Artificial cells as a novel approach to gene therapy - Artificial Cells, Cell Engineering and Therapy - page 258

Microencapsulation
As an alternative to the above gene therapy strategies, -glucuronidase-secreting
fibroblasts enclosed in alginate microcapsules were implanted into mutant MPS
VII mice. After 24 h, -glucuronidase activity was detected in the plasma,
reaching 66% of physiological levels by 2 weeks post-implantation. Significant
-glucuronidase activity was detected in the liver and spleen for the duration of
the 8-week experiment. Concomitantly, the intralysosomal accumulation of
undegraded glycosaminoglycans was dramatically reduced in liver and spleen
tissues and urinary glycosaminoglycan content was reduced to normal levels.
Secondary elevation of the lysosomal enzymes -hexosaminidase and -
galactosidase were also reduced. However, implanted mutant MPS VII mice
developed antibodies against the murine -glucuronidase as observed in other
methods of ERT. When the antibody response was transiently circumvented
with a single treatment of purified anti-CD4 antibody co-administered with the
microcapsules, both levels and duration of -glucuronidase delivery were
increased. This is the proof-of-principle that cell-based therapy via micro-
encapsulation is a feasible alternative to traditional gene therapy (Ross et al.,
2000a).
Similarly, when these -glucuronidase-producing microencapsules were
directly implanted into the ventricles of the mutant mouse, -glucuronidase
was delivered throughout most of the CNS, reversing the pathology and reducing
the previously elevated levels of lysosomal enzymes -hexosaminidase and -
galactosidase, surrogate measures of efficacy. The effectiveness of this approach
was further demonstrated with improvements in the mutant circadian rhythm
behavioral abnormalities. The grooming and circadian disruptions characteristic
of the mutants were all significantly improved, and further behavioural deteriora-
tion was arrested. Hence, this alternative cell-based gene therapy demonstrates
biochemical, histological and behavioral efficacy and provides a potentially cost-
effective and nonviral treatment applicable to all lysosomal storage diseases with
neurological deficits (Ross et al., 2000b).
10.5 Cancer gene therapy ± an expansion from
Mendelian disorders
Applications of artificial cells in gene therapy are well suited to treat simple
disorders that require a single therapeutic product for replacement. This is par-
ticularly relevant to Mendelian disorders described above that require product
replacement for a prolonged period. Cancer, however, is a more complex
multifactorial disease. Its etiology is variable and it can be mediated through
many possible molecular mechanisms. Thus, it is not possible to engineer a
single product replacement to treat all types of cancers, or even to treat all cases
of the same type of cancer.