Head of the Sanofi Genzyme R&D Center Rich Gregory, PhD, tells MJFF how his company is developing a critical research tool for use in a clinical trial at the University of California San Francisco.

Gene therapy is a novel approach to treat, cure or prevent disease by changing the expression of a person’s genes. In Parkinson's disease (PD), this research primarily seeks to repair or restore the function of dopaminergic neurons in the brain.

Last fall, the European Medicines Agency approved a gene therapy for the first time, for a rare disease called lipoprotein lipase deficiency.  While no gene therapy for any disease has of yet received regulatory approval in the U.S., currently several trials into various gene therapy approaches targeting PD are ongoing.  One such approach will soon enter into a second clinical trial being conducted through a novel collaboration between The Michael J. Fox Foundation (MJFF), the biotechnology company Genzyme, and study lead Krystof Bankiewicz, MD, PhD, of the University of California San Francisco.

PD is marked by the progressive loss of dopamine-producing neurons a region of the brain called the substantia nigra, which leads to the motor symptoms of the disease. Bankiewicz’ approach seeks to address this dopamine depletion by targeting an enzyme in the brain called aromatic L-amino acid decarboxylase, or AADC.

AADC is necessary to convert levodopa (the gold standard PD treatment) into dopamine. As dopamine neurons die off, the enzyme AADC also lessens. By getting more AADC into the right areas of the brain, it’s hoped, Parkinson’s patients taking levodopa might be able to lessen doses of the drug necessary for effect. Limiting doses of levodopa could, in turn, help to prevent the dyskinesias that are often a side effect of the drug. 

One of the tricks to making this approach work is to find a way to get this AADC into the brain. Enter Genzyme, who is producing and optimizing the tool to do this, called a viral vector —basically a virus stripped of the bad stuff, and engineered to deliver a particular therapeutic to specific places in the body.  The viral vector is implanted into the brain with a surgical technique. In this case, the Genzyme vector will focus on getting AADC into an area of the brain called the putamen. By going directly into the putamen, the hope is that the newly implanted AADC will serve to enable the more efficient production of dopamine.

Here, MJFF speaks with Rich Gregory, PhD, Head of the Sanofi Genzyme R&D Center, to learn more about the technology itself, and the partnership driving forward this particular gene therapy approach. 

MJFF: Tell us more about why you decided to get involved with this project.

RG: Our goal at Genzyme has always been to do things that are transformative. One of our great successes has been to develop a drug for Gaucher disease, a genetic disorder that often begins in childhood, and can lead to a range of serious complications, among them brain damage. 

We’ve long been invested in Parkinson’s disease, and the work being done by Krys’ team is especially intriguing. We’ve worked with Krys on other Central Nervous System disorders, and he understands this space so well, so we were eager to continue to collaborate with him. 

MJFF: What are some of the challenges to this project, and what are you doing to overcome them?

RG: The biggest challenge in drug development on the whole is navigating the translational space: How do we get potential therapies from laboratories to the clinic, and then ultimately, to the patients who need them? In particular, the Parkinson’s disease space is particularly difficult. It’s an incredibly complex disease, so encouraging people with particular expertise to work together is paramount to success. Our work with Krys is a fantastic example of how industry and academia can come together toward solving a problem.  

And this is where The Michael J. Fox Foundation is playing a major role. Its knowledge of the disease area, connection to patients, and ability to invest at places along the pipeline where others might not want to take a risk, make MJFF a real ally to those of us looking to develop PD therapies. 

This will be our second phase 1 trial testing this approach in patients. Our results from the first trial weren’t clear cut, but we remained optimistic that the therapy could work. We still thought that the target and approach was sound, but that maybe we weren’t getting the results we needed due to how we were delivering the treatment, and at what dose.  We wanted to better optimize the delivery of the therapy, and MJFF intervened to help us do this, providing $2 million. In the drug development world, it can be very difficult to get the funding for one phase 1 trial, much less two.  MJFF is keeping this treatment moving forward.  Without them, I’m not sure we would have continued to invest in this work. 

MJFF: What can you tell us about the timeline for this treatment, and other gene therapy approaches for PD, to potentially come to market? 

RG: I personally have a huge level of faith and excitement that this approach could work. But there’s quite a bit of work still ahead of us. An overriding concern with any brain surgery is safety. If we’re able to return positive results from this study and better understand dosing response, and we continue to show a good safety profile, then our next step would be to move into a phase 2 study to more thoroughly measure the effectiveness of the therapy. A larger phase 3 study to confirm any positive results would then follow that, in a best case scenario. So even if everything goes right, we’re still some years away.

It’s an encouraging time for gene therapy on the whole in 2013: Last fall, the European Medicines Agency approved a gene therapy for the first time, for a rare disease called lipoprotein lipase deficiency.  Other gene therapy approaches into neurotrophic factors are also currently in the clinic and I expect we’ll learn more about the potential of these proteins in the coming year. There is certainly a lot going on here, and the field will await these results with anticipation.   

I’m particularly excited about gene therapy of AADC because I believe it focuses on patients who are further along in the disease course; it could help those who have lost the ability to use standard of care treatments. AADC-based gene therapy has the potential to dial back a patient’s disease, making living with Parkinson’s much more manageable.