Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome

Gordon, Leslie B.; Kleinman, Monica E.; Massaro, Joseph M.; D’Agostino, Ralph B.; Shappell, Heather; Gerhard‐Herman, Marie; Smoot, Leslie; Gordon, Catherine M.; Cleveland, Robert H.; Nazarian, Ara; Snyder, Brian D.; Ullrich, Nicole J.; Silvera, V. Michelle; Liang, Marilyn G.; Quinn, Nicolle; Miller, David T.; Huh, Susanna Y.; Dowton, Anne A.; Littlefield, Kelly; Greer, Maya Mundkur; Kieran, Mark W.

doi:10.1161/circulationaha.116.022188

Cited by 136 publications

(143 citation statements)

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“…Farnesyl diphosphate synthase (FDPS) may promote the formation of misshapen nuclei upon progerin expression, and it is also a target of bisphosphonate drugs which are used for clinical trials against HGPS (Gordon et al, 2016; Varela et al, 2008). We found increased FDPS expression in progerin‐expressing cells, in human HGPS cells, and in mouse model (Figure 5a–c).…”

Section: Resultsmentioning

confidence: 99%

“…It has previously been suggested that FDPS could promote the formation of misshapen nuclei upon progerin expression, and it is also a target of bisphosphonate drugs which are used for clinical trials against HGPS (Gordon et al, 2016; Varela et al, 2008). Bisphosphonates target FDPS, and according to our results, FDPS levels increased upon progerin and prelamin A expression (i.e., in HGPS‐derived cells and Zmpste24 ‐deficient bone, respectively) and targeting FDPS with pamidronate overcame progerin‐induced senescence and misshapen nuclei.…”

Section: Discussionmentioning

confidence: 99%

“…Independently of this known effect, bisphosphonates also decrease misshapen nuclei in HGPS cells, which are proposed to participate in the disease, and trials using this drug have been set up for this reason (Gordon et al, 2016; Varela et al, 2008). Our results point out that bisphosphonate strongly impacts senescent phenotype reinforcing a potential functional link between bone fragility during aging and increase cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

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Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

et al. 2018

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Hutchinson–Gilford progeria syndrome (HGPS) is a lethal premature aging that recapitulates many normal aging characteristics. This disorder is caused by mutation in the LMNA gene leading to the production of progerin which induces misshapen nuclei, cellular senescence, and aging. We previously showed that the phospholipase A2 receptor (PLA2R1) promotes senescence induced by replicative, oxidative, and oncogenic stress but its role during progerin‐induced senescence and in progeria is currently unknown. Here, we show that knockdown of PLA2R1 prevented senescence induced by progerin expression in human fibroblasts and markedly delayed senescence of HGPS patient‐derived fibroblasts. Whole‐body knockout of Pla2r1 in a mouse model of progeria decreased some premature aging phenotypes, such as rib fracture and decreased bone content, together with decreased senescence marker. Progerin‐expressing human fibroblasts exhibited a high frequency of misshapen nuclei and increased farnesyl diphosphate synthase (FDPS) expression compared to controls; knockdown of PLA2R1 reduced the frequency of misshapen nuclei and normalized FDPS expression. Pamidronate, a FDPS inhibitor, also reduced senescence and misshapen nuclei. Downstream of PLA2R1, we found that p53 mediated the progerin‐induced increase in FDPS expression and in misshapen nuclei. These results suggest that PLA2R1 mediates key premature aging phenotypes through a p53/FDPS pathway and might be a new therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

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“…15 Investigations into the mechanism and treatment of HGPS may yield new insights into the treatment of age-related cardiovascular disease. 16 …”

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Precision Medicine and Progress in the Treatment of Hutchinson-Gilford Progeria Syndrome

Hisama

Oshima

2018

JAMA

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Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare autosomal dominant genetic disorder, with an incidence of 1 in 4 million live births, for which there is no known cure.Children with HGPS appear normal at birth but present in infancy with severe failure to thrive, accompanied by a prematurely aged appearance, alopecia, and progressive lipoatrophy, joint contractures, skeletal dysplasia, and atherosclerosis, although intellectual development is normal. 1 Accelerated cardiovascular disease results in death due to myocardial infarction or stroke at an average age of 14.6 years. 2 It took 117 years after the initial description of the phenotype in the 1880s 3,4 to identify the cause of classic HGPS as a recurrent, single base substitution, c.1824C>T in the LMNA

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“…3 Characterized 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.…”

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confidence: 99%

Seeking a Cure for One of the Rarest Diseases: Progeria

Collins

2016

Circulation

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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

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Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome

Cited by 136 publications

References 31 publications

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes

Precision Medicine and Progress in the Treatment of Hutchinson-Gilford Progeria Syndrome

Seeking a Cure for One of the Rarest Diseases: Progeria

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