Although the principle of delivering genes to a cell and repairing a defect in a metabolic pathway has been demonstrated in vitro, translating this basic finding into providing life-long correction to patients with genetic diseases has proven to be extremely difficult. Alternatively, transient correction could prove therapeutic if the regimen could be administered repeatedly. In both cases, it is necessary to avoid detection by the immune system, which recognizes the viral and sometimes the therapeutic protein as foreign, extinguishing their expression and producing antibodies, which interfere with readministration. The initial attempts at gene therapy for genetic metabolic diseases have revealed basic gaps in our knowledge on the mechanisms of vector entry, gene expression and immune surveillance. The vectors currently under investigation have a variety of properties that may be useful for some gene therapy applications.
Retroviruses can transduce dividing cells and provide long-term expression but at low frequencies.
Lipoplexes have provided mostly transient expression but may be amenable to strategies for targeted delivery and for evading the immune system. Clearly, more work is needed to explore novel methods and novel combinations to develop regimens for long-term gene correction for genetic metabolic diseases. Delivery of genes to treat brain disorders poses unique problems. Direct administration of vectors into the brain may cause problems associated with cytotoxicity and physical tissue damages. NIMH supports research on delivery methodologies to target brain regions and nuclei that regulate cortical development and plasticity, emotion, cognition, memory, and behavior.