# A novel treatment of aortic disease in Marfan Syndrome targeting oxidative stress and PKG dysregulation

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $716,987

## Abstract

Summary
Aortic aneurysms and dissections are the most serious and deadly manifestations of Marfan Syndrome (MFS),
and current therapies to prevent aortic dilation are only moderately effective. MFS is caused by mutations or
deletions in fibrillin-1 (Fbn1), a component of extracellular microfibrils, which surround and connect elastic fibers
to smooth muscle cells (SMCs) in the aortic media. Reduced fibrillin function alters signaling between
extracellular matrix and SMCs, resulting in SMC apopotosis and extracellular matrix degradation. In addition, the
altered signaling leads to increased production of reactive oxygen species (ROS) and nitric oxide (NO),
increasing oxidative and nitrosative stress and activating protein kinase G (PKG) via the NO/cGMP pathway.
Although the increased ROS, reactive nitrogen species (RNS), and PKG activation contribute to aneurysm
formation in MFS, neither the sources of ROS/RNS nor the effects of oxidative/nitrosative stress on SMC
functions are fully understood. The vitamin B12 analog cobinamide, on which we hold several patents, is a strong
and versatile antioxidant that can neutralize ROS and RNS, including NO. During the last grant period, we
showed that mice with an activating PKG1 mutation (Prkg1R177Q) that causes thoracic aneurysms and dissections
in humans, develop aortic dilation associated with increased oxidative stress and media degeneration⸺elastic
fiber fragmentation, increased matrix metalloproteinase activity, media fibrosis, and SMC apoptosis; cobinamide
treatment completely prevented these changes. Preliminary data show that cobinamide also reduces aortic
dilation and prevents elastic fiber fragmentation and SMC apoptosis in a mouse model of MFS (Fbn1C1041G/+),
while reducing markers of oxidative stress and excess PKG signaling. We hypothesize that increased ROS/RNS
combined with PKG activation from increased NO synthase (NOS2) drive abnormal SMC functions and aortic
pathology in MFS, and that an optimized dose schedule of cobinamide will prevent aortic dilation and improve
survival in mice with MFS, especially when combined with a -blocker. In Aim 1, we will determine the mecha-
nisms and consequences of excess ROS/RNS generation in human fibrillin1-deficient or mutant (iPSC-derived)
SMCs, using shRNA knockdown and pharmacological approaches to inhibit ROS/RNS-generating enzymes and
PKG in vitro. We will assess contributions of excess NO synthase and PKG activity to the progression of aortic
disease in vivo, by inducing SMC-specific knockout of NOS2 or PKG1 in Fbn1C1041G/+ mice. We will also test
whether ROS detoxification by SMC-specific catalase overexpression ameliorates aortic pathology. In Aim2, we
will determine the optimal cobinamide dose and starting time to prevent aortic dilation and death from aortic
dissections in mice with moderate (Fbn1C1041G/+) and severe (Fbn1mgR/mgR) MFS, respectively. In addition, we will
combine cobinamide with the β-blocker propranolol, because cobinamide prev...

## Key facts

- **NIH application ID:** 10805486
- **Project number:** 5R01HL132141-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** RENATE B PILZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $716,987
- **Award type:** 5
- **Project period:** 2016-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805486

## Citation

> US National Institutes of Health, RePORTER application 10805486, A novel treatment of aortic disease in Marfan Syndrome targeting oxidative stress and PKG dysregulation (5R01HL132141-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10805486. Licensed CC0.

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