53rd Annual Meeting of the American Academy of Neurology
May 2 - 6, 2001, Philadelphia, Pennsylvania
Treatment of Huntington's Disease - Pietro Mazzoni MD, PhD
One of the most exciting findings in the field of HD treatment was
a report from last year that suggested the possibility of arresting and perhaps even reversing the neurodegeneration
caused by this disease. Yamamoto and colleagues studied a transgenic mouse model of HD. They inserted the gene
with the HD mutation into the mouse's genome and made the expression of this gene dependent on a drug. Thus, when the mice
are given a specific drug (in this case, tetracycline or doxycycline), the gene is not expressed. Without this drug, this
gene is expressed. This experimental system (referred to as a "conditional" transgenic mouse model) allows the comparison,
in the same animal, between having and not having the HD mutation.
In their initial study, these investigators found that,
as expected, turning the gene on produced degeneration of neurons in the mice's striatum, as occurs in people with HD. The
amazing finding was that if the gene was subsequently turned off, the progression of the neurodegeneration appeared not only
to stop, but also to partly reverse itself. This finding raised hopes that interfering with the abnormal HD gene in people
could some day affect the course of their disease for the better.
At this year's meeting, the group from Messina, Italy, and New York
City bolstered the expectation that we may in the future be able to treat HD itself, and not only its symptoms. Arancio and
associates studied the strength of connections between cells in the brains of mice with the conditionally expressed
HD mutation. The strength of these connections is known to increase when the connected cells are active at the same time.
This strengthening, known as long-term potentiation (LTP), is likely one of the fundamental components of the biological substrate
of learning and memory. The researchers found that LTP is impaired when the HD mutation is turned on, and that this impairment
disappears when the mutated gene is turned off. The impairment in LTP may be part of the reason why HD patients develop cognitive
deficits. If this is the case, then the fact that the LTP impairment can disappear when the gene mutation is blocked strengthens
the hope that reversing HD may be possible. Based on these studies, therapies should be aimed at blocking the expression of
the mutated HD gene, or interfering with the action of this gene's product (a protein known as "huntingtin").
Another study, described by Kieburtz, from Rochester, NY,
was also aimed at affecting the course of HD. Because creatine has been shown to prolong survival in transgenic
mice with the HD mutation, the Huntington's Study Group began a double-blind placebo-controlled study to examine the effect
of 2 doses of creatine on HD patients. The investigators reported that the drug was tolerated and safe in 50 patients with
HD. This was a step forward in the evaluation of this treatment for HD. The study is ongoing, and whether creatine has any
beneficial effect on HD is still unknown.
14. Yamamoto A, Lucas JJ, Hen R. Reversal of neuropathology
and motor dysfunction in a conditional model of Huntington's disease. Cell. 2000;101:57-66.
15. Arancio O, Battaglia F, Yamamoto A, et al. Reversal
of synaptic plasticity impairment in a conditional model of Huntington's disease. Program and abstracts of the 53rd Annual
Meeting of the American Academy of Neurology; May 5-11, 2001; Philadelphia, Pennsylvania. Neurology. 2001;56(suppl 3):A385.
16. Kieburtz K, for the Huntington Study Group. Placebo-controlled
trial of creatine in Huntington's disease. Program and abstracts of the 53rd Annual Meeting of the American Academy of Neurology;
May 5-11, 2001; Philadelphia, Pennsylvania. Neurology. 2001;56(suppl 3):A386. Abstract S49.004.