Most people would associate the idea of a vaccination primarily with protection from infectious diseases, but the immune system is much more of a multitasker.
Cancer is just one other disease in which the immune system plays an active role. And researchers have been working on the idea of using the immune system to help clear proteins that accumulate and/or misfold. In the June 16, 2005, issue of Neuron, researchers from Dublin, Ireland-based Elan Corp. plc and the University of California at San Diego demonstrate that vaccination can be effective in reducing the accumulation of a mutant protein, alpha-synuclein, in a mouse model of Parkinson's disease.
"The quick answer is no one is quite sure," said Dale Schenk, senior vice president of discovery research at Elan, when asked about the normal function of alpha-synuclein. In knockout animals, as Schenk's collaborator Eliezer Masliah from UCSD has demonstrated, "you can remove it and the mice seem to have almost no effects."
One thing alpha-synuclein apparently can do, though, is give you Parkinson's; genetic mutations in the alpha-synuclein gene, through a combination of overproduction and misfolding, lead to the accumulation of alpha-synuclein in so-called Lewy bodies.
In a separate paper published in the June 17, 2005, issue of the Journal of Biological Chemistry, researchers from the University of Texas Southwestern Medical Center in Dallas and the University of Pennsylvania in Philadelphia describe the biochemical mechanisms of that clumping. Some mutations of alpha-synuclein can lead to the abnormal cutting of the protein when it is slated for degradation. The abnormally cut fragments, in turn, promote further clustering of both abnormally clustered fragments and normal full-length proteins, in what the authors term "a vicious cycle of cytotoxicity."
Parkinson's disease is one example of Lewy body disease; another example is Alzheimer's. Though Alzheimer's and Parkinson's, as well as Huntington's and mad cow disease - two more diseases caused by protein misfolding - are neurodegenerative, the utility of enlisting the immune system to clear misfolded proteins theoretically is not limited to brain disease. "Neurons, for one reason or another, tend to accumulate proteins - probably because they don't degenerate," Schenk said. But the immunization against such accumulation is applicable to other diseases as well.
Schenk is lead author on the Neuron study, which is co-authored by researchers from Elan and UCSD, showing that vaccination can be an effective countermeasure to synuclein's deleterious effects.
The authors first vaccinated mice that were transgenic for human alpha-synuclein with repeated administrations of alpha-synuclein over the course of eight months. One lucky feature of mutant alpha-synuclein, at least from a drug development standpoint, is that while regular alpha-synuclein is located inside the cell, the mutant protein will move to the cell surface, where it is preferentially accessible to antibodies.
Transgenic mice, but not normal control mice, showed antibody responses to alpha-synuclein in response to such vaccination, with the strength of the antibody affinity strongly correlated with its effectiveness in reducing neuropathology in the transgenics. Immunized mice accumulated less alpha-synuclein in their nerve terminals.
Further experiments showed that while the alpha-synuclein antibodies first bind to the mutant alpha-synuclein on the neuronal surface, they quickly are taken up into the interior of the cell, where they are degraded.
One risk of immunizing against an endogenous protein is that of an autoimmune response, though Schenk noted that the immune system itself has multiple checks and balances to ensure that an immune response does not go "into the red zone."
Nevertheless, the researchers currently are testing whether passive immunization, or the administration of antibodies, might also be effective against the accumulation of alpha-synuclein. Given the wide variation in antibody affinity, and therapy effectiveness, that the scientists observed after immunization with alpha-synuclein itself, such immunization might also be more uniformly successful; in the Neuron paper, the success of the vaccination approach varied strongly depending on the exact epitope that the antibodies recognized.
Whether via active immunization or antibody therapy, the clinical development prospects of the approach currently are unclear. "Of course, when you have promising results like this, you at least consider clinical development," Schenk said. But no decision on how and whether to proceed has been made yet.