Heaven help those perseverant souls who pursue translational research on neurodegnerative disorders. New interventions in this area have just about the highest failure rate of any area of medical research. And last week, yet another promising strategy was shown ineffective in a phase II study.
The trial in question was testing Ceregene’s gene transfer strategy against Parkinson’s Disease (PD). Ceregene was second out of the gate testing gene transfer against PD (the first was Neurologix). In April 2008, I wrote about their phase 1 study results, which on the one hand seemed to suggest safety, while on the other hand did not show signs of a dose-effect nor a change in dopamine metabolism by imaging. For me, the most troubling aspect of this protocol was its aggressiveness: researchers delivered vector along eight needle tracks to deep brain structures. Based on surgical complication rates in the published literature, the risk of causing permanent neurological deficits from cerebral hemorrhage was on the order of 7% in this study- and that’s not including the additional risk associated with the vector itself.
On November 26, Ceregene announced results of its sham controlled phase II study of CERE-120. First the good news: the press release described CERE-120 as “safe and well tolerated.” The bad news is that the investigators saw no difference in outcomes between the sham and active arms. The press release does not say whether any adverse events were reported; nor does it say anything about surgical complications. In the next few weeks, expect to see data on why, precisely, the strategy might have failed. (photo credit: bebob717 2006).
Chicago in plastic and balsa. If only animal models were as convincing as the one pictured above from the Museum of Science and Industry.
The August 7 issue of Nature ran a fascinating feature on how many scientists are reassessing the value of animal models used in neurodegenerative preclinical research (“Standard Model,” by Jim Schnabel).
The story centers on the striking failure to translate promising preclinical findings to treatments for various neurodegenerative diseases. In one instance, a highly promising drug, minocycline, actually worsened symptoms in patients with ALS. In other instances, impressive results in mice have not been reproducible. According to the article, a cluster of patient advocacy groups, including organizations like Prize4Life and a non-profit biotechnology company ALS TDI, are spearheading a critical look at standard preclinical models and methodologies.
Much of the report is about limitations of mouse models. Scientists from the Jackson Laboratories (perhaps the world’s largest supplier of research mice) warn that many mouse strains are genetically heterogenous; others develop new mutations on breeding. Other problems described in the article: infections that spread in mouse colonies, problems matching sex or litter membership in experimental and control groups, and small sample sizes. The result is Metallica-like levels of noise in preclinical studies. Combined with nonpublication of negative studies, and the result is many false positives.
The article bristles with interesting tidbits. One that struck me is the organizational challenges of changing the culture of model system use. According to the article, many academic researchers and grant referees have yet to warm to criticisms of models, and some scientists and advocates are asking for leadership from the NIH. Another striking point in the piece-alluded to in the article’s closing-is a fragmentation of animal models that mirrors personalized medicine.
“Drugs into bodies.” That’s the mantra of translational research. It is an understandable sentiment, but also pernicious if it means more poorly conceived experiments on dying patients. What is needed is a way to make animal models- and guidelines pertaining to them- as alluring as supermodels. (photo credit: Celikens 2008)