Unlocking the potential of mRNA for the future treatment of rare diseases 


mRNA technology helped us to vaccinate the world against SARS-CoV-2. As we turn our focus to new potential applications and disease areas for the platform, scientists and companies must consider the potential life-saving impact on rare, inherited diseases, says Archana Gupta, PhD, staff scientist in genetic sciences at Thermo Fisher Scientific. 

Approximately 7,000 rare and ultra-rare diseases have been described, and yet, 90% have no approved therapeutic options1. And while these conditions are rare, the patients and families affected are many. Three hundred and fifty million people in the world, with 37 million in the United States and Canada, have been diagnosed with rare disease, 80% of which are inherited and genetic in origin2. 

With only 10% of these conditions indicated for an approved therapy, there is a sizable opportunity for scientists and companies to develop treatments for patients with no other options to turn to. At a time when the messenger ribonucleic acid (mRNA) platform solved one of the greatest global health challenges of our lifetime – vaccinating the world against SARS-CoV-2 – its potential to advance relief for rare diseases deserves increased focus, attention and investment.  

From life-saving vaccines to life-saving therapeutics 

While mRNA mostly became known during the Covid-19 pandemic as the scientific platform that helped vaccinate the world against SARS-CoV-2, the technology has been investigated for more than a decade as a potential therapeutic, and it was hoped to have a particular advantage for rare diseases3 

Now, given the extraordinary success of the Covid-19 vaccines, the mRNA platform may bring renewed hope as researchers explore its potential to advance medicines for rare diseases.  

Interestingly, at least 80% of all rare diseases originate from monogenic mutations, meaning that they arise from mutations in a single gene4. This presents a unique opportunity for mRNA-based therapies to potentially restore normal cell function by supplying copies of the functional transcript for the cell to read.  

mRNA enables the delivery of a transiently expressed genetic molecule that is translated into a target protein using the machinery of the host cell. Therefore, the risk for off-target insertional mutagenesis is greatly reduced. In addition, it may be easier to target the therapeutic molecule to the correct cell or tissue. The half-life of proteins expressed through the mRNA technology is also much longer than those of direct protein delivery, which suggests that it could be more effective as a treatment strategy for rare diseases. Finally, dosing and timing may be controlled simply by adjusting the amount of mRNA delivered to the cells, rather than relying on inducible systems that are integrated into the genome. 

Today, there are several programmes in health industries that are currently investigating the therapeutic potential of mRNA vaccines for rare diseases, particularly for cystic fibrosis, as well as rare, inherited metabolic disorders caused by genetic mutations that lead to non-functional versions or abnormal levels of a particular protein.  

Moderna Therapeutics, a biotechnology company that has developed SARS-CoV-2 mRNA vaccines, has at least six rare disease programmes currently in preclinical and clinical development (Table 1). On one of the programmes, the company collaborated with a research group at University Hospital at Padova, Italy, on preclinical studies investigating a potential therapeutic for methylmalonic acidemia5. Arcturus Therapeutics has one rare disease program focused on ornithine transcarbamylase deficiency in Phase II clinical study, as well as a preclinical program to investigate an mRNA medicine for cystic fibrosis. Additionally, Vertex Pharmaceuticals has been investigating potential mRNA-based treatments for cystic fibrosis caused by incorrect modulation of CFTR protein, a condition that impacts approximately 5,000 people around the world. 

Table 1: Overview of rare disease programmes in industry studying the mRNA platform6

Disease area Company Stage of Development 
Crigler-Najjar Syndrome Type 1 (CN-1)
Moderna Therapeutics Preclinical 
Phenylketonuria (PKU)
Moderna Therapeutics Preclinical 
Ornithine transcarbamylase deficiency (OTC)
Moderna Therapeutics Preclinical 
Cystic Fibrosis Arcturus Therapeutics
Cystic Fibrosis Vertex Pharmaceuticals Preclinical + Phase 1 Clinical 
Methylmalonic acidemia (MMA)
Moderna Therapeutics Phase 1 Clinical  
Glycogen storage disease type 1a (GSD1a)
Moderna Therapeutics Phase 1 Clinical 
Propionic acidemia (PA)
Moderna Therapeutics Phase 2 Clinical  
Ornithine transcarbamylase deficiency Arcturus Therapeutics 


Phase 2 Clinical 

Genetic analysis – a critical component of developing mRNA therapeutics 

The research and development of mRNA therapies is based upon rigorous analysis and quality control to enable potential treatments.   

The manufacturing process begins with the construction of a DNA vector into which the template from which the mRNA will be transcribed in vitro from, is inserted. Genetic analysis tools such as Sanger sequencing by Capillary Electrophoresis (CE) and qPCR are an integral part of the vector construction process to confirm and validate that the correct sequence of the gene is inserted into the vector backbone. After sequence confirmation, the plasmid is propagated, purified and linearised, following which it is in vitro transcribed (IVT) to synthesize the mRNA transcripts. The mRNA transcripts are then purified from the IVT reaction. At this stage, qPCR can be used to check for IVT efficiency, residual DNA contamination and adventitious agents such as microbes. The identity of the transcript is confirmed by Sanger sequencing. In addition, the purity of the final product can be evaluated by using ultrasensitive digital PCR, to detect any residual non-mRNA products, and 16S sequencing, to identify bacterial contamination.  

The structure of the mRNA is of key importance as it influences the translation efficiency and stability of the transcript in the cell. For mRNA-based therapeutics, the synthetic mRNA can be chemically modified by manipulating the termini, using altered bases, as well as modifying the sugar backbone to achieve maximum potential efficacy7. These modifications can also ensure the mRNA forms the correct structure and can influence biologic stability. 

The delivery mechanism of mRNA for therapeutic purposes can vary. From a lipid nanoparticle-based formulation to the use of polymers such as polyethyleneimine (PEI), several delivery systems and routes of administration continue to be evaluated in an effort to achieve maximum efficacy and safety.  

Future outlook: Bringing hope to rare disease

The mRNA platform has already begun to transform the way we think about vaccine development. Given its recent success, I believe we will see continued innovation in the field that extends into mRNA-based therapeutics for several diseases, especially those that have had limited or ineffective drug options so far. 

Rare diseases often have few, if any, therapeutic options for their condition. With the science we have available to us now, these patients deserve our increased attention, focus and investment. Recent progress on mRNA therapeutics – with at least five programmes in clinical studies – is encouraging, and I hope that we will only see more scientific advancement in the years to come. 


  1. Rare Disease Facts and Statistics | NORD (rarediseases.org) 
  2. Rare Genetic Diseases (genome.gov) 
  3. A New Era for Rare Genetic Diseases: Messenger RNA Therapy – PubMed (nih.gov) 
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223693/ 
  5. Rare diseases the next target for mRNA therapies (nature.com) 
  6. https://www.modernatx.com/research/product-pipeline   
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198544/ 


Archana GuptaAbout the Author 

Dr Archana Gupta is a staff scientist in genetic sciences at Thermo Fisher Scientific, where she leads high impact teams through research & development with particular focus on genetic analysis solutions. She is passionate about advancing research in the pursuit of healthier lives for all.



Related Articles

Join FREE today and become a member
of Drug Discovery World

Membership includes:

  • Full access to the website including free and gated premium content in news, articles, business, regulatory, cancer research, intelligence and more.
  • Unlimited App access: current and archived digital issues of DDW magazine with search functionality, special in App only content and links to the latest industry news and information.
  • Weekly e-newsletter, a round-up of the most interesting and pertinent industry news and developments.
  • Whitepapers, eBooks and information from trusted third parties.
Join For Free