Give a man a fish and you feed him for a day. Teach a man to fish and you feed him for a lifetime. Perhaps the saying could loosely apply to neurons in Parkinson's disease (PD). A pill supplements dopamine levels for a few hours. What if the brain could be coaxed to make its own? Gene and cell therapies aim to do just that. In the first-ever human trial of a lentivirus used to treat a neurodegenerative disease, researchers led jointly by Stéphane Palfi, Hôpitaux Universitaire Henri Mondor, Créteil, France, and Kyriacos Mitrophanous, Oxford Biomedica, U.K., tried to get striatal cells to do just that. The results of their Phase 1/2 open-label trial appeared in the January 10 Lancet. Fifteen volunteers tolerated the gene therapy for up to four years and showed some signs of motor improvement. Meanwhile, in a January JAMA Neurology article, researchers present two case reports on the long-term follow-up of two men who received fetal dopaminergic cell transplants almost two decades ago and still get by without dopaminergic medication. " In taking care of Parkinson's patients, it's important to have a wide variety of therapies at our disposal," said Andrew Feigin, Feinstein Institute for Medical Research, Manhasset, New York. 

Viral therapy improves dopamine levels

Six months after injection with ProSavin (right), PET imaging shows that a patient takes up less 11C-raclopride, a dopamine antagonist, at the site of the viral injection than at baseline (left). The authors interpret this to mean the treatment improves production of dopamine in the brain. Image courtesy of The Lancet

Previous attempts at PD gene therapy used adeno-associated viruses to introduce single genes into various regions of the brain to compensate for the loss of dopaminergic cells (see Mar 2011 news story; Jan 2013 news story; and Muramatsu et al., 2010). These small viruses can carry up to two transgenes each and exist separately from host DNA. They met with varied success. Lentiviruses can carry more cargo and integrate into chromosomal DNA. Palfi and colleagues loaded all three genes needed for dopamine synthesis—tyrosine hydroxylase, cyclohydrolase 1, and aminoacid decarboxylase—onto a single lentiviral vector to create ProSavin. 

To test ProSavin, the scientists injected it into the striata of monkey models of PD. Local striatal neurons made dopamine, and the treatment corrected motor deficits (see Jarraya et al., 2009). Striatal neurons usually make no dopamine, getting it from neurons that project from the substantia nigra, the main site of neurodegeneration in PD. Palfi and colleagues set out to see if ProSavin worked safely in humans as well.
The researchers enrolled 15 patients aged 48 to 65 for an open-label trial. Each received a single low, medium, or high dose of ProSavin bilaterally in the putamen, part of the dorsal striatum. The scientists evaluated patients first monthly, then trimonthly for the first year. They checked motor control with the Unified Parkinson’s Disease Rating Scale (UPDRS) scores, evaluated quality of life, took blood samples, checked for dyskinesia, and noted adverse events. At six months, PET measures of dopamine uptake and release were taken using 11C-raclopride and 18F-levodopa.

At six- and 12-month follow-up, patients averaged a beneficial 30 percent reduction in UPDRS motor scores when not taking levodopa, a standard treatment for PD. The group given the highest dose improved most. Total UPDRS score, which accounts for non-motor factors such as mood and activities of daily living, also improved both on and off medication. Most drug-related adverse events were mild, and included on-medication dyskinesias. These turned up more often in the high-dose group, and tended to go away with reduced oral dopamine treatment. Immunological assays showed no apparent immune response to the treatment, and MRI detected no inflammation. 

In an ongoing follow-up trial, the researchers will evaluate these patients semiannually for three years and annually for seven more. The scientists provided some of the available follow-up data in the paper. A few patients have reached their fourth year and most still exhibit improved off-medication motor scores. 

Though these results suggest improvement, the lack of a control group prevents conclusions about efficacy, wrote the authors. Since the magnitude of change is similar to that reported for control groups in other surgery-related PD trials, it could be explained by a placebo effect, said the authors. However, they note that the dose response hints otherwise. While scientists not involved in the study accepted that such an invasive early trial had to go unblinded, the lack of a control was their chief caution. Feigin noted that previous positive open-label trials in PD have been followed by discouraging placebo-controlled studies. 

For others, efficacy was not the most important outcome. "The safety profile is encouraging," and "build[s] on an impressive safety record for gene therapy in neurological diseases," Raymond Bartus, RTBioconsultants, Inc., San Diego, wrote to Alzforum (see full comment below). Feigin echoed that sentiment. "The more people do these trials and realize it can be done without putting patients at risk, the more people will find novel forms of gene therapy to pursue," he said. 

In an accompanying editorial, Jon Stoessl, University of British Columbia, Vancouver, Canada, pointed out that striatal cells are ill-equipped to store, release, or take up dopamine in a controlled way, which could explain the elevated dyskinesias. Despite these limitations, these positive safety results pave the way for gene therapy that targets both motor and non-motor symptoms of PD, he added. Before starting blinded trials, Palfi said his group is in the process of using non-human primates to validate an optimized version that allows cells to produce more dopamine.

Cell Graft Recipients—Where Are They Years Later?

In a related attempt to boost dopamine in the brain, researchers transplanted fetal dopaminergic neuroblasts into the brains of 18 people with Parkinson's in Lund, Sweden, in the mid-1990s. In their JAMA Neurology paper, researchers led by Thomas Foltynie and Zinovia Kefalopoulou, University College London, describe the clinical states of two of those patients in the United Kingdom, 15 and 18 years post-surgery. The others patients in the cohort have been lost to follow-up, Kefalopoulou explained, citing the challenges of keeping tabs on people who came from three different countries for so long. A previous review detailed the variable outcomes of transplantation in this cohort (see Lindvall and Björklund, 2004). Back then, some patients saw a 40 to 60 percent improvement in UPDRS motor scores but others experienced little or no benefit. The two patients reported on now fell into the former category. 

Both men now have a better UPDRS motor score than their original baseline. It gradually improved after transplantation and then leveled off. Both men tapered off their oral levodopa use, and neither has developed dementia. While Parkinson's usually progresses steadily, these men appear to have actually improved slightly after their grafts, suggesting transplantation may change the natural history of the disease, Kefalopoulou wrote to Alzforum in an email. Some graft-induced dyskinesias did occur after surgery, but the benefits outweigh that side effect, wrote the authors. 

Postmortem data from other graft recipients showed Lewy bodies in some transplanted cells (see Apr 2008 news story) and similar pathology likely occurs in these two patients’ transplants. Nonetheless, they seem to function, wrote the authors. "Dopaminergic cell transplantation may offer a substantial and very long-lasting compensatory effect in PD," they added. Fetal tissue is difficult to obtain, but recent developments in stem-cell technology are renewing interest in using dopaminergic cells to treat PD (see Nov 2011 news storyJul 2011 news story). 

Curt Freed, University of Colorado, Denver, reiterated the authors' caveat that these results do not represent the average outcome of the 18 patients originally in this cohort. He is skeptical that transplants will completely alleviate the need for levodopa in most patients, and warned against too much optimism when interpreting these results, as they are atypical. However, Freed said that transplants usually do replace half the dose of levodopa, and may be a cheaper surgical option than deep-brain stimulation, which comes with a sustained risk of infection due to the implanted equipment. While all three can improve movement, none stops the underlying neurodegenerative process in PD, he said.—Gwyneth Dickey Zakaib


  1. The study by Palfi et al. is a welcome addition to the literature, reporting the results of 15 Parkinson’s patients treated with a lenti-viral vector intended to enhance dopamine function in the terminal field of the degenerating dopamine neurons. The trial, launched in 2008, is an uncontrolled, open-label, dose-escalation safety study and the first reporting the use of a lenti-viral vector for a neurological disease. Described as a Phase 1/2 trial, this study does not differ substantially from past dose-escalation gene therapy Phase 1 safety studies in Parkinson’s, rendering the Ph1/2 distinction more a semantic preference than a representation of substantial difference in study design. The safety profile is encouraging, with most adverse events being mild and deemed unrelated to treatment. Thus, the data from this trial build on an impressive safety record for gene therapy in neurological diseases, now involving nearly a dozen clinical trials and scores of treated subjects (mostly in Parkinson’s and Alzheimer’s), spanning a decade. Collectively, these trials demonstrate that the major safety hurdles previously suppressing CNS gene therapy have been solved, for none produced any evidence of untoward risk or harm after administration of various vector-delivery systems. More importantly, several of those studies also demonstrated controlled, highly persistent generation of biologically active proteins, selectively targeted to structures deep in the human brain. The modest efficacy improvements reported in the current Palfi et al. Lancet paper are comparable to those reported in many prior open-label gene therapy Parkinson’s studies; importantly double-blind, controlled studies of those treatments could not adequately differentiate between treatment and placebo. The Palfi data therefore further emphasize the difficult nature of producing robust effects in the later stages of Parkinson’s disease. Indeed, the authors concluded that they will not conduct a more definitive double-blind placebo-controlled trial until “we have an optimal mode and dose of delivery," thereby acknowledging the unfortunate reality that a more robust response is required that presumably will require further iterations to the product, its dosing, and possibly clinical design.

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News Citations

  1. First Phase 2 Success for Gene Therapy in Parkinson’s
  2. Cut to the Chase: Therapies Go Directly to Central Nervous System
  3. Dopaminergic Transplants—Stable But Prone to Parkinson’s?
  4. Therapeutic-Grade Dopaminergic Neurons From Stem Cells?
  5. Faster, Safer Ways to Cook Up Dopaminergic Neurons

Paper Citations

  1. . A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther. 2010 Sep;18(9):1731-5. Epub 2010 Jul 6 PubMed.
  2. . Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia. Sci Transl Med. 2009 Oct 14;1(2):2ra4. PubMed.
  3. . Cell therapy in Parkinson's disease. NeuroRx. 2004 Oct;1(4):382-93. PubMed.

External Citations

  1. open-label trial
  2. follow-up trial

Further Reading


  1. . Bioactivity of AAV2-neurturin gene therapy (CERE-120): differences between Parkinson's disease and nonhuman primate brains. Mov Disord. 2011 Jan;26(1):27-36. PubMed.

Primary Papers

  1. . 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 Mar 29;383(9923):1138-46. Epub 2014 Jan 10 PubMed.
  2. . Gene therapy for Parkinson's disease: a step closer?. Lancet. 2014 Mar 29;383(9923):1107-9. Epub 2014 Jan 10 PubMed.
  3. . Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 2014 Jan;71(1):83-7. PubMed.