Skip to main content
/ Delivering on the promise of mRNA ther...
19 December 2017

Delivering on the promise of mRNA therapies for rare diseases

Stephen Hoge
M.D., President
Paolo Martini
Chief Scientific Officer, Rare Diseases

2017 has been both an exciting, and by all measures, a highly productive year here at Moderna.  We began with four clinical programs and are ending the year with ten. In January, we unveiled 12 development candidates (DCs) and have since added six more to our pipeline.

We are proud of the development program pipeline, the work of our teams and continued focus on addressing high unmet need across several therapeutic areas. The naming of our first rare liver disease DC earlier this year – an mRNA therapeutic for methylmalonic acidemia (MMA) – was a particularly significant milestone for our team.     

In many ways, development of mRNA medicines for rare diseases represents our highest technical bar to date. Unlike our other existing applications, where interventions with our mRNA technology are relatively short (such as with a vaccine or an intratumoral immuno-oncology therapeutic), in rare diseases we will need to maintain chronic dosing in patients – potentially over a lifetime, initiating treatment in both children and infants.  

With the announcement of our MMA program in September, we signaled that we believe we’ve made strides in solving some of the key obstacles to chronic, repeat dosing of an mRNA therapeutic to the liver. Today, in the publication Cell Reports, we were proud to share the first preclinical data supporting our MMA program, and the ability to repeat dose mRNA therapeutics.

While these are early data and we have a long journey ahead of us – into and through clinical trials for this program – today’s publication marks an important milestone as we advance mRNA therapeutics for MMA and other rare liver diseases.  

A potentially transformative approach to enzyme replacement

MMA is a systemic chronic disease that affects the nervous, GI, hematological and cardiac systems. A pediatric disease, MMA often leads to recurring, life-threating metabolic events as the patient’s blood becomes highly acidic from eating certain foods. It is caused by a genetic defect that results in too little or no production of a critical metabolic enzyme produced by liver cells (known as methylmalonyl-CoA mutase, or MUT for short).  

Currently, liver and/or kidney transplant is the only effective long-term therapy. Consider that for a moment: needing to remove and replace an entire organ in the body to address one defective enzyme. 

The data published today demonstrate that intravenous (IV) administration of an mRNA therapeutic encoding for MUT enabled liver expression of the enzyme in mouse models, leading to a significant reduction in methylmalonic acid and the survival of the full cohort of treated mice versus the control group.

survival curve of untreated

Put more simply, what we showed in these initial experiments was that by using mRNA we were able to address the mutation and effectively replace the enzyme in the cell. 

Our approach is meaningfully different from current enzyme replacement therapies, which work by making only certain types of proteins that can be made outside the body and introducing them into the body through IV administration. This can be highly effective for patients in only a subset of diseases. However, in many rare diseases, like MMA, a mitochondrial protein is missing. Current approaches don’t allow for correct localization of many proteins unless made naturally by the body, leaving many, many diseases without an effective therapy.

With mRNA therapeutics, we deliver a set of instructions into cells and direct those cells to produce a protein of interest. In the case of MMA, the liver cells produce and express a functional MUT protein.

This ability to get inside cells and instruct them to produce a functional protein could have critical implications in a significant number of rare diseases. 

We were also pleased to see in this study that repeat IV dosing did not increase markers of liver toxicity or inflammation, key safety factors.

Today’s data not only show the early potential of utilizing our mRNA technology to address MMA, but also to address a broad spectrum of rare liver diseases. One of the promises of our mRNA platform is the idea that if we can solve a technological problem for one disease, then it is possible that a whole family of diseases becomes addressable.

This is what we have previously shown in vaccines, moving from one to nine in a very short timeframe. Our hope is to replicate this approach in rare diseases – starting with the family of organic acidemias.   

There's a tremendous unmet need in these rare diseases and many of these patients are living with life threatening complications. We take our responsibility to these children and their families very seriously, and recognize the commitment to the patient community and to developing a treatment that can help to change lives. In the coming year, we look forward to sharing even more data as we advance these development candidates toward the clinic.

Dr. Stephen Hoge, President, and Paolo Martini, Ph.D., CSO Rare Diseases, discuss newly published preclinical data supporting Moderna’s first rare liver disease development program, an mRNA therapeutic for methylmalonic acidemia (MMA).