Genetic Engineering and Gene Therapy

As an early effort at what might be regarded as "genetic engineering" in the mid 70's, Richard Mullen of the Neuroscience Program of the IDDRC developed the skill of combining eight-cell-stage rodent embryos from genetically normal and abnormal individuals to produce surviving chimeras (Science, 1976;  Nature, 1977). This approach was applied to the study of animals with neurological abnormalities, one with retinal degeneration and visual disturbance, and the other, with cerebellar Purkinje cell degeneration and clinical ataxia. In both instances, the clinical disorder was ameliorated in the chimera. The principal value of the experiment was the resulting ability to analyze the cellular abnormality.

An early effective effort at gene therapy evolved as a collaborative project between investigators of this IDDRC and the California Institute of Technology. Thus, Readhead et al. (Cell, 1987) described the first successful use of gene transfer to treat a neurological disorder, i.e., the Shiverer mouse, which has an inherited deficiency of myelin basic protein causing tremor and death. Gene transfer was accomplished by inserting the normal myelin basic protein gene into mouse embryos. Crossbreeding of mice with the incorporated gene with Shiverer mice was successful in introducing the myelin basic protein gene into the offspring. This gene repaired the myelin deficiency, and those animals who had two copies of the gene were asymptomatic, while those with one copy showed partial benefit. This work forms some of the roots of the existing studies in gene therapy using immortalized cells and viral vectors to correct both developmental deficits and neurogenetic and neuroendocrine disorders (Kunkel, Mulligan, Macklis, Geller and Snyder).