A Textbook of Clinical Pharmacology and Therapeutics

94 CELL-BASED AND RECOMBINANTDNATHERAPIES

Table 16.4:Prevalence of some genetic disorders which result from a defect

in a single gene

Disorder Estimated prevalence

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

GENE THERAPY

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 treat-
ment, let alone cure.
Gene therapy is the deliberate insertion of genes into
human cells for therapeutic purposes. Potentially, gene ther-
apy 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 trans-
mitted in Mendelian fashion from one generation to the next.

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 ini-

tially 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 pres-

ent 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

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-2Rαreceptor 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

100

MABEL

Therapeutic

range

Dose or exposure

Unacceptable

toxicity

80

60

Effect 40

20

0

10 100 1000 10000

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.