Surgical Approaches

Dr. Paul Larson (UCSF) and Dr. Jamie L. Eberling (MJFF) discuss the current state of neurosurgical approaches for treating PD.

JE:  Which neurosurgical approaches for treating PD are currently in use at UCSF?

PL: Our mainstay of surgical therapy for PD continues to be deep brain stimulation, typically in the subthalamic nucleus (STN) although we have studied other targets including the pedunculopontine nucleus (PPN).  Most of our implantations are done using conventional stereotactic surgery with microelectrode recording in awake patients.  Five years ago we started a clinical trial using real-time interventional MRI to place electrodes in the STN based completely on direct visualization of the STN on 1.5T magnetic resonance imaging.  We have placed over 70 electrodes to date performing the implantation surgery inside an MRI scanner with very good results.

We have also recently participated in two gene therapy trials for Parkinson’s disease, and are in the planning stages for several more.  Although exciting, these are studies are highly experimental and far from standard surgical treatment.

JE: Can you comment on strengths and weaknesses of these approaches?

PL: Traditional DBS surgery has a very proven track record and has been performed in tens of thousands of patients with excellent results and low complication rates.  However, it does have limitations and challenges.  It uses a skull-mounted frame and requires an awake, cooperative patient who must be off of their Parkinson’s medications during surgery.  The process of microelectrode recording is time consuming and technically demanding, and typically involves multiple penetration of the brain to “map” the target region to ensure proper electrode placement.  Even with all of this, the surgeon cannot be absolutely certain the electrode is properly placed until the patient has brain imaging after surgery with either CT or MRI.

Interventional MRI (iMRI) DBS surgery can overcome some of these challenges.  Because the surgeon can see the brain target directly on the MRI images throughout the surgery, there is no need to perform microelectrode recording.  This means the patient can be under general anesthesia, does not have to undergo multiple brain penetrations and can take their medications the morning of surgery.  No skull-mounted frame is required.  The implantation procedure takes about half the time of a traditional implantation, and the team can see that the electrode position is adequate before the surgery is completed.  However, the procedure does require specialized surgical instrumentation that is safe for the MRI environment, and does require the surgical team to alter their usual practices fairly significantly.

Gene therapy has promise as a potentially restorative or even disease progression altering treatment.  It has the advantage of not having the complications associated with implanted hardware such as skin erosion or infection, and does not require multiple visits to the neurologist after surgery for programming.  There are also no batteries that need to be replaced every few years.  However, gene transfer is still very much an investigational therapy, and although preliminary studies have shown it to be safe, its actual effectiveness has yet to be demonstrated.

JE:  You were a participating neurosurgeon in two recent gene therapy trials for PD, the Phase II Ceregene trial (Cere-120, AAV2- NTN) and the Phase I Genzyme trial (hAAV2-AADC), both of which used AAV2 vectors to deliver therapeutic genes to the putamen. The Ceregene trial yielded disappointing results by failing to meet its primary endpoint of  improvement in the UPDRS motor score at 12 months follow-up.  A  Phase II placebo-controlled trial for hAAV2-AADC is still in the planning stages. At this point in time it would seem that the jury is still out with respect to gene therapy for PD.  What do you see as the critical next steps for advancing the gene therapy field for PD and what are some of the potential pitfalls?

PL: Although the Phase II Ceregene trial was negative, I do not believe this is or should be the end of gene therapy.  The trials done to date have shown that the AAV vector can successfully transfer genes of interest to the human brain, that the genes do turn “on” and produce the desired proteins, and that the technique appears to be quite safe.  Much still needs to be learned however, including what the effective “dose” is for the specific genes being transferred, what area or areas of the brain should be targeted, and what delivery method is best.  I am a surgeon and so admittedly tend to focus on delivery technique, but I think making sure we adequately transfer enough vector to the intended target and spread vector evenly throughout that target is a critical issue.  We are not sure why Phase II Ceregene was negative, but one distinct possibility is that we did not cover the putamen adequately enough and/or evenly enough.  The method of infusion is also critical – there is good work showing that convection enhanced delivery, an infusion method that allows even, widespread and atraumatic delivery of viral vector, may be superior to other injection methods.  Finally, adequate confidence or confirmation of the actual brain volume infused with vector needs to be achieved.  Even if a transferred gene is biologically successful at the cellular level, the therapy as a whole will fail if the gene is not delivered adequately and to the right location.  Interventional MRI may play a role in this, as it would allow real-time visualization of the infusion while it is occurring; this has been done in animal gene therapy infusion studies at our institution for years now.

JE:  Do you have any safety concerns with the use of unregulated viral vectors for gene delivery to the CNS?

PL: No.  If we did, we certainly would not have participated in the trials that we have so far.  In the Genzyme trial, the enzyme that is produced by the gene (AADC) acts on peripherally administered levodopa, so that system can be “regulated” in essence by limiting how much levodopa the patient takes.  The growth factors such as Neurturin in the Ceregene trial cannot be regulated, but the pre-clinical animal studies have demonstrated a very convincing safety profile, and this has been borne out in the human subjects treated to date.