The conquest of Wilson's disease.

When (Samuel Alexander) Kinnier Wilson described a new disease involving the liver and the lenticular nucleus of the brain in 1912, he was unable to recommend any form of treatment, although that remained his life long ambition (Wilson, 1912; Fig. 1). Until the underlying cause of the disease was understood, this inevitably remained a somewhat forlorn hope. A role for copper, as a possible pathogenic agent, was suggested the year after Wilson’s original publication when Rumpel (1913) reported finding excess copper in the liver of a patient who had died of this newly described disease. But this observation was not followed until, in 1948, (John) Cumings (1948) demonstrated that copper is present in excess both in the brain and liver of patients with Wilson’s disease. This observation led Cumings to suggest that treatment with the newly developed chelating agent British antilewisite (Dimercaprol) might arrest the progress of the disease. It is generally held, not unreasonably, that all major advances in therapeutics are made by the multi-national pharmaceutical companies. There are, however, a few exceptions to this rule as illustrated in ‘Orphan Drugs’ by Fred Karch (1982). Accounts of seven attempts to introduce new drugs, discovered by individual research workers, are presented here. There is, therefore, still a role for the individual researcher to make significant advances, although these are likely to remain confined to the treatment of rare diseases. The large pharmaceutical companies will, by the very nature of free market economics, confine their research and development programmes to common diseases offering the prospect of large profits. The cost of introducing a new drug is now so large—an average figure as high as 800 million dollars has recently been suggested—that no other course is possible. Wilson’s disease illustrates this state of affairs. All treatments now available were introduced as a result of individual or small team research. The story did not begin in 1948 when Cumings suggested that treatment with Dimercaprol might arrest the course of Wilson’s disease by eliminating copper from the body. When World War II started in 1939 it was feared that Hitler would attack the British Isles with the arsenical war gas ‘lewisite’ and a team of workers in Oxford, under the direction of Sir Rudolph Peters, Professor of Biochemistry, started the search for an antidote, publishing the results of this work in 1945 (Peters and Stocken, 1945). The molecule they designed, dimercaptopropanol, was a short-chain alcohol with two substituted sulphydryl (–SH) groups. These gave dimercaptopropanol the ability to bind arsenic in a tight five-membered ring, rendering it non-toxic. This compound later became known as British antilewisite (BAL). It was BAL that Cumings hypothesized might arrest the progress of Wilson’s disease. Four years later Cumings (1951), in London, and Denny Brown and Porter (1951), working independently at the Boston City Hospital, reported favourably on this form of treatment. Whilst this represented a significant advance in the treatment of Wilson’s disease, it soon became apparent that repeated courses of BAL had a decreasing effect and were also associated with a high incidence of toxic reactions, besides being painful through having to be administered by deep intramuscular injection. Thus, whilst a very significant advance in the management of Wilson’s disease, BAL was clearly not the final answer. Research into Wilson’s disease really took off in the early 1950s. Working separately, Bearn and Kunkel (1952) and Scheinberg and Gitlin (1952) reported a deficiency or absence of the serum copper carrying protein, caeruloplasmin, in patients with Wilson’s disease, although the exact significance of this has never become apparent (Fig. 2). At the same time a number of attempts to improve treatment were made using high protein diets, steroids and the chelating agent ethylenediamine tetraacetic acid. None of these proved beneficial. doi:10.1093/brain/awp149 Brain 2009: 132; 2289–2295 | 2289