Hutchinson-Gilford Progeria Syndrome (HGPS or progeria) is a rare autosomal dominant """"""""premature aging"""""""" disease. Children die at a median age of 13 years due to heart attacks and strokes caused by accelerated, global arteriosclerosis. The HGPS mutation lies within the LMNA gene, which codes for the protein, lamin A, which is expressed in all differentiated cells. Progerin, the aberrant form of lamin A produced in HGPS, contains a mutation which removes the splice site for the farnesyl group responsible for localization of the protein to the nuclear membrane. Permanent intercalation of progerin within the nuclear membrane leads to widespread signaling defects and multisystemic disease. Importantly, progerin is also produced by normal individuals at low levels and builds up in nuclei with increasing age, so that inhibition of progerin farnesylation may provide therapeutic options for vascular disease in both HGPS and the aging population. We hypothesize that blocking progerin farnesylation will ameliorate some aspects of HGPS. To test this hypothesis, we will treat patients for 24 months with three different drugs, each of which inhibits farnesylation at a different point along the pathway. This open label phase II efficacy trial will evaluate pravastatin, zoledronic acid and lonafarnib, and is based on our two previous clinical trials for HGPS. In the first trial with single agent lonafarnib, tolerability and activity was demonstrated with some improvement noted for weight gain and vascular wall characteristics although incomplete inhibition of the pathway limited the effect of therapy. By adding two additional inhibitors, we will attempt to further reduce accumulation of progerin within the nuclear membrane. In a separate one month pilot trial of the three drug combination in 4 patients, therapy was well tolerated. Analyses will compare naove, previously lonafarnib-treated and triple therapy patients. Both preclinical and clinical studies support our hypothesis. Farnesylation inhibition normalizes nuclear phenotype in cultured HGPS cells, and results in improved disease phenotype and extended lifespan in several mouse models of HGPS, using various combinations of the three proposed drugs.
Specific aims are 1) To recruit 45 of the world's 60 known children with progeria;2) To continue defining toxicity profiles for the three drug combination;3) To investigate the natural history of progeria and its relationship to cardiovascular disease and aging via extensive pre-therapy testing;4) To assess treatment efficacy using both physiological and biological endpoints in all systems affected by disease in HGPS. These include evaluating baseline status and changes in a host of novel biomarkers of disease we have identified through studying off-drug blood and urine samples from HGPS patients. Our research team is uniquely positioned to study HGPS, as we have treated more children with progeria than any institution worldwide. These investigations will not only aim to improve outcome for a fatal childhood disease, but will offer new avenues of study of cardiovascular and cerebral vascular disease.
Progeria (HGPS) is a rare autosomal dominant disease that possess many features of 'premature aging'including death at a median age of 13 years due to myocardial infarction and stroke. The protein implicated in this disease is progerin, a mutated form of lamin A that is also found in the cells of normal individuals as they age. We will undertake a phase II trial of three drugs (a farnesyltransferase inhibitor -lonafarnib, a statin -pravastain that inhibits both farnesylation and geranylation, and a bisphosphonate -zolendronic acid which inhibits farnesylation) to assess the activity of this combination and reducing or ameliorating this disease.
| Bassir, Seyed Hossein; Chase, Isabelle; Paster, Bruce J et al. (2018) Microbiome at sites of gingival recession in children with Hutchinson-Gilford progeria syndrome. J Periodontol 89:635-644 |
| Gordon, Leslie B; Kleinman, Monica E; Massaro, Joe et al. (2016) Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome. Circulation 134:114-25 |
| Gordon, Leslie B; Massaro, Joe; D'Agostino Sr, Ralph B et al. (2014) Impact of farnesylation inhibitors on survival in Hutchinson-Gilford progeria syndrome. Circulation 130:27-34 |
| Rork, Jillian F; Huang, Jennifer T; Gordon, Leslie B et al. (2014) Initial cutaneous manifestations of Hutchinson-Gilford progeria syndrome. Pediatr Dermatol 31:196-202 |
| Cleveland, Robert H; Gordon, Leslie B; Kleinman, Monica E et al. (2012) A prospective study of radiographic manifestations in Hutchinson-Gilford progeria syndrome. Pediatr Radiol 42:1089-98 |
