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Leslie B. Gordon Professor of Pediatrics (Research)

Brown Affiliations

research overview

Dr. Gordon's research revolves around Progeria, a rare, fatal genetic condition characterized by an appearance of accelerated aging in children. Children with Progeria die of heart disease at an average age of thirteen years. She is co-founder and Medical Director of The Progeria Research Foundation (PRF), whose mission is to find the cause, treatment and cure for Progeria. She is Principal Investigator for the PRF Diagnostics Testing Program, Cell & Tissue Bank, and Medical & Research Database. She conducts both cellular and clinical studies for Progeria.

research statement

In Vitro Studies of Progeria:

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare and uniformly fatal syndrome of previously unknown inheritance affecting 1 in 4 to 1 in 8 million live births. All children die as a consequence of severe atherosclerosis at an average age of thirteen years (range 8 to 21 years). We have determined that HGPS is an autosomal dominant disease and that the gene defect responsible for HGPS is a single base change from C > T in codon 608 of the LMNA gene. The base change produces a silent amino acid mutation, where GGC and GGT both code for glycine. However, the base change activates a cryptic splice site and results in a protein product lacking 50 amino acids towards the C-terminal end of the Lamin A protein. Although the genetic basis for disease is now determined, definitive cellular disease phenotypes and the biochemical basis of disease are undetermined and warrant intensive investigation.

Lamin A is normally expressed by most differentiated cells, and requires posttranslational farnesylation to incorporate into the nuclear membrane. The lamin A C-terminal peptide, including the farnesyl group, is subsequently cleaved, and mature lamin A becomes a prominent component of the nuclear scaffold just internal to the nuclear membrane, affecting nuclear structure and function. The defective protein product in HGPS (progerin) lacks the cleavage site for removal of the C-terminal farnesylated peptide, and produces disease via dominant negative effects on the nuclear structure and function of various cell types that express lamin A.

Both in vitro cellular and in vivo vascular HGPS phenotypes have been established. In vitro, our data demonstrate that HGPS skin fibroblasts and progerin-transfected HeLa cells and vascular smooth muscle cells (VSMCs) display disruption of nuclear architecture, premature senescence, and apoptosis.

The current research proposes that these features can be improved or reversed in vitro and in vivo by blocking posttranslational processing via treatment with farnesyl transferase inhibitors (FTIs). Dr. Gordon is testing whether reduction of the quantity of mature progerin will improve the function of HGPS cells and vessels. Preliminary evidence in HEK-293 cells indicates that exposure to FTIs prohibits the interaction between progerin and the nuclear membrane where it normally functions, and eliminates nuclear deformity. We are assessing the ability of two different FTIs to block the cellular phenotype in HGPS dermal fibroblasts and vascular cell types transfected with the G608G gene defect. This research explores the hypothesis that FTIs will significantly improve cellular and vascular phenotypes caused by mature progerin in HGPS. We are producing the HGPS gene defect in VSMCs and vascular endothelial cells (VECs), and assessing the effects of two FTIs currently used in Phase III clinical trials for cancer therapy on HGPS dermal fibroblasts, progerin-transfected HeLa, 293, VSMCs and VECs using outcome parameters such as growth curves, apoptosis, and nuclear morphology.

Natural History Study of Progeria:

We are in the midst of conducting a longitudinal clinical study to investigate the disease characteristics of Progeria. Hypothesis: Progeria is a multisystem disease with objective clinical markers that can be followed over time.

Objectives: 1) To identify clinically significant abnormalities associated with Progeria; 2) To create objective measures of disease status that could be followed over time in multiple systems; and 3) To define measures to assess treatment effects in future clinical trials¬ódisease stabilization or improvement.

Methods: Progeria patients are admitted to the NIH Clinical Center as inpatients for approximately 6 days, during which time baseline clinical studies are performed to analyze all systems affected by the disease process. Data from 10 patients' initial visits has been analyzed.

Results: We demonstrate significant, analyzable abnormalities in growth and body composition, bone density, joints, and endocrine function. 1) Results show classic growth retardation, with weight decreased for height. Dual X-ray absorptiometry (DXA) reveals significant global lipodystrophy, most dramatically in the limbs. Sources of growth failure were investigated. Analysis of caloric intake and energy expenditure reveal that Progeria children receive adequate caloric intake for growth. 2) We next investigated cellular energy utilization by analyzing fasting insulin and glucose, and administering glucose tolerance testing. Six of nine children tested exhibited significant insulin resistance. All three children with normal testing have been receiving recombinant growth hormone treatment at home. 3) Joint contracture is a classic finding in Progeria. Potential causes of joint contracture include muscular weakness and structural myotendinous abnormalities. We measured joint flexibility throughout the body, and assessed whether the origin of the contractures are a reflection of muscular weakness or structural abnormalities in tendons. Testing revealed normal motor function, normal muscle strength for size, and measurable joint contractures globally that are indicative of shortened tendons and therefore tendon structure as the primary origin of contractures. 4) Boney abnormalities typical in Progeria include bone resorption and coxa valga, normal bone age and decreased bone density on X-ray. However, X-ray cannot objectively assess bone density. We performed whole body DXA analysis of bone density and found that, in all patients tested, bone mineral density and bone mineral content were decreased more than two standard deviations below the mean when adjusted for either age or for height. 5) Finally, audiological testing reveals a low frequency conductive hearing loss in all patients tested, as well as a high frequency conductive hearing loss in older subjects. We hypothesize that this is caused by either tympanic membrane structural irregularity due to an ECM defect, or ossicular structural/developmental defect.

The information emanating from these ongoing studies will provide a better understanding of the variations in phenotype of HGPS, stimulate new research into HGPS, and assist in defining outcome parameters for future treatment trials in Progeria.

funded research


  1. 1992-1994 $3,000 American Cancer Society Institutional Research Grant
    ACS IN-45-34 , Principal Investigator

  2. 1999-2000 $76,390 Progeria Research Foundation Grant: "The Pathophysiology of Atherosclerosis in Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  3. 1999-present Progeria Research Foundation Project: "The Progeria Research Foundation Cell and Tissue Bank", Principal Investigator

  4. 1999-present Progeria Research Foundation Project: "Creating a Medical and Research Database for Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  5. 2000-2003 $240,000; American Heart Association Scientist Development Grant #0030217N; "The Pathophysiology of Atherosclerosis in Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  6. 2000-2004 $104,000; Progeria Research Foundation Grant: "The Role of Hyaluronic Acid in Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  7. 5/2003 $4,736; Natalie V. Zucker Research Center for Women Scholars: "The Pathophysiology of Atherosclerosis in Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  8. 6/2003 $200,000 National Institutes of Health R21 Exploratory/Development Grant: "Creating a Medical and Research Database for HGPS", Principal Investigator

  9. 1/2004-1/2006 $100,000 Basil O'Connor Award, March of Dimes: "The Role of Lamin A in Hutchinson-Gilford Progeria Syndrome", Principal Investigator

  10. 10/04-10/07 National Human Genome Research Institute Natural History Study: "Clinical Investigations into Hutchinson-Gilford Progeria Syndrome", Associate Investigator

  11. 6/2005-6/2007 $200,000 Bench to Bedside Award from the Office of Rare Diseases, National Institutes of Health: "Testing Treatment of Hutchinson-Gilford Progeria Syndrome (HGPS) with Farnesyl Transferase Inhibitors", Principal Investigator