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Neurological Review
April 2008

Gene-Targeted Therapies for the Central Nervous System

Author Affiliations

Author Affiliations:Neurosciences Department, University of California, San Diego, San Diego (Dr Miller); Ludwig Institute for Cancer Research, La Jolla, California (Drs Miller and Kordasiewicz); Center for Neurologic Study, La Jolla, California (Dr Smith); and Columbus Children's Research Institute and Ohio State University, Columbus (Dr Kaspar). Dr Miller is now with the Department of Neurology, Washington University School of Medicine, St Louis, Missouri.



Arch Neurol. 2008;65(4):447-451. doi:10.1001/archneur.65.4.nnr70007

The identification of the genes and proteins involved in many neurodegenerative diseases1offers the exciting possibility of modifying those disease-linked proteins to develop novel, targeted therapies for diseases such as amyotrophic lateral sclerosis (ALS) or Huntington disease. In many of these diseases, the simplest modification—decreasing the amount of the offending protein—may represent a potent therapy. This realization, coupled with great strides in the techniques for decreasing specific proteins, has set the stage for moving these new therapies from animal models to clinical trials in the near future.

Multiple methods are currently being studied for their ability to decrease levels of unwanted proteins, including immunization strategies, small molecules, RNA interference (RNAi), and antisense oligonucleotides. Immunization strategies were an early favorite for clearing proteins from the central nervous system (CNS), with impressive results in Alzheimer disease mouse models, in which active immunization with amyloid-β peptide led to a decrease in the age-dependent amyloid-β deposition.2One appeal of this strategy is a long medical practice of immunizations in humans. Based on these promising results in mice, a clinical trial in patients with Alzheimer disease was launched. However, the development of meningoencephalitis in 6% of the patients stopped the phase 2 trial.3The strategy itself remains feasible; perhaps passive immunization may prove similarly effective while avoiding a T-cell response, allowing for the control of antibody levels and the ability to stop treatment. More careful antigen selection may also help eliminate T-cell epitopes. A similar immunization strategy for a superoxide dismutase 1 (SOD1) ALS model delayed disease.4