At ACTA2 Alliance, we believe research is what turns uncertainty into understanding, and understanding into progress. For families affected by ACTA2 and Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS), every study, every publication, and every shared data point helps move the field forward.
This section brings together the key research areas in MSMDS and ACTA2: published medical literature, current research projects, and patient registries and participation opportunities.
When families join registries, contribute clinical histories, or take part in studies, they help build the knowledge needed to better understand ACTA2 conditions over time. That knowledge can support earlier recognition, stronger clinical guidance, better standards of care, and future therapeutic development.
Learn how to participate in researchLearn about the main research efforts shaping the future of MSMDS, from natural history studies to emerging therapies and gene-targeted approaches.
Start HereAccess a curated collection of scientific publications on MSMDS and ACTA2, including case reports, reviews, and research studies.Understanding how these conditions develop and affect different systems is key to improving care and outcomes.
The MSMDS Patient Registry is a secure global platform hosted by Sanford CoRDS designed to improve understanding of the condition and support the development of future treatments. Open to all MSMDS patients (ACTA2, MYH11 and related conditions). Secure and confidential. Available in multiple languages
Progress in MSMDS does not happen in isolation.
It happens when families share, clinicians document, researchers investigate, and advocates keep the field moving forward.
Every contribution matters. Every connection matters. Every study matters.
Together, we are helping build a stronger future for everyone affected by MSMDS.
Research in MSMDS & ACTA2 is advancing through growing international collaboration and an expanding network of clinicians, researchers, and affected families working to better understand the disease and develop future therapies.
Although the condition remains ultra-rare and underfunded, the field has changed significantly over the past decade. What once consisted mainly of isolated case reports has evolved into a growing international research landscape involving natural history studies, repurposed therapies, RNA-based approaches, and gene-targeted strategies.
Today, several complementary research pathways are actively being explored. Some aim to better understand the disease and improve daily quality of life, while others focus on regulating smooth muscle cell behavior or directly correcting the underlying ACTA2 mutation.
This progress has not happened by accident. In ultra-rare diseases, progress depends not only on science itself, but on building the infrastructure, patient data, visibility, and collaboration needed to make research possible.
This page highlights the main active research lines currently shaping the future of MSMDS and ACTA2 families.
The Natural History Study (NHS) is the first international effort designed to understand how MSMDS develops and evolves over time.
Led by Dr. Patricia Musolino at Massachusetts General Hospital, this study brings together patients from around the world to build a shared scientific foundation and standardized clinical dataset.
Participants contribute in two ways:
What this study aims to achieve
In rare diseases, strong natural history data is one of the most important tools for accelerating therapeutic development.
The most recent results were presented at the International MSMDS Conference in Danvers, MA, USA (June 2025).
While there is currently no approved treatment specifically for MSMDS, several research teams are exploring therapies that may improve
vascular stability, protect organs, and enhance quality of life.
Nicotinamide riboside (NR), a derivative of vitamin B3 and a precursor of NAD⁺, is currently being evaluated as a potential therapeutic strategy for ACTA2-related conditions. The rationale behind this approach comes from evidence suggesting that impaired cellular energy production and mitochondrial dysfunction may contribute to abnormal smooth muscle cell behavior in MSMDS.
Preclinical mouse studies have shown promising findings including:
These findings led to the launch of a clinical trial using Niagen®, a clinical-grade NR formulation authorized by the FDA for research use. Because NR already has an established safety profile, this represents a relatively near-term and clinically actionable research pathway.
The trial is led by Dr. Dianna Milewicz and her team and is currently in the recruitment phase.
The trial uses a clinical-grade formulation of NR. This is not equivalent to over-the-counter supplements, which differ in purity and are not part of this research.
Sapropterin – Repurposed Therapy
Sapropterin is an FDA-approved drug used in children with phenylketonuria (PKU), now being explored as a potential MSMDS treatment.
Led by Patricia Musolino, this therapy was identified after screening more than 1,500 existing medications. The goal with Sapropterin is to improve smooth muscle cell function and potentially reduce complications associated with the disease.
Early findings from preclinical studies suggest:
Some patients are already receiving Sapropterin off label after discussion with their medical teams. While insurance coverage is still inconsistent and often difficult to obtain, several families have successfully received approval and prescription coverage.
Researchers and clinicians are actively working to expand the medical literature around Sapropterin in MSMDS in order to improve future access and insurance support for patients.
To read the latest Sapropterin research article, follow this link:
To hear Dr. Musolino’s presentation on Sapropterin effects at the International Conference 2025, watch this recording on Youtube: https://youtu.be/BrDWPV5iyiI?si=aXHP_KvO19rUf0eA&t=1345
This work is supported by the Belanger Family Foundation, created by a family directly affected by MSMDS.
MicroRNA Therapy
A separate research line led by Prof. Andrew Baker in Edinburgh is exploring the use of microRNA-based therapies for ACTA2-related vascular disease.
Rather than correcting the mutation directly, this approach aims to regulate how genes are expressed within vascular smooth muscle cells. The goal is to reduce the abnormal vascular remodeling associated with ACTA2 mutations, including vessel wall thickening and narrowing.
Current work includes:
MicroRNA therapies may offer a complementary strategy capable of modifying disease behavior without permanently editing DNA.
This could potentially expand treatment options for patients who may not be candidates for gene-editing approaches.
Another promising RNA-based strategy currently under development involves inhibitory small RNA (sRNA) therapy. This approach is designed to suppress harmful gene activity and improve abnormal smooth muscle cell behavior.
Importantly, similar inhibitory RNA approaches are already being used in human vascular disease in other contexts, which may help accelerate future translational development.
Current work includes:
This therapy represents one of the most promising medium-term translational strategies currently in development. Because RNA-based therapies may be adaptable across multiple variants and pathways, they could eventually become part of a broader platform for vascular genetic diseases.
Most advanced therapeutic approaches are increasingly focusing on the ACTA2 R179H mutation, as it is the most common and severe variant associated with the condition.
By understanding how this specific mutation affects smooth muscle function, researchers are now beginning to move beyond symptom management and explore targeted strategies aimed at addressing the underlying genetic cause.
One of the most advanced research programs currently underway is an AAV-based gene therapy strategy led by Dr. Patricia Musolino.
This approach uses adeno-associated viral (AAV) vectors combined with gene-editing technologies to correct the ACTA2 mutation directly within smooth muscle cells.
Preclinical results show:
This is considered a potentially transformative or curative strategy because it targets the root genetic cause of the disease. The current development pathway may eventually progress toward first-in-human studies if ongoing preclinical and regulatory milestones are successfully completed.
AAV therapies also benefit from existing human experience in other diseases, with thousands of patients already treated using similar delivery systems.
A second gene-targeted strategy under development uses lipid nanoparticles (LNPs) instead of viral vectors.
Like AAV therapy, the goal is to correct the ACTA2 mutation directly within vascular smooth muscle cells. However, the delivery system is fundamentally different.
Advantages of LNP approaches:
LNP therapies represent one of the most important long-term platform technologies currently being explored for vascular genetic diseases.
If successful, they could eventually make mutation-specific therapies more accessible and adaptable across multiple rare conditions.
The VESSEL Project, led by Dr. Patricia Musolino at Massachusetts General Hospital, has been awarded up to $25.8 million from ARPA-H to support five years of research developing gene-editing treatments for MSMDS and other rare genetic vascular diseases.
The project combines base-editing technology with vascular-targeted delivery approaches to explore ways of addressing disease-causing genetic variants at their source.
While a treatment is not yet available and significant research remains ahead, this major investment provides new resources and momentum to advance potential therapies for MSMDS.
ACTA2 Alliance is proud to have patient representation on the VESSEL Patient Advocacy Committee, with Warren Anderson, Lydia Anderson, and Angela Cas representing the patient and family community.
The MSMDS-ACTA2 research landscape has changed dramatically in only a few years. The field is no longer asking whether meaningful research is possible, but how quickly these therapies can move forward and whether sufficient funding can be secured to make that possible.
Many of these programs require:
For the first time, multiple therapeutic approaches are actively moving through the pipeline,
from treatments aimed at improving daily quality of life to gene-targeted strategies designed to address the underlying cause of the disease itself.
The hope is that future updates to this page will not only describe research in development, but also therapies already reaching patients and changing lives.
Continued support for MSMDS & ACTA2 research can help make that future arrive faster.
1. Kaw, A., Majumder, S., Esparza Pinelo, J.E. et al. Immature Acta2R179C/+ smooth muscle cells cause moyamoya-like cerebrovascular lesions in mice prevented by boosting OXPHOS. Nat Commun 16, 6105 (2025).https://www.nature.com/articles/s41467-025-61042-3
2. Advances in Research – Nicotinamide Riboside, Dra. Dianna Milewicz (UTHealth) Presented in: 2025 ACTA2 Alliance / MSMDS Family & Research Conference. https://youtu.be/d27pokXpNxs?si=28vYt8WMRt35_mRO&t=1619
3. State of the Natural History Study, Diana Tambala, Emily Da Cruz, & Benjamin Ondeck (MGH). Presented in: 2025 ACTA2 Alliance / MSMDS Family & Research Conference. https://www.youtube.com/watch?v=s1fibSP-l78&list=PL9i5mdmWtAp4VhC76CV1OJ2WJNtnNXME7&index=16
4. Advances in Research – Sapropterina, Dra. Patricia Musolino (Harvard/MGH). Presented in 2025 ACTA2 Alliance / MSMDS Family & Research Conference. at https://youtu.be/BrDWPV5iyiI?si=p_Ewq1_taWdoeirM&t=1347
5. Christiano R. R. Alves, Sabyasachi Das, Vijai Krishnan et al. In vivo Treatment of a Severe Vascular Disease via a Bespoke CRISPR-Cas9 Base Editor bioRxiv 2024
https://www.biorxiv.org/content/10.1101/2024.11.11.621817v1
6. Updates in gene therapy for MSMDS, Dra. Patricia Musolino (Harvard/MGH). Presented in: 2025 ACTA2 Alliance / MSMDS Family & Research Conference. https://youtu.be/BrDWPV5iyiI?si=2gjvbxwcQ8ZH6U07&t=1865
7. Qianqian Ding, PhD, Peiheng Gan, PhD, MBBS, Zhisheng Xu, PhD, Hui Li, PhD, et al.Genomic Editing of a Pathogenic Sequence Variant in ACTA2 Rescues Multisystemic Smooth Muscle Dysfunction Syndrome in Mice. Circulation, 2025.
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.125.074218
*This content is not intended as a substitute for professional medical advice, diagnosis, or treatment. Should you require medical advice, please contact a qualified medical professional who is familiar with Multisystemic Smooth Muscle Dysfunction Syndrome.
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