Surgical Delivery of Therapeutics

There are a number of gene therapy clinical trials being conducted for PD.

A study supported by Neurologix involves treatment with AAV-GAD, a biosynthetic enzyme for GABA, with the goal of providing symptomatic relief. A third clinical study focuses on delivery of AADC, a biosynthetic enzyme for dopamine. These phase I clinical studies have not reported any significant adverse events, to date, suggesting that gene therapy may be a viable approach for PD.

Clinical trials for the trophic factor GDNF have utilized direct brain infusion technologies. These studies have resulted in ambiguous results as to the efficacy of GDNF as the success of the delivery of the molecule to the target brain regions remains uncertain. The Cere-120 study, funded by Ceregene, Inc, involves injection of the gene for the trophic factor Neurturin into the putamen.

After two decades of painstaking work, pressure-driven infusion is emerging as drug delivery method of choice for introducing substances with large molecules into the brain parenchyma.  Some half a dozen trials involving infusion of Parkinson’s-related substances have taken place in the last few years with more being planned in the near future.

Some of these trials are safety trials; others are aimed at establishing efficacy.  Following standard protocols, the efficacy trials are double blind and compare the infused substance with a placebo. Placebo in this case is a sham surgery in which holes are drilled into the skulls of trial participants without introducing any drugs.

 I wonder how necessary this method is.  Wouldn’t one such placebo trial be sufficient to establish the extent to which a placebo effect takes place in all similar circumstances?

Figure 1 Outcome of sham surgeriesFigure 1 shows data from the sham surgeries of three different surgical trials.  In two of these, burr holes were drilled in the patients’ skulls without breaking through the dura.  In the third, the holes were completed and a cannula was introduced but only saline solution was pumped into the patients’ brains.

The three sham trials produced very similar outcomes.  This should not be surprising:  in all of these cases, the surgeries were similar and the patients had reason to hope for a good outcome. 

Figure 2 Outcome of Phase I infusion trials compared to the sham surgeries of Figure 1.Figure 2 shows the outcomes of five different open label trials along with the placebo results of Figure 1.  The open label trials had no controls.  They were only intended to establish that the procedures and the substances in question were safe.  Each of these trials followed extensive pre-clinical studies which gave reason for high expectations.  The comparison of these open label trials to the sham results indeed suggests marked improvement. 

Pressure-driven infusion, combined with accurate stereotaxic placement of cannulas, proper control of the flow of the infusate and confirmation with interoperative MRI may emerge in the near future as the standard method for delivering substances involving large molecules.  Consequently, this may be a good time to think through how we can redesign such trials so they don’t bring with them a corresponding explosion in the number of sham surgeries.

To be sure, we rely on the reproducibility of the results of the sham surgeries.  Figure 1 supports this.  (If the results of a sham surgery cannot be reproduced, why would infusions of the drug be reproducible?)  Another issue is the natural optimism of the investigators which can cast doubt on the rating of clinical results.  This can be addressed either by having the clinical rating be performed by third party clinicians and/or by the incorporation of objective measurement techniques which have been developed in the last few years, and may be ready for use. 

As infusion enters mainstream use, we should avoid institutionalizing the practice of drilling sham holes just because it has been the practice in the past.  Such a reexamination would also allow us to focus early on the question, which of the competing infused substances is most effective – an issue we have to deal with urgently, as suggested by Figure 2.

References in press:  

Christine CW, et al., Safety and tolerability of putaminal gene therapy for Parkinson’s disease, Neurology, In Press, 2009