Progeria Hope!

REFERENCE: Gordon et al. “Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.” PNAS (2012) 109(41) pgs. 16666 – 166671

                Between pharmaceutical companies and academic laboratories, the amount of compounds and antibodies available that can treat any number of diseases is staggering.  Either through rational design (choosing to target a protein’s particular function, shape, size, etc) or from blind mining (high throughput screens looking for a particular effect from any possible molecule), scientists are constantly searching for drugs to treat diseases.  Sometimes a particular drug is developed, honed, and specialized to treat a specific disease but its capabilities fall short.  Such was the case for lonafarnib, a farnesyltransferase inhibitor (FTI) that was originally designed to inhibit hydrophobic membrane-anchoring of GTPases, particularly Ras, which is overactive in many different cancer types.  Researchers studying Hutchinson-Gilford progeria syndrome (HGPS, also called progeria) recently decided to repurpose this FTI to see if it could also help patients suffering this lightening fast aging disease.

                Progeria is incredibly rare: only seen in one of four million live births.  Its patients suffer from diseases of old age (stiff joints, loss of body fat, cardiovascular disease) when they are only children.  No treatment or cure currently exist and, for this reason, progeria is considered 100% fatal.  Most children do not live past the age of 13.

                A single base mutation in the LMNA gene, which encodes for the protein lamin A, causes the lamin A RNA to splice differently and therefore encode for a shorter protein, known as progerin.  Progerin lacks the proteolytic cleavage site necessary to remove its C terminal farnesyl group.  Unfortunately, this means that all copies remain membrane bound and cluster specifically on the inner nuclear membrane.  Scientists believe that progeria symptoms are, in part, due to the increased progerin concentration at the nuclear membrane.  Lonafarnib, however, can bind to farnesyltransferase target proteins and inhibit them from ever gaining a farnesyl group.  An excellent candidate for this would be the progerin protein.  Early success for progeria research showed progerin-expressing cells normalizing in structure and function following lonafarnib treatment.  Mouse models treated with the drug also display improved health.  For these reasons, Gordon et al. designed a two year initial clinical trial for lonafarnib beginning in 2007 and now they report the encouraging results.

                Twenty five children, which account for 75% of all progeria patients in the world, completed the trial.  Side effects were allegedly mild and included fatigue, nausea, anorexia, depressed serum hemoglobin, vomiting, and diarrhea.  However, several improvements in progeria-related factors were noted within the patients: increased rate of weight gain, improved cardiovascular stiffness, improved bone structure and improved audiological status.  Every child in the study improved in at least one of the listed areas.

                Aortic stiffness is an indicator of cardiovascular health.  Before treatment, the average aortic stiffness age among the progeria patients was 60 – 69 years.  Following treatment, the average dropped 40 – 49 years.  For a disease that ultimately kills via cardiovascular problems (heart attacks, strokes), these results are very encouraging.

                Interestingly, even healthy individuals express progerin and its production increases with age.  The authors speculate that aging treatments in the future might rely on FTIs should they find that progerin plays a major role in aging among non-progeria patients.