01. Gene therapy Boulikas.pdf - Gene therapy & Molecular Biology

instead, candidate genes in the 4q21-q23 region include
alcohol dehydrogenase, formaldehyde dehydrogenase,
synuclein, and UDP-N-acetylglycosamine
phosphotransferase (Polymero-poulos et al, 1996).
A mutation was identified in the α-synuclein gene,
which codes for a presynaptic protein thought to be
involved in neuronal plasticity, in the Italian kindred with
autosomal dominant inheritance for the PD phenotype
(Polymeropoulos et al, 1997). The missense mutation in
the α-synuclein gene suggested that at least some fraction
of familial PD with diffuse Lewy bodies is the result of an
abnormal protein that interferes with normal protein
degradation leading to the development of inclusions and
ultimately neuronal cell death. Furthermore, a peptide
fragment of α-synuclein is known to be a constituent of
Alzheimer's disease plaques; there may be common
pathogenetic mechanisms involved in α-synuclein
mutations in PD and β-amyloid and presenilin gene
mutations in Alzheimer's disease (Nussbaum and
Polymeropoulos, 1997).
D. Gene and cell therapy for PD
1. Grafting of dopamine neurons
Transplantation of human embryonic dopamine
neurons have been performed on patients with Parkinson's
disease but the amelioration of the symptoms is transient;
Boulikas: An overview on gene therapy
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death of therapeutic cells was thought to arise from
hypoxia, oxidative stress, and trauma during preparation
and grafting of the cells. Grafting of dopamine neurons
into transgenic mice overexpressing the Cu/Zn superoxide
dismutase increased 4-fold the survival of the transplanted
cells providing a direct support to the free radicalmediated
death of dopaminergic neurons in brain tissue
grafts (Nakao et al, 1995).
Cells transduced with tyrosine hydroxylase and GTP
cyclohydrolase I were grafted alone or in combination
with cells transduced with aromatic L-amino acid
decarboxylase into the 6-hydroxydopamine-denervated rat
striatum; it was concluded that there is sufficient aromatic
L-amino acid decarboxylase near striatal grafts producing
L-DOPA and that the close proximity of L-amino acid
decarboxylase to TH-producing cells is detrimental for
optimal dopamine production (Wachtel et al, 1997).
2. Tyrosine hydroxylase (TH)
Since adult brain cells are nonproliferative, they are
refractory to retroviral infection that could deliver the TH
gene to the brain to alleviate degeneration at the
nigrostriatal pathway. Gene therapy of PD has been
approached ex vivo using PD animal models with TH
deficiency. Unilateral destruction of dopaminergic
nigrostriatal neurons in PD animal models with 6hydroxydopamine
and administration of apomorphine
causes PD rats to turn contralaterally (7-15 rotations/min).