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.
