infancy, 15 patients studied with a new delivery system is encouraging for the field,” said Andrew Feigin, MD, a professor of neurology in the Center for Neuroscience at the Feinstein Institute for Medical Research in NY, who has been involved in other PD gene therapy studies. Dr. Feigin also serves on the editorial advisory board of Neurology Today. [See “Gene Therapy for Parkinson's — Where it Failed, Where It's Heading.”]


DR. STÉPHANE PALFI: “Patients reported improvements in rigidity and walking. There were fewer off-times and they were less severe. Brain scans using positron emission tomography showed a significant increase in dopamine, up to 10 percent at the highest dose. We are optimistic with the results.”

In an editorial accompanying the Lancet study, Jon Stoessl, MD, professor and head of the division of neurology at the University of British Columbia in Vancouver, wrote: “This approach taken by Palfi and colleagues is novel in that it is the first time that lentiviral vectors have been successfully applied to the treatment of neurological disease in humans and does not depend on survival of dopaminergic neurons, but rather assumes that transfected striatal neurons preserved in Parkinson's disease will develop the capacity to synthesize dopamine...the safety of this approach could be seen as a proof of principle for future studies focused on rigorous assessment of efficacy as well as targeting these devastating problems.”

“The good news is that it is safe, and it is a nice first step,” agreed Jeffrey Kordower, PhD, professor of neurosurgery at Rush Presbyterian-St. Luke's Medical Center and director of the section on neuroscience. “It seems to have had a consistent effect. All patients improved. But it is an open-label experiment, which is open to bias.”

Anders Björklund, MD, PhD, a professor of histology at Lund University in Sweden, called the findings “promising,” adding: “Right now, the doses they got are not sufficient or optimal. With a new vector they may be able to increase the delivery of dopamine.”

“My belief is that the new generation of treatments for Parkinson's will be based on gene or cell delivery,” Dr. Björklund told Neurology Today. “What is needed to put gene therapy back on the agenda is some positive news. We will all benefit from that. I think this approach with a consistent delivery of dopamine is a very attractive, concrete approach.”

Howard Federoff, MD, PhD, executive vice president for health sciences and executive dean at Georgetown University School of Medicine, said he is also “encouraged by the results of the study in The Lancet. But he, too, acknowledged that the placebo effect can be a factor in open-label studies.

“Much, if not all, of the clinical improvement could be attributed to placebo effect,” said Dr. Federoff, who is collaborating with a group of researchers in partnership with the NIH on another gene therapy trial. But, he added, “these scientists are in a good position to extend their work. It needs to be tested against a sham surgery control to really know if it is effective.”


The Parkinson's gene therapy world has been hit with failures and setbacks since the first trials began more than a decade ago. Two companies closed down gene therapy trials after deciding that the benefits did not justify the expense for developing treatments. Other groups continue to work on designing more effective gene therapy vectors that can carry a bigger load of genetic material to areas of the brain hard hit by disease.

The National Institutes of Health has teamed up with researchers in academic centers to test another gene therapy approach in Parkinson's. The first of 24 study patients has already received an infusion of genes packed into adeno-associated virus (AAV). The genes are designed to manufacture glial cell-line derived neurotrophic factor (GDNF) that promote survival of dopamine-producing neurons (in lab and animal studies).

Krystof Bankiewicz, MD, PhD, a professor of neurosurgery and neurology and vice chair of neurological surgery and director of the interventional neurology center at the University of California in San Francisco (UCSF), is one of the investigators involved in the NIH partnership. His team is testing another gene therapy approach using amino acid decarboxylase (AADC). They finished a pilot study using a small dose and they are now gearing up to start another clinical trial using a higher dose. They use an MRI scan during delivery of the infused genes, which Dr. Bankiewicz said is critical for optimal distribution of the genes into the target region.

Andrew Feigin, MD, a professor of neurology in the Center for Neuroscience at the Feinstein Institute for Medical Research in NY, was involved in a gene therapy trial for Parkinson's that offered enough promise that the company, Neurologix, Inc., took it into a double blind controlled trial. The company, testing a non-dopaminergic approach delivering an inhibitory gene — glutamic acid decarboxylase or GAD — that makes GABA, closed down in 2012. The company reported that study participants who received the active treatment, dubbed NLX-P191, showed a statistically significant improvement in off-medication motor scores compared with subjects who received sham surgery. Dr Feigin said that the closing of the trial, and the company, was based on finances.

And last April, the San Diego-based biotech company Ceregene, Inc. announced it too was cancelling its Parkinson's disease gene therapy trial. Its double-blind controlled phase 2b trial did not meet its primary endpoint to increase control of motor function on the Unified Parkinson's Disease Rating Scale-motor off scale. The gene therapy delivered the neurotrophic factor, neurturin. The genes delivered into the brains of 51 patients showed no safety concerns, but both the treated group and those in the sham surgery arm improved following the surgery so it was suggested that there is a strong placebo effect.

C. Warren Olanow, MD, chairman emeritus of the department of neurology and professor of neuroscience at the Mount Sinai School of Medicine in New York and a clinical advisor to Ceregene, said that the results from the Ceregene study “illustrate how difficult it is to establish clinical efficacy with entirely novel therapeutic approaches in complicated neurological diseases.”

—Jamie Talan


•. Palfi S, Gurruchaga JM, Ralph GS, et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet 2014; E-pub 2014 Jan. 10.
    •. Stoessl AJ. Gene therapy for Parkinson's disease: A step closer. Lancet 2014; E-pub 2014 Jan. 10.
      •. Allen PJ, Feigin A. Gene-based therapies in Parkinson's disease. Neurotherapeutics 2014; 11(1):60–67.
      •. Neurology Today archive on gene therapy for Parkinson's disease: