Seeking a Cure for One of the Rarest Diseases: Progeria

Abstract

More than 5700 human conditions have now had their molecular causes defined, the majority of which are rare diseases that were molecularly characterized in the past 25 years.1 Yet, even today, approved therapies exist for only ≈500 of these conditions.2 Clearly, an urgent need exists for therapeutic advances to help people suffering from rare diseases, a need fraught with many challenges.The private sector's interest in developing molecularly targeted therapies has been growing but still remains quite limited for the rarest diseases that have very little market potential. Given the costs, it is difficult to embark on such a therapeutic development effort from scratch; historically, the failure rate is very high, and it has taken an estimated 14 years and several billion dollars to develop and gain approval for a therapy aimed at a molecular target.2 The National Institutes of Health is working to overcome these obstacles through a variety of innovative efforts at its National Center for Advancing Translational Sciences, with repurposing of compounds developed for other applications being one particularly attractive option.A poignant example of the pressing need for effective treatments is one of the rarest of rare diseases: Hutchinson-Gilford progeria syndrome (HGPS), and this issue of Circulation reports the results of a triple-combination therapy trial for HGPS. 3Characterized by accelerated aging, HGPS has a prevalence of ≈1 in 20 million living individuals or ≈350 children worldwide at any given time. Without treatment, children with HGPS, who have completely normal intellectual development, die of atherosclerotic cardiovascular disease at the average age of 14.6 years. 4,5 In 2003, my laboratory at the National Institutes of Health and another group in France determined that HGPS is caused by a point mutation (C-to-T) in the lamin A (LMNA) gene. The mutation activates a splice donor in the middle of an exon, leading to the production of an abnormal protein, now called progerin, that is missing 50 amino acids near the C terminus. 6,7 Nearly 2 decades of previous work by lamin A cell biologists furnished rapid insights into how this mutation might cause disease. Lamin A is posttranslationally modified, with the addition of a farnesyl group at the C terminus that assists in zipcoding the protein to the inner surface of the nuclear membrane. The protein then needs to be released from this tether, which is accomplished by an enzyme called ZMPSTE24. The abnormal splice event that gives rise to progerin eliminates the ZMPSTE24 cleavage site, so progerin remains permanently tethered, with negative consequences to cell morphology and longevity. Knowledge of these steps predicted that farnesyltransferase inhibitor (FTI) drugs, which reduce the amount of permanently farnesylated progerin, might hold therapeutic potential for this disorder. Indeed, tests in HGPS cells and mouse models of HGPS laid the groundwork for the first clinical trial of a potential therapy for HGPS: an FTI called lonafarnib, which

A Tissue Engineered Blood Vessel Model of Hutchinson-Gilford Progeria Syndrome Using Human iPSC-derived Smooth Muscle Cells

“…This indicates a key limitation of these models for drug screening purposes. The need still exists, however, to discover therapeutics and conduct clinical trials even with limited patient populations 34 . In order to overcome these limited test populations, personalized medicine efforts have focused on creating patient-specific in vitro models using iPS-derived cell sources in order to tailor drug testing efforts to that particular patient 35 , 36 .…”

Commonalities Between Vasculature and Bone

“…In preclinical models, intermittent parathyroid hormone receptor signaling can increase bone mass while limiting vascular sclerosis and stiffness 2 . In children afflicted with progeria, a precocious aging phenotype characterized by osteoporosis and arteriosclerosis, treatment with the farnesyltransferase inhibitor lonafarnib alone improves bone mass while reducing arterial stiffness-- and treatment increases longevity 4 (references therein). In post-menopausal women, aminobisphosphonates – inhibitors of osteoclast function - improve vertebral bone mass and apparently decrease arterial stiffness and aortic calcification 2 .…”

“…In post-menopausal women, aminobisphosphonates – inhibitors of osteoclast function - improve vertebral bone mass and apparently decrease arterial stiffness and aortic calcification 2 . However, drugs such as aminobisphosphonates may negatively impact arterial structure and function in other age groups and genders, viz., in premenopausal or younger individuals 4 . Indeed, even daily dietary calcium supplementation for bone health may exert gender-specific influence on cardiovascular disease risk 5 .…”

New vascular insights into premature aging

“…Tremendous advances have been made in research uncovering the pathophysiology of HGPS -but a cure remains elusive (17). The current new studies reveal novel insights into accelerated atherosclerosis in HGPS.…”