Artificial cells as a novel approach to gene therapy - Artificial Cells, Cell Engineering and Therapy - page 249

We will examine two of these disorders in detail to highlight the important
concepts in artificial cell gene therapy, as well as the pitfalls. The disorders are:
hemophilia B and mucopolysaccharidosis type VII (Sly disease) ± both very
rare, single gene disorders. Hemophilia B is an X-linked recessive bleeding
disorder that results from defects in the gene for coagulation factor IX (FIX).
Patients with hemophilia B do not produce sufficient functional FIX, leading to
prolonged clotting times, chronic bleeding into the joints and the constant threat
of hemorrhage. In contrast, mucopolysaccharidosis type VII is an autosomal
recessive disorder caused by the deficiency of the lysosomal enzyme beta-
glucuronidase. Patients with this disorder cannot break down glycosamino-
glycans (mucopolysaccharides), which leads to storage of the material in the
lysosomes. The systemic effects of this deficiency include severe bone
malformations, enlarged organs and mental retardation.
10.4.1 Hemophilia
Disease biology and treatment technology: finding the right match
A number of factors make coagulation disorders such as hemophilia good
candidates for bioartificial cell gene therapy. First, the proteins exist and
operate in a very accessible part of the body, the intravascular space. Second,
the genes for these proteins have all been cloned and there is a significant body
of knowledge about their biochemistry. Significantly, there is no need for tight
regulation at the gene expression level, because most of these proteins circulate
as inactive precursors that become activated in response to other stimuli. Third,
there are animal models for some of these disorders, which are crucial to obtain
sufficient preclinical data to justify human trials. These factors make it possible
to undertake bioartificial cell gene therapy, but the burden of disease also
makes it desirable to find better treatment. Hemophilia B, for instance, affects
approximately 1 in 25 000 male births (Bell et al., 1995). Current treatment for
hemophilia B involves the delivery of either plasma derived or recombinant
FIX during acute bleeding episodes. Owing to the high cost of this form of
therapy, prophylactic treatment is often not economically feasible.
Consequently, arthropathy and potentially fatal internal hemorrhage remain
significant risks. Furthermore, the repeated delivery of replacement clotting
factors is inconvenient and costly over time. Hence, the development of gene
therapy offers a more promising and potentially curative approach to the
treatment of hemophilia.
The final factor that makes hemophilia B an ideal candidate for initial efforts
in artificial cell gene therapy is the current use of recombinant FIX as part of
standard therapy. Thus, the efficacy of the recombinant protein has already been
established. All that remains to be demonstrated is the artificial cell as a method
to deliver the recombinant protein.