Huntington’s Disease: Clinical Experimental Therapeutics

Excerpt

Successful treatment of a neurodegenerative disorder depends on three interdependent factors: (1) the “right” treatment candidates; (2) the ability to detect the therapeutic effects in an appropriate clinical population; and (3) clinically meaningful treatment effects. Each contribution is necessary but insufficient by itself to realize therapeutic gains and ultimately clinical benefits.

These issues are illustrated for hepatolenticular degeneration, or Wilson’s disease, which in 1911 was first recognized by Samuel Alexander Kinnier Wilson as a disorder that was familial, progressive, fatal, and associated with softening of the lenticular nucleus (pallidum and putamen) and cirrhosis. Hepatolenticular degeneration was linked in 1913 to an accumulation of hepatic copper and hypothesized in 1921 to be inherited in an autosomal recessive fashion. However, chelating therapy was not developed and reasoned to be an effective experimental treatment until 1948–1958. Coincidentally, the copper-binding protein ceruloplasmin was found to be deficient in individuals who inherited two copies of the gene responsible for Wilson’s disease. Experimental decoppering treatments would eventually be found to slow and even reverse neurological and hepatic deterioration in clinically affected individuals.

In the case of Wilson’s disease, the right treatment emerged from an incremental knowledge base and the rational understanding that copper accumulated in vital organs could be removed or prevented by effective and reasonably safe treatments. The therapeutic effects of decoppering therapy (2,3-dimercaptopropanol or British anti-Lewisite and later penicillamine) were of such large magnitude and relatively small variance that benefits could be detected in just a few patients without placebo controls.4 The clinical meaningfulness of penicillamine therapy became clear by 1968 when this intervention was demonstrated to prevent the onset of clinical features in premanifest individuals who had deficient ceruloplasmin, increased hepatic copper, and were presumed to carry the homozygotic genetic defect accounting for Wilson’s disease. Again, the treatment effects were sufficiently strong and uniform as to be convincing without placebo controls. As may occur with disease-modifying therapies, treatment may result in initial clinical worsening (as can be the case with penicillamine) before clinical improvement. Improvements in therapy would later ensue in the form of trientine and zinc treatments., Although success in the experimental therapeutics of Wilson’s disease seemed in retrospect to come in quantum scientific leaps, therapeutic benefits accrued slowly but steadily through incremental gains in clinical research. Interestingly, a molecular understanding of the genetic defects underlying Wilson’s disease only followed the development of successful treatment.

The clinical and hereditary aspects of Huntington’s disease (HD) were first described by George Huntington in 1872. It took nearly a century to unravel the relatively selective pattern of neuronal loss and gliosis and the associated neurochemical abnormalities that characterized the neurodegeneration of HD. In the 1980s and 1990s, studies of large and multiple families and the development and application of molecular genetic techniques led eventually to identification of the gene responsible for HD. In the past two decades, a remarkable and collaborative scientific inquiry has elucidated the key relationship of genetic dosage (CAG repeat length) to clinical features (age at onset), identified the mutant huntingtin protein, provided insights into the mechanisms underlying neuronal degeneration, and enabled the development of genetic animal models. The ability to detect premanifest HD in individuals who have inherited the mutant gene and its expanded CAG repeat has provided the opportunity to develop preventive therapies aimed at postponing or preventing the onset of illness.