Nucleic-acid- and cell-based therapeutics - Pharmaceutical Biotechnology: Concepts and Aapplications - page 422

Table 14.1 Some diseases for which gene-based therapeutic approaches are
currently being appraised in clinical trials. Many of these examples are discussed
in more detail later in this chapter.

Cancer, various forms AIDS

Cystic fi brosis Haemophilia

Familial hyper-cholesterolaemia Severe combined immunodefi ciency

diseases (SCID)

Gaucher's disease α 1 -antitrypsin defi ciency

Purine nucleoside phosphorylase defi ciency CGD

Rheumatoid arthritis Peripheral vascular disease

An increased understanding of the molecular basis of various other diseases, including cancer,
some infectious diseases (e.g. AIDS) and some neurological conditions, also suggests a role for
gene therapy in combating these. Indeed two-thirds of all gene therapy trials conducted to date
aim to treat cancer. Table 14.1 lists the major disease types for which a gene therapy treatment is
currently being assessed in clinical trials. The fi rst such trial was initiated in the USA in 1989.
Thus far, some 1200 different clinical studies have/are being undertaken worldwide. The majority
(estimated at 67 per cent) have/are being undertaken in the USA, with most of the remaining trials
being undertaken in Europe (mainly in the UK and in Germany). The majority of trials (62 per
cent) are in early stage (phase I) and only some 2.2 per cent of all trials have reached phase III.
Despite the initial enthusiasm, only a handful of such studies have revealed a therapeutic benefi t
to the patient.
Moreover, gene therapy, like all other medical interventions, is not without associated risk. A
US patient died in 1999 as a result of participating in one such trial. Even more disturbingly, the
ensuing FDA investigation unearthed allegations that at least six other deaths attributed to clini-
cal trial treatments had gone unreported to the regulatory agency; and further, that only a fraction
of serious adverse effects had been reported. As a result, regulatory regulation and monitoring of
gene therapy trials has been increased. Further serious adverse effects, including some fatalities,
have been reported subsequently, as discussed later.
Such disappointing results do not refl ect any fl aw in the concept of gene therapy. They instead
refl ect the need to develop more effective technical means of accomplishing gene therapy in prac-
tice. These initial studies have highlighted the technical innovations required to achieve success-
ful gene transfer and expression. These, in turn, should render future ('second-generation') gene
therapy protocols more successful.

14.2.1 Basic approach to gene therapy

The basic approach to gene therapy is outlined in Figure 14.1. The desired gene must usually be
packaged into a vector system capable of delivering it safely inside the intended recipient cells.
A variety of vectors can be used to effect gene transfer. These include both viruses (particularly
retroviruses and adenoviruses) and non-viral carriers, such as plasmid-containing liposomes/
lipoplexes (Table 14.2 and Figure 14.2). Each such vector has its own unique set of advantages and
disadvantages, as discussed subsequently in this chapter.