Pompe's disease - RePub - Erasmus Universiteit Rotterdam

Chapter 1
the indirect approach can be taken, that is to transfect the cells ex vivo and transplant them
back into the body. These are the theoretical options. The widespread practical application is
hampered by the lack of versatile vectors and problems encountered in clinical studies. For
instance, the recent treatment of patients with the X-linked form of SCID (OMIM 300400) was
successful for some patients but others developed leukemia (46). A patient with Ornithine
transcarbamylase (OTC, OMIM 311250) defi ciency succumbed by exposure to an overdose of
adeno virus. The ideal vector for gene therapy has not yet been found. All viral vectors have
their limitations. Some elicit a restrictive immunologic response when they are used for the
second time. Others are potentially harmful when they incorporate into the host-cell DNA. For
these reasons non-viral vectors are also developed for the delivery of genes, and transfection
effi ciency enhancers are studied. But, this is still in an experimental stage. The HIV-1 TAT
protein regulating the transcriptional activation of HIV-1 has been shown to function as a
protein transduction domain, penetrating the cell membrane in a manner different from the
classical endocytotic route. The TAT peptide presents a nuclear localisation signal, which
enables nuclear targeting (47).
Enzyme replacement therapy
The idea to treat lysosomal storage disorders with intravenous enzyme administration was
brought up by de Duve shortly after the historic discovery of acid α-glucosidase defi ciency
in Pompe’s disease. He suggested that the therapeutic enzyme could possibly reach the
lysosome through heterophagy. The fi rst clinical attempt dates from 1964 and was performed
in a case of infantile Pompe’s disease with acid α-glucosidase from the fungus Apergilles Niger
(48, 49). The longest study by Hug et al. lasted 116 days (50). Initially there was an increase
in acid α-glucosidase activity in the liver of the patients but not in the skeletal muscle. The
patient then developed an immune nephritis as reaction to the foreign enzyme and eventually
died. Several studies followed whereby acid α-glucosidases of different sources were used.
Similar pioneering studies were also undertaken in other lysosomal storage disorders in the
years 1965-1980 (51-54) but none was successful enough to proof the feasibility of enzyme
replacement therapy. On the contrary it became clear that the therapy could not be used in
lysosomal storage disorders involving the brain as the corrective enzyme did not cross the
blood brain barrier (53). But, new insights in the role of cell surface receptors as effective
mediators of endocytosis kept the concept of enzyme replacement therapy alive. Especially the
discovery of the mannose and the mannose 6-phosphate receptors (21, 55) and the exchange
of lysosomal enzymes between cells in culture were important events (41, 56, 57). In 1989
a patient with Gauchers disease type I was the fi rst to benefi t from enzyme replacement
therapy. The therapeutic enzyme (glucocerebrosidase) was extracted from human placenta
and modifi ed so as to expose mannose residues (58, 59). They could serve as a ligand for the
mannose receptor to target the enzyme to the Kupfer cells and tissue macrophages that are
the major sites of storage in Gaucher’s disease.
In the same period, enzyme replacement for Fabry disease was developed. Single dose
studies proved that intravenously infused enzyme could decrease the level of accumulated
plasma Globotraiosylceramide. Phase I and II clinical trials proved the safety and effi cacy of
enzyme replacement therapy for both Gauchers and Fabry disease but further research has to
be conducted to optimize the therapy. In collaboration with the pharmaceutical industry both
medicines are now registered for the treatment of these two lysosomal storage disorders.
The development of ERT for other LSD’s like Niemann-Pick, Mucopolysaccharidosis type I and
Pompe’s disease is well on its way (60, 61).
1.4 Pompe’s disease
Pompe’s disease or Glycogen storage disease type II (GSDII, OMIM 232300) is an autosomal
recessive myopathy caused by mutations in the acid α-glucosidase gene. The resulting
total or partial defi ciency of lysosomal acid α-glucosidase causes glycogen to accumulate in
lysosomes (62). In 1932 the most severe phenotype was described by the Dutch pathologist,
Dr. J. C. Pompe, who reported about a girl of 7 months old with idiopathic hypertrophy of the
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