Periodic Reporting for period 4 - GENOMIA (Genomic Modifiers of Inherited Aortapathy)
Reporting period: 2023-07-01 to 2023-12-31
Thoracic aortic aneurysm and dissection (TAAD) is a significant cause of morbidity and mortality in the Western world, with a substantial genetic component—around 20% of affected individuals have a positive family history. Over the past decade, numerous genes have been identified as contributors to both syndromic (e.g; Loeys-Dietz syndrome) and non-syndromic forms of TAAD. While not all cases are fully explained by these discoveries, they have illuminated three major pathological mechanisms underlying TAAD: disrupted extracellular matrix homeostasis, dysregulated TGFβ signaling, and impaired smooth muscle cell contractility.
The advent of next-generation sequencing technologies delivered the promise of accelerating our molecular understanding of TAAD. In this project important clinical-molecular challenges were addressed. Many syndromic and non-syndromic cases exhibit non-penetrance and substantial variability in clinical presentation, even among individuals carrying the same genetic mutation. This variability ranges from asymptomatic cases to sudden aortic dissection leading to early death, with the mechanisms behind this diversity still poorly understood. This project employed four innovative strategies to uncover genetic modifiers that influence aortopathy in humans and mice.
The advent of next-generation sequencing technologies delivered the promise of accelerating our molecular understanding of TAAD. In this project important clinical-molecular challenges were addressed. Many syndromic and non-syndromic cases exhibit non-penetrance and substantial variability in clinical presentation, even among individuals carrying the same genetic mutation. This variability ranges from asymptomatic cases to sudden aortic dissection leading to early death, with the mechanisms behind this diversity still poorly understood. This project employed four innovative strategies to uncover genetic modifiers that influence aortopathy in humans and mice.
This research has delivered significant advancements in the understanding thoracic aortic aneurysm and dissection (TAAD) and Loeys-Dietz syndrome (LDS). First our project delivered novel patient-derived iPSC models: especially iPSC-VSMC models from patients with TGFB3 and SMAD3 pathogenic variants have been developed and made available to the TAAD research community. Second, we discovered IPO8 as an important TAAD gene resulting in a Loeys-Dietz syndrome subtype. Moreover The identification of IPO8 as a novel TAAD-associated gene has positioned it as a key molecule at the downstream end of the TGFβ signaling pathway, offering potential as a therapeutic target. Thirdly, our research established two novel mouse models for aneurysm and dissection research: AngII-infused Bgn-deficient mice and Ipo8 knockout mice, the latter being one of the few spontaneous aortic dissection models. Notably, the inability to replicate the previously reported high mortality of male Bgn-knockout mice led to the development of a novel AngII infusion model demonstrating severe dissection without hypertension. RNA sequencing of aorta mouse models (SMAD3 and IPO8) led to the identification of a potential biomarker and drivers of aortic aneurysmal disease, culminating in a patent application. Finally, the combined mouse and iPSC study delivered three potential modifiers for TAAD severity. With regard to dissemination of research findings, we organized the first European LDS patient and research networking meeting, which uniquely combined patient engagement with setting the research agenda for the field over the next several years.
This project has produced several key findings that hold great promise for advancing the understanding and treatment of thoracic aortic aneurysm and dissection (TAAD).
First, the previously reported high mortality of male Bgn-knockout mice in the Balb/C background could not be replicated, necessitating the development of an alternative model. Through this work, it was demonstrated that a low dose of angiotensin II (AngII)—not inducing hypertension—provokes a severe dissection phenotype, offering a new and reliable platform for studying TAAD pathogenesis. Second, the identification of IPO8 as a critical molecule in TAAD pathogenesis in both mice and humans represents a breakthrough. Human pathogenic variants in IPO8 have led to the discovery of a novel subtype of Loeys-Dietz syndrome (LDS) and the first recognized human importin-related disease. These findings not only expand the genetic landscape of aortic disease but also open avenues for in-depth exploration of IPO8-related mechanisms and their therapeutic implications. The development of advanced mouse models for Bgn and Ipo8, coupled with iPSC-based cellular systems, offer powerful tools for identifying genetic and molecular modifiers that influence TAAD progression. These models will facilitate a deeper understanding of the functional consequences of primary mutations, providing critical insights into the variability in disease expression and outcomes.
By uncovering additional modifiers on top of the ones already pinpointed in this project, the research aims to enhance precision medicine for TAAD, enabling personalized treatment strategies and revealing novel therapeutic targets.
First, the previously reported high mortality of male Bgn-knockout mice in the Balb/C background could not be replicated, necessitating the development of an alternative model. Through this work, it was demonstrated that a low dose of angiotensin II (AngII)—not inducing hypertension—provokes a severe dissection phenotype, offering a new and reliable platform for studying TAAD pathogenesis. Second, the identification of IPO8 as a critical molecule in TAAD pathogenesis in both mice and humans represents a breakthrough. Human pathogenic variants in IPO8 have led to the discovery of a novel subtype of Loeys-Dietz syndrome (LDS) and the first recognized human importin-related disease. These findings not only expand the genetic landscape of aortic disease but also open avenues for in-depth exploration of IPO8-related mechanisms and their therapeutic implications. The development of advanced mouse models for Bgn and Ipo8, coupled with iPSC-based cellular systems, offer powerful tools for identifying genetic and molecular modifiers that influence TAAD progression. These models will facilitate a deeper understanding of the functional consequences of primary mutations, providing critical insights into the variability in disease expression and outcomes.
By uncovering additional modifiers on top of the ones already pinpointed in this project, the research aims to enhance precision medicine for TAAD, enabling personalized treatment strategies and revealing novel therapeutic targets.