Cell-Specific Enhancer Domains for Neuronal Gene Expression

McLean Hospital
posted on 03/04/2009

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There is a great need for efficient promoter systems that can direct high level, long-term expression of therapeutic genes in a cell type-specific manner. Such systems would be extremely useful in various gene therapy approaches, because most gene therapy procedures to date have used viral or other nonregulated promoters that have resulted in transient and nonspecific expression in most cell types, even those in which expression was not necessarily desired. Cell-specific enhancers or promoters would particularly be of value in possible gene therapy approaches to diverse brain disorders, in particular neurodegenerative diseases such as Parkinson’s Disease.
Potential Commercial Uses: These inventions comprise novel nucleic acid constructs of enhancer elements that are capable of increasing gene expression by at least two orders of magnitude with respect to wild type gene expression. The first invention (MCL 180.0) comprises multiple copies of noradrenergic (NA) cell-specific enhancer domains isolated from the human dopamine-beta-hydroxylase (DBH) gene. These constructs increased minimal promoter activity by 100- to 200-fold in noradrenergic cell lines, and were shown to drive noradrenergic cell type-specific gene expression in animal brains using a stereotaxic injection procedure. Specific engineered modifications of these sequences can increase expression levels even higher. The second invention (MCL 1827.0) comprises multiple copies of dopaminergic (DA) cell-specific enhancer domains, that can increase minimal promoter activity at least 100-fold. These enhancer constructs can be used with any desired gene, for targeting their expression into the appropriate cell type, for implantation into the brain in a gene therapy protocol. The constructs should be most valuable for gene therapy of neurodegenerative diseases. In addition, the noradrenergic-specific enhancers could be useful for modulating gene expression of specific neurons that regulate cardiovascular/autonomic functions.
Patent Status: McLean Hospital is the owner of U.S. Patent Nos. 6,525,189, 7,037,715 and 7,585,962 claiming these inventions.
Licenses Available: McLean Hospital is offering a worldwide exclusive license to this technology, although we can consider licensing on a non-exclusive or exclusive-by-field basis.