Treaty. Children with progeria brandish trophies after completing 2 years of a clinical trial for lonafarnib now reported to prolong the lifespan.
The Progeria Foundation
It's been 7 years that dozens of children with progeria, a devastating disease that causes symptoms resembling premature aging, began receiving an experimental drug called lonafarnib. That's an eternity for them and their parents as most afflicted with the extremely rare condition die in their teenage years. There is now a clue that this medical bet paid off, at least to a small extent. The Progeria Research Foundation (PRF), which funded the initial drug testing and ongoing monitoring and involving two other medicines, announced this week that interventions have probably added on average about 19 months for periods children's life.
This is "an important first step," said Leslie Gordon, a physician who, with her husband, founded PRF after their son was diagnosed with progeria. "Although these drugs are not curative, we show for the first time that life can be affected in children with progeria. "But this finding, detailed in a study published online may 2 in Traffic , has many scientists wondering if the results are significant, because the tests were missed an untreated control group as is sometimes the case for treatments for extremely rare diseases.
Only about one in 4 million to 8 million newborns have a mutation in a gene called LMNA causes what is officially known as progeria syndrome Hutchinson-Gilford. LMNA normally produces a protein that helps to provide a scaffold for the nucleus of a cell. The mutation leads to the accumulation of an abnormal version of the protein, causing deformed nuclei and other changes in the cells. The end result is a set of symptoms resembling premature aging of certain tissues: hair and weight loss, thin skin, joint stiffness, and atherosclerosis. This leads to heart attacks that cause the majority of deaths from the disease.
In 05, a study conducted by researchers at the University of California, Los Angeles, showed that a class of farnesyl transferase inhibitors drugs called (FTI), which block the binding of a molecule to defective protein allowing it to accumulate around the nucleus, restored normal form to kids with progeria cells. Several working groups with mice with the same mutation following established that the drug also reduces the signs of premature aging in rodents. Because FTI had already been tested in children with cancer without significant side effects, PRF quickly pushed to start a test of lonafarnib FTI in 07. Gordon, in collaboration with a team led by Mark Kieran oncologist Institute Dana-Farber Cancer Boston, initially followed 25 children as they received the drug for at least 2 years. The results of the test, published in 2012, showed that most patients had small gains and weight reductions in the stiffness of their blood vessels, although some scientists have found inconclusive and difficult to interpret.
In the new analysis, Gordon and his colleagues wanted to see if the children treated to date, including the first trial lonafarnib and those in an ongoing trial that adds two other drugs for the treatment survived more long as untreated children. But because there are so few children with progeria, and the disease is always fatal, PRF and designers in the study had agreed not to create a group receiving a placebo; all those who participated in the study received the drug, including the son of Gordon. For a comparison group, Gordon and colleagues instead of collecting data on untreated children from historical documents in the international register of the foundation, previously published case reports, and public databases.
This is what makes some question whether the extension of the apparent life is real. Studies with historical controls are "notoriously unreliable" said Donald Berry, a biostatistician at the University of Texas MD Anderson Cancer Center in Houston. Because various studies and databases can have an inclusion criteria patient, factors outside the drug's effectiveness could contribute to the life of differences. Gordon and his colleagues, however, have tried to solve this problem by matching children in the treatment group with untreated children the same age and sex, born after the subjects. the comparison showed that within 6 years after the start of treatment, those receiving the drug survived an average of 1.6 years longer than their untreated counterparts. in during this period, 21 of 43 children with progeria that has not included in the study died, against 5 of the 43 who had received treatment.
the discovery "is very rewarding and encouraging" said the doctor -geneticist Francis Collins, director of the National Institutes of Health in Bethesda, Maryland, whose research team studied the mechanisms and potential treatments for progeria. Collins acknowledges that the lack of direct control group enrolled in the trial is "not ideal", but noted "there was really not much of an alternative to what has been done, namely, to an open trial where all children had the chance to have access to the drug. "
But others, including Berry, are struggling to draw a positive conclusion from the study in the light of this limitation. It notes that a more dramatic improvement in life could overcome his doubts: "If patients have lived a normal life, then the results were convincing but even improved 'only' 10 years (and maybe even 5 years) would have been sufficient to establish the principle. which the treatment was effective. "
In addition to age and gender issues the Gordon team sent there differences between the countless trial participants and the untreated group, notes Howard Worman, a cell biologist and physician at Columbia University, who was the first to characterize LMNA gene. Children and their parents who enroll in a clinical trial may be more aware of their disease and more proactive with their health than non-participants, for example. "Until there is a matched group at the same time, ideally placebo-controlled, it is difficult to say whether there really is a survival advantage," he said.
Gordon and his colleagues are continuing to follow the children in the study who are still taking the IFT and the more time drug other two can make a clear survival advantage. His son, recently the subject of an award-winning documentary, died in January.
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