Dr. Teresa McNally,  October 17, 2013

Hutchinson-Gilford Progeria (HGPS) is a rare genetic disease for which there is no treatment.    HGPS patients age approximately seven times more rapidly than the normal population and usually die from age related cardiovascular disease before their 30th birthday.  Recent clinical studies from NIH have shown that the anti-cancer drug, lonafarnib, can improve the cardiovascular health of HGPS patients.  These promising studies demonstrate, for the first time, that the symptoms of HGPS can be reduced by therapeutic intervention. They have paved the way for future clinical trials to increase lifespan in this patient population.

TED is a series of conferences on technology, entertainment and design, originated by the non-profit Sapling group, with the slogan “ideas worth spreading”.    Dr. Francis Collins, Director of the National Institutes of Health (NIH) and a former leader of the human genome project, is a strong proponent of drug repurposing as a means to helping patients with unmet medical needs, as is Cures Within Reach.  In a TEDMED presentation in 2012, Dr. Collins presented a striking example of a successful repurposing project that has evolved over the past few years.

HPGS occurs in approximately 1 in 4 million births.  Patients develop several characteristics of old age during childhood, suffer from low body weight, auditory problems and bone and dental abnormalities.  Affected individuals develop atherosclerosis by their teens and the most common causes of death, which occur before their 30's are heart attack or stroke. There is currently no treatment for HGPS.  The genetic mutation that gives rise to HGPS was identified by Dr. Collins' group in 2003 and occurs in the gene for lamin A (LMNA). In normal cells, lamin A is modified by an enzyme, farnesyl transferase, before being packed into the nuclear membrane. In HGPS, the mutated lamin protein, called progerin, has an unusual shape which cannot be packed packaged correctly.  The cells of patients with HGPS have bumpy looking nuclei that don't work properly.

In 1998, scientists at Schering-Plough (now Merck) discovered a potent and selective inhibitor of farnesyl transferase, lonafarnib. Farnesyl transferase is thought to be essential to the unrestricted cell growth and survival that is seen in cancer.  Unfortunately Lonafarnib treatment alone does not stop tumor growth in clinical models of cancer, likely because there are other enzymes that can take its place in tumor cells, but this is thought to be unlikely to occur in non-cancer cells.  In HGPS, problems arise when the mis-shaped progerin protein is packaged into the nuclei of cells.  If it were possible to block progerin packaging, perhaps it could ameliorate the symptoms of the disease.  Since farnesyl transferase activity is required for progerin packaging, lonafarnib should block it.  When cells from HGPS patients are treated with lonafarnib, the bumpy nuclei disappear.  Tests in mouse models of HGPS show improvements in cardiovascular parameters.  This data hastened the progress to human clinical trials.  Researchers at Children's Hospital in Boston enrolled 25 HGPS volunteers, who took lonafarnib for 4 to 24 months, in an open label trial.  Encouraging results were published last year.   Arterial stiffness before treatment was similar to that of a healthy 60-69 year old in HGPS patients, who actually had a mean age of 7 years.  This was decreased to that of a healthy 40-49 year old after treatment with lonafarnib. Arterial stiffness is known contributing factor in cardiovascular disease, the major cause of death in this population.  Treatment also increased body-weight, which was encouraging as normal people tend to lose weight on this type of therapy.   A recent second paper shows a decrease in the number of headaches, transient ischemic events and seizures with treatment. This should correlate to a decrease in frequency of stroke, another major cause of death in this population.  A new clinical trial testing lonafarnib in HPGS patients in combination with zoledronic acid, a drug that improves bone density, and prevastatin, a cholesterol lowering compound that also has effects on farnesyl transferase activity, has been initiated.  Results are expected to be even more striking than with lonafarnib alone.

This example from the NIH shows how strategic repurposing of a disappointing anti-cancer therapeutic can help patients with what was considered to be untreatable condition. Cures Within Reach exists to support the rapid development of existing therapies to help patients with life threatening diseases.  As the drug repurposing movement gains momentum, more development opportunities that will benefit patients with no access to treatment will be identified.

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