Current Research in MSMDS

Emerging Therapeutic Approaches

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.

Repurposed Drug: Nicotinamide Riboside (NR)

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:

• Reduction in stroke-related mortality
• Neuroprotection
• Improved vascular function
• Multisystemic functional improvement 

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.

Highlight: 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:

• Prevention of aortic aneurysms
• Reduced vascular tortuosity
• Improved cerebral blood flow
• Increased energy levels
• Better gut motility and digestion

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:
https://quebecphilanthrope.org/wp-content/uploads/2023/12/Kuvan.pdf

To hear Dr. Musolino’s presentation on Sapropterine’s 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:

• Testing in human vascular tissue
• Development of preclinical models
• Planned mouse studies
• Future FDA-oriented translational development

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.

Inhibitory sRNA Therapy 

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:

• Testing in human vascular tissue
• Planned mouse studies
• Future manufacturing and clinical translation pathways

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.

Research Targeting the ACTA2 Mutation

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.

AAV Gene Therapy

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:

• Prevention of vascular disease
• Improved survival
• Restoration of smooth muscle function
• Improvement across multiple organs including brain, gut, bladder, and lungs

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.

Lipid Nanoparticle (LNP) Gene Therapy

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:

• Potentially re-dosable
• More scalable in the future
• Potentially easier adaptation to additional ACTA2 variants
• Lower projected future treatment costs
  
  

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.

Why research funding matters now

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:

• Preclinical studies
• Manufacturing development
• Regulatory preparation
• Clinical trial coordination
• Long-term patient follow-up
• Dedicated scientific personnel
  
  

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.