II-61Short invited lectures – abstracts
RIVASTIGMINE TREATMENT IN HUNTINGTON’S DISEASE –
COMPARISON OF CLINICAL RESPONSE AND GENE
EXPRESSION BIOMARKERS
Luca Lovrecic1, Jan Kobal2, Borut Peterlin1
1 Division of Medical Genetics, Department of Obstetrics and Gynecology, University Medical Center
Ljubljana, Slajmerjeva 3, Ljubljana, Slovenia
2 Department of Neurology, University Medical Centre, Zaloska 2, Ljubljana, Slovenia;
lucalovrecic@gmail.com
Background Huntington’s disease (HD) is a late-onset neurodegenerative disorder, inherited in an au-
tosomal dominant manner. The disease manifests at a mean age of 35 years and is fatal
after 15–20 years of progressive neurodegeneration. To date, no effective treatment to
cure the disease or to slow its progression has been found. Currently, the therapy is only
symptomatic, concentered on helping to handle some of the symptoms. On the other hand,
use of cholinesterase inhibitor rivastigmine has shown some minor improvements in cog-
nitive and motor functions in HD patients.1–3 Unfortunatelly, after the onset of HD when
disease progression is relatively slow, clinical rating scales like the Unified Huntington’s
Disease Rating Scale (UHDRS) and Total Functional Capacity (TFC), have high measure-
ment variability.4 Thus, both scales are insensitive to progression over short periods of time.
Moreover, the scales have limited ability to distinguish effects on disease progression from
symptomatic benefit. In addition, HD patients present with variable clinical phenotypes
and this makes direct comparative assessments using clinical scales difficult. Therefore,
there is a demanding need for validated biomarkers that may facilitate an accurate evalu-
ation of the effectiveness of new therapies and improve the safety and efficiency of clinical
trials. Global gene expression changes in blood of HD patients were already shown to exist
and their potential as biomarkers was suggested.5 A double-blinded clinical study was pro-
posed to assess potencial beneficial clinical effect of rivastigmine for HD patients and suit-
ability of gene candidates for monitoring the response to treatment.
Methods All patients were rated according to the UHDRS by two independent neurologists before
the application of rivastigmine/placebo and 1 and 6 months later. Blood samples were
taken at the same time points. 18 HD patients were included, 12 were given rivastigmine
and 6 placebo. At the beginning rivastigmine was given 2 times daily in a dose of 1,5mg
and after one month the dose was increased to 3mg 2 times daily. The control group was
given placebo in the same capsules as the active substance. Laboratory protocols for RNA
isolation and gene expression analysis were described elsewhere.5 There were 2 dropouts
in the clinical study – 1 patient died of acute pancreatitis and 1 patient decided to stop his
participation after few weeks of treatment.
Results In the group of patients that were treated with rivastigmine, 7 out of 11 (63.6 %) patients
after one month and 8 out of 11 (72.7 %) after six months showed improvement on UH-
DRS motor score. In the group of patients that were receiving placebo 2 out of 5 (40 %)
patients after one month and 4 out of 5 (80 %) patients after six months showed improve-
ment on UHDRS motor scores. No significant change was observed between both groups.
When analysing gene expression, 9 out of 11 HD patients showed lower expression of
candidate set after one month of treatment with rivastigmine and 7 out of these 9 HD
patients still showed lower expression of candidate set after 6 months of treatment. The
changes reached statistically significant difference in 5 out of 11 patients at both time
points. In the placebo group not a single patient showed statistically significant lower ex-
SHORT INVITED LECTURES – ABSTRACTS
KRATKA VABLJENA PREDAVANJA – POVZETKI
II-62 Zdrav Vestn 2007; 76: SUPPL II
pression of candidate set at both time points. When analysing expression of each gene
separately, all 12 genes were downregulated in the group treated with rivastigmine at both
time points, although the changes did not reach statistical significance. In the group of
patients that were receiving placebo there were minor changes in the expression of the 12
genes. After 1 month the expression was upregulated for all 12 genes and after 6 months
there was no change in expression of 6 genes and minor up- or downregulation of other 6
genes. None of the changes reached statistical significance.
Discussion Our results suggest that gene expression changes may be useful as an instrument in treat-
ment response monitoring. When comparing gene expression in patients before treatment
with rivastigmine and 1 and 6 months later we have shown that expression of limited
number of preselected genes have not only changed but have also changed in an opposite
direction as before treatment for some patients. Since clinical symptoms in HD change
relatively slowly, more time is needed to correlate gene expression changes with clinical
outcome, but we clearly showed a potential of expression profiles in blood as a surrogate
markers.
References
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3. De Tommaso M, Difruscolo O, Sciruicchio V, Specchio N, Livrea
P. Two years’ follow-up of rivastigmine treatment in Huntington
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4. Henley SM, Bates GP, Tabrizi SJ. Biomarkers for neurodegenera-
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Genome-wide expression profiling of human blood reveals biom-
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