Protein farnesylation inhibitors extend the estimated lifespan of children with progeria. That is the conclusion from a new study by Dr Leslie Gordon and colleagues published in Circulation
[Epub ahead of print
]. This is very exciting news for a condition known to result in premature death by the age of about 14 in most children with progeria.
Progeria is caused by a mutation in the LMNA gene that eventually leads to abnormal levels of the protein progerin that disrupt the nucleus of cells and causing children with this condition to age prematurely.
Children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. Almost all children with progeria die of atherosclerosis (heart disease) at an average age of fourteen years.
Currently there is no approved treatment for Progeria. However, since 2007, protein farnesylation inhibitors, such as lonafarnib, have been given to some patients to reduce the toxic effects of progerin in single arm studies. Now that about 6 years has passed since lonafarnib was first administered in a clinical trial to children with Progeria, enough time has elapse to allow for a survival analysis to take place.
In the report by Gordon et al, they looked at the data obtained from The Progeria Research Foundation International Registry, published scientific and news article, and publicly available databases to compare survival rates in children given farnesylation inhibitors with age- and gender-matched untreated cohorts.
Overall, 43 children treated with farnesylation inhibitors were compared to 43 untreated children with progeria (of an eligible 161 subjects) in a matched analysis.
At the time of study completion, there were 5 deaths reported in the treated group (11.6%) compared to 21 deaths in the untreated group (48.8%). Median follow-up time in both groups was 5.3 years.
During the first 6 years following treatment initiation, mean survival time was calculated to be 1.6 years longer in the treated group compared to the matched untreated group.
In a press release,
Dr Gordon said, “This is the first study to assess whether treatments influence patient survival, and thanks to a robust PRF registry and the clinical trials, we have been able to conclude that lifespan extension is possible for children with Progeria. Moreover, the study provides parameters for future assessments of changes in survival with other potential treatments for Progeria, as we continue working to discover drugs that extend life even further.”
Elizabeth G. Nabel, President of Brigham and Women’s Hospital, and former Director of the National Heart, Lung and Blood Institute added, “These findings give hope to the children and families who face this incurable and fatal disease. Through the support of The Progeria Research Foundation, these researchers have taken one more step in the process of finding a treatment and a cure for this disease.”
Last year, the protein farnesylation inhibitor, lonafarnib, was shown in a clinical study
to increase weight gain and improve several cardiovascular outcomes in children with progeria. This new study is the first to show that the drug also statistically increases survival.
More rigorous studies with lonafarnib are currently underway.
Gordon LB, Massaro J, D’Agostino Sr RB, et al. Impact of farnesylation inhibitors on survival in hutchinson-gilford progeria syndrome . Circulation. 2014 [epub ahead of print].