A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

94 CELL-BASED AND RECOMBINANT DNA THERAPIES
Table 16.3: Licensed monoclonal antibodies (examples)
Monoclonal antibody Mode of action Indication
Abciximab Inhibits glycoprotein IIb/IIIa, platelet Angioplasty
aggregation
Omalizumab Anti-IgE Prophylaxis of severe allergic asthma
Infliximab, Adalimumab Anti-TNFα Rheumatoid arthritis, psoriatic arthritis
Basiliximab, Daclizumab Bind to IL-2Rα receptor on T cells, prevent Prophylaxis of acute rejection in
T-cell proliferation, causing
allogenic renal transplantation
immunosuppression
Bevacizumab (Avastin®) Inhibits vascular endothelial growth factor Metastatic colorectal cancer
(VEGF), hence inhibits angiogenesis
Pegaptanib and ranibizumab lnhibit VEGF Neovascular age-related macular
degeneration
Effect
100
80
60
40
20
MABEL
GENE THERAPY
Therapeutic
range
Unacceptable
toxicity
0
10 100 1000 10000
Dose or exposure
Figure 16.1: Explanation of minimum anticipated biological
effect level (MABEL) (kindly provided by P Lloyd, Novartis, Basel,
Switzerland). Unbroken line, desired effect; dashed line,
undesired effect.
The increasing potential to exploit advances in genetics and
biotechnology raises the possibility of prevention by gene
therapy both of some relatively common diseases which are
currently reliant on symptomatic drug therapy, and of genetic
disorders for which there is currently no satisfactory treatment,
let alone cure.
Gene therapy is the deliberate insertion of genes into
human cells for therapeutic purposes. Potentially, gene therapy
may involve the deliberate modification of the genetic
material of either somatic or germ-line cells. Germ-line
genotherapy by the introduction of a normal gene and/or
deletion of the abnormal gene in germ cells (sperm, egg or
zygote) has the potential to correct the genetic defect in many
devastating inherited diseases and to be subsequently transmitted
in Mendelian fashion from one generation to the next.
Table 16.4: Prevalence of some genetic disorders which result from a defect
in a single gene
Disorder
Familial hypercholesterolaemia 1 in 500
Polycystic kidney disease 1 in 1250
Cystic fibrosis 1 in 2000
Huntington’s chorea 1 in 2500
Hereditary spherocytosis 1 in 5000
Duchenne muscular dystrophy 1 in 7000
Haemophilia 1 in 10 000
Phenylketonuria 1 in 12 000
Estimated prevalence
The prevalence figures for inherited diseases in which a single
gene is the major factor are listed in Table 16.4. However,
germ-line gene therapy is prohibited at present because of the
unknown possible consequences and hazards, not only to the
individual but also to future generations. Thus, currently,
gene therapy only involves the introduction of genes into
human somatic cells. Whereas gene therapy research was initially
mainly directed at single-gene disorders, most of the
research currently in progress is on malignant disease. Gene
therapy trials in cancer usually involve destruction of tumour
cells by the insertion of a gene that causes protein expression
that induces an immune response against those cells, or by the
introduction of ‘suicide genes’ into tumour cells.
Cystic fibrosis (CF) is the most common life-shortening
autosomal-recessive disease in Europeans. It is caused by a
mutation in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene. Over 600 different CF mutations
have been recognized, although one mutation (F508) is present
on over 70% of CF chromosomes. Phase I studies using
adenoviral or liposomal vectors to deliver the normal CFTR
gene to the airway epithelium have shown that gene transfer
is feasible, but with current methods is only transient in