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4.10 Encapsulated Xenogeneic Choroid Plexus
Transplants for Huntington's Disease Therapy
Huntington's disease is a devastating, autosomal-dominant neurodegenerative dis-
order characterized by an intractable course of mental deterioration and progressive
motor abnormalities that invariably results in death. There are no effective treatments.
Unlike many other neurodegenerative diseases, the polyglutamine expression in HD
permits an unequivocal diagnosis of HD early in life, even in utero . The ability to
identify presymptomatic individuals provides the opportunity to design interventions
that could be applied before the development of substantial neurodegeneration and
expression of the behavioral changes. Accordingly, the neuronal cytoarchitecture and
physiology of the striatum could be maintained or preserved, while forestalling the
debilitating consequences of the disease.
To determine if CP transplants have therapeutic potential in HD, neonatal por-
cine CP was encapsulated within alginate microcapsules and tested for its neuro-
protective potential in a rat model of HD [5] . In these studies, the animals received
stereotaxic transplants of either empty capsules or CP-loaded capsules directly into
the striatum. Three days later, the same animals received unilateral injections of the
excitotoxin quinolinic acid (QA; 225 nmol) into the ipsilateral striatum. After surg-
ery, transplanted animals gained body weight more rapidly than controls. After sur-
gery, animals were also behaviorally tested for function of their forepaws, using the
placement test. When given 10 trials on the behavioral test, the control rats were able
to make only 1-2 directed motor responses. In stark contrast, the rats receiving CP
transplants were virtually indistinguishable from normal animals on this task, as they
made greater than 9 out of 10 correct responses. Nissl-stained sections further dem-
onstrated that CP transplants significantly reduced (by more than 80%) the volume
of the striatal lesion produced by QA.
Based on the benefits of CP transplants in the QA rodent model of HD, a simi-
lar experiment was conducted using young adult cynomolgus monkeys [3] . Using
stereotaxic techniques, 20 cell-loaded capsules were loaded into a cannula and
implanted into the head of the caudate and the right putamen. A total of four mon-
keys received cell-loaded implants; three monkeys served as controls and received
implants of empty capsules. Seven days following capsule implantation, each mon-
key received an injection of QA (5 l for a total of 900 nmol of QA) approximately
2 mm posterior to the previous implant site. All monkeys were sacrificed four weeks
after the QA lesion. The brains were removed and frozen sections (40 m) were cut
on a sliding microtome. A mouse anti-neuronal nuclei (NeuN) monoclonal antibody
was used to label striatal neurons for determination of striatal cell counts and lesion
volumes. The number of NeuN immunoreactive (NeuN-ir) neurons within the cau-
date and putamen nuclei was estimated stereologically using an optical fractionator
unbiased sampling design. The volume of intact striatum was also estimated on a
series of equispaced NeuN-ir sections along the striatum.
The histological results paralleled those observed in the previously described
rodent studies. In controls (animals receiving QA and empty capsule implants), QA
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