Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome

Gordon, Leslie B.; Shappell, Heather; Massaro, Joseph M.; D’Agostino, Ralph B.; Brazier, Joan F.; Campbell, Susan; Kleinman, Monica E.; Kieran, Mark W.

doi:10.1001/jama.2018.3264

Cited by 173 publications

(168 citation statements)

References 22 publications

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“…HGPS is due to the synthesis of progerin, which arises from abnormal LMNA splicing and subsequent abnormal post-translational maturation of mutated prelamin A. Progerin remains permanently farnesylated and forms an abnormal lamina network, tightly bound to the inner nuclear membrane [19,20]. Therapeutic trials using farnesyl transferase inhibitors showed evidence of cardiovascular benefit in patients with HGPS, in favor of a prominent pathophysiological role of the abnormal farnesyl moiety of progerin present in vascular cells [17,21], which is also supported by murine models [12,22,23]. Several studies, including ours, have shown that other LMNA pathogenic variants, responsible for atypical progeroid syndrome or FPLD2, could also lead to abnormal prelamin A accumulation, which could contribute to vascular senescence and atherosclerosis by targeting endothelial and/or vascular smooth muscle cells [4,[24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects.A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.

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Section: Discussionmentioning

confidence: 99%

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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“…Others have reported that administration of sodium nitrate to HGPS mice (del Campo et al 2019) and administration of Lonafarnib, a farnesyltransferase inhibitor, to HGPS children reduce arterial stiffness (Gordon et al 2012;Gordon et al 2018). Furthermore, the reduction in arterial stiffness by lonafarnib was associated with an increased lifespan of HGPS children (Gordon et al 2018). These studies did not distinguish between effects on axial versus circumferential mechanics, nor are the mechanisms by which nitrate and lonafarnib reduce arterial stiffness fully clear.…”

Section: Discussionmentioning

confidence: 99%

Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition

Kleeck

Brankovic

Roberts

et al. 2019

Preprint

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Arterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the key molecular regulators initiating arterial stiffening in HGPS remain unknown.To identify these early events, we compared arterial mechanics and ECM remodeling in very young HGPS (LMNA G609G/G609G ) mice to those of age-matched and much older wild-type mice.Biaxial inflation-extension tests of carotid arteries of 2-month mice showed that circumferential stiffness of HGPS arteries was comparable to that of 24-month WT controls whereas axial arterial stiffening, an additional hallmark of normal aging, was mostly spared in HGPS. Transmission electron microscopy could identify slightly increased amounts of collagen within the elastin folds of HGPS carotid arteries, but this change was barely detectable by immunostaining carotid cross sections or qPCR of isolated aortas. In contrast, immunostaining and RT-qPCR readily revealed an increased expression of Lysyl oxidase (LOX) and its family members in young HGPS arteries.Moreover, treatment of HGPS mice with the pan-Lox inhibitor -aminopropionitrile (BAPN) restored near-normal circumferential arterial mechanics to HGPS carotid arteries, causally linking LOX upregulation to premature arterial stiffening in HGPS. Finally, we show that this premature increase in arterial LOX expression in HGPS foreshadows the increased expression of LOX that accompanies circumferential arterial stiffening during normal aging.

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“…The first clinical trial using a farnesyltransferase inhibitor (FTI), lonafarnib, showed an improvement of cardiovascular phenotypes. Leslie B. Gordon (Progeria Research Foundation, USA) presented the latest results of the FTI trail, which was very encouraging in that mortality was reduced from 29.6% to 3.7% (untreated vs treated) during a 2.2 year follow-up (Gordon et al, 2018). Another trial with FTI and the mTOR inhibitor, everolimus, is ongoing.…”

Section: Hutchinson-gilford Progeria Syndromementioning

confidence: 99%

RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting

Oshima

Kato

Maezawa

et al. 2018

Mechanisms of Ageing and Development

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Progeroid syndrome is a group of disorders characterized by the early onset of diseases that are associated with aging. Best known examples are Werner syndrome, which is adult onset and results from disease-causing DNA sequence variants in the RecQ helicase gene WRN, and Hutchison-Gilford progeria syndrome, which is childhood-onset and results from unique, recurrent disease-causing DNA sequence variants of the gene LMNA that encodes nuclear intermediate filaments. Related single gene RecQ disorders are Bloom syndrome and Rothmund-Thomson syndrome. The RecQ disorders Cockayne syndrome and xeroderma pigmentosum result from disease-causing DNA sequence variants in genes involved in the nucleotide excision repair pathway. RECQ2018: The International Meeting on RECQ Helicases and Related Diseases was held on February 16–18, 2018 in Chiba, Japan. The purpose of the meeting was to facilitate clinical and research collaborations for the goal of developing effective treatments for RECQ disorders and other progeroid syndromes.

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Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome

Abstract: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow-up. Study interpretation is limited by its observational design.

Cited by 173 publications

References 22 publications

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Premature arterial stiffening in Hutchinson-Gilford Progeria Syndrome linked to early induction of Lysyl Oxidase (LOX) and corrected by LOX inhibition

RECQ helicase disease and related progeroid syndromes: RECQ2018 meeting

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