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Genetically engineering and screening cell lines producing dopa/dopamine Parkinson’s
Disease (PD) is a degenerative disorder of the central nervous system,
where a loss of dopaminergic cells occurs in a region called the
substantia nigra. There are no current cures for the disease. The most
widely prescribed therapy is levodopa, or L-Dopa. L-Dopa, given over an
extended period of time has diminished clinical benefit and can result
in serious side effects, such as abnormal involuntary movements (AIMs).
Cell based delivery of dopa and/or dopamine has recently been evaluated
as an alternative therapy. Unfortunately, some side effects have been
reported. Some patients developed AIMs that may be related to the
uncontrolled release of dopamine from the transplants. The ability to
control the amount of dopamine produced by transplanted cells would be
an effective way to try and eliminate AIMs. We are currently engineering
cells to express tyrosine hydroxylase and/or dopa decarboxylase using a
regulatable genetic construct. Using the tetracycline-off system we have
engineered neuronal, astroglial, and oligodendrocytic cell lines. HPLC
analysis has shown that dopa is produced in several cell lines
engineered with TH. Additional engineering with DDC is expected to
produce dopaminergic cells. Our goal is to identify a cell line that has
high dopa and/or dopamine production and tight regulation and to
transplant these cells into a rat model of PD plus established AIMs. The
control of AIMs by controlled expression of the therapeutic molecule can
then be investigated. Support provided by: National Science Foundation - Research at Undergraduate Institutions Grant |
