Person: Gordon, Leslie
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Leslie
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Gordon, Leslie
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Publication The decision‐making process and criteria in selecting candidate drugs for progeria clinical trials(John Wiley and Sons Inc., 2016) Gordon, Leslie; Kieran, Mark W; Kleinman, Monica; Misteli, TomHutchinson–Gilford progeria syndrome (progeria) is an extremely rare premature aging disease with a population prevalence of 1 in 20 million. Nevertheless, propelled by the discovery of a causal mutation in the lamin A/C gene (LMNA) (De Sandre‐Giovannoli et al, 2003; Eriksson et al, 2003) and strong patient advocacy (Gordon & Gordon, 2014), progeria has rapidly become a vibrant field of study, attracting a wide range of researchers from basic cell biologists to clinicians.Publication Sulforaphane enhances progerin clearance in Hutchinson–Gilford progeria fibroblasts(BlackWell Publishing Ltd, 2014) Gabriel, Diana; Roedl, Daniela; Gordon, Leslie; Djabali, KarimaHutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare multisystem childhood premature aging disorder linked to mutations in the LMNA gene. The most common HGPS mutation is found at position G608G within exon 11 of the LMNA gene. This mutation results in the deletion of 50 amino acids at the carboxyl-terminal tail of prelamin A, and the truncated protein is called progerin. Progerin only undergoes a subset of the normal post-translational modifications and remains permanently farnesylated. Several attempts to rescue the normal cellular phenotype with farnesyltransferase inhibitors (FTIs) and other compounds have resulted in partial cellular recovery. Using proteomics, we report here that progerin induces changes in the composition of the HGPS nuclear proteome, including alterations to several components of the protein degradation pathways. Consequently, proteasome activity and autophagy are impaired in HGPS cells. To restore protein clearance in HGPS cells, we treated HGPS cultures with sulforaphane (SFN), an antioxidant derived from cruciferous vegetables. We determined that SFN stimulates proteasome activity and autophagy in normal and HGPS fibroblast cultures. Specifically, SFN enhances progerin clearance by autophagy and reverses the phenotypic changes that are the hallmarks of HGPS. Therefore, SFN is a promising therapeutic avenue for children with HGPS.Publication Temsirolimus Partially Rescues the Hutchinson-Gilford Progeria Cellular Phenotype(Public Library of Science, 2016) Gabriel, Diana; Gordon, Leslie; Djabali, KarimaHutchinson-Gilford syndrome (HGPS, OMIM 176670, a rare premature aging disorder that leads to death at an average age of 14.7 years due to myocardial infarction or stroke, is caused by mutations in the LMNA gene. Lamins help maintain the shape and stability of the nuclear envelope in addition to regulating DNA replication, DNA transcription, proliferation and differentiation. The LMNA mutation results in the deletion of 50 amino acids from the carboxy-terminal region of prelamin A, producing the truncated, farnesylated protein progerin. The accumulation of progerin in HGPS nuclei causes numerous morphological and functional changes that lead to premature cellular senescence. Attempts to reverse this HGPS phenotype have identified rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), as a drug that is able to rescue the HGPS cellular phenotype by promoting autophagy and reducing progerin accumulation. Rapamycin is an obvious candidate for the treatment of HGPS disease but is difficult to utilize clinically. To further assess rapamycin’s efficacy with regard to proteostasis, mitochondrial function and the degree of DNA damage, we tested temsirolimus, a rapamycin analog with a more favorable pharmacokinetic profile than rapamycin. We report that temsirolimus decreases progerin levels, increases proliferation, reduces misshapen nuclei, and partially ameliorates DNA damage, but does not improve proteasome activity or mitochondrial dysfunction. Our findings suggest that future therapeutic strategies should identify new drug combinations and treatment regimens that target all the dysfunctional hallmarks that characterize HGPS cells.Publication Progeria: Translational insights from cell biology(The Rockefeller University Press, 2012) Gordon, Leslie; Cao, Kan; Collins, Francis S.Cell biologists love to think outside the box, pursuing many surprising twists and unexpected turns in their quest to unravel the mysteries of how cells work. But can cell biologists think outside the bench? We are certain that they can, and clearly some already do. To encourage more cell biologists to venture into the realm of translational research on a regular basis, we would like to share a handful of the many lessons that we have learned in our effort to develop experimental treatments for Hutchinson-Gilford progeria syndrome (HGPS), an endeavor that many view as a “poster child” for how basic cell biology can be translated to the clinic.Publication Everolimus rescues multiple cellular defects in laminopathy-patient fibroblasts(National Academy of Sciences, 2018) DuBose, Amanda J.; Lichtenstein, Stephen T.; Petrash, Noreen M.; Erdos, Michael R.; Gordon, Leslie; Collins, Francis S.LMNA encodes the A-type lamins that are part of the nuclear scaffold. Mutations in LMNA can cause a variety of disorders called laminopathies, including Hutchinson-Gilford progeria syndrome (HGPS), atypical Werner syndrome, and Emery-Dreifuss muscular dystrophy. Previous work has shown that treatment of HGPS cells with the mTOR inhibitor rapamycin or with the rapamycin analog everolimus corrects several of the phenotypes seen at the cellular level—at least in part by increasing autophagy and reducing the amount of progerin, the toxic form of lamin A that is overproduced in HGPS patients. Since other laminopathies also result in production of abnormal and potentially toxic lamin proteins, we hypothesized that everolimus would also be beneficial in those disorders. To test this, we applied everolimus to fibroblast cell lines from six laminopathy patients, each with a different mutation in LMNA. Everolimus treatment increased proliferative ability and delayed senescence in all cell lines. In several cell lines, we observed that with treatment, there is a significant improvement in nuclear blebbing, which is a cellular hallmark of HGPS and other lamin disorders. These preclinical results suggest that everolimus might have clinical benefit for multiple laminopathy syndromes.Publication Intermittent treatment with farnesyltransferase inhibitor and sulforaphane improves cellular homeostasis in Hutchinson-Gilford progeria fibroblasts(Impact Journals LLC, 2017) Gabriel, Diana; Shafry, Dinah Dorith; Gordon, Leslie; Djabali, KarimaHutchinson-Gilford progeria syndrome (HGPS) is a rare genetic condition associated with mutations in the LMNA gene. This disease recapitulates some aspects of normal aging, such as hair loss, thin skin, joint stiffness, and atherosclerosis. The latter leads to heart attack or stroke that causes death at an average age of 14.6 years in children with HGPS. The typical LMNA mutation results in the production of a truncated prelamin A protein, progerin, that remains permanently farnesylated and abnormally associated with the nuclear envelope. Farnesyltransferase inhibitors (FTIs) reverse nuclear structure abnormalities that are characteristic of HGPS cells. The first clinical trial using the FTI, Ionafarnib, demonstrated some improvements in HGPS children and, in particular, showed a decrease in arterial stiffness. Recently, we reported that sulforaphane, an antioxidant derived from cruciferous vegetables, efficiently stimulates autophagy and enhances progerin clearance in HGPS fibroblasts. In the present study, we investigated the effect of combined lonafarnib and sulforaphane treartment in HGPS fibroblast cultures. We report that co-administration of both drugs exerts a synergistic and additive positive effect on autophagy activity but was cytotoxic to HGPS cells. In contrast, intermittent treatment with lonafarnib followed by sulforaphane separately and in repeated cycles rescued the HGPS cellular phenotype. We propose that intermittent treatment with FTI and SFN separately might be a promising therapeutic avenue for children with HGPS.