Michael Houston Ph.D. CSO PhaseRx

Safe Shuttles May Pick Up Where Traditional ERT Falls Short

The market for conventional enzyme replacement therapy is large and growing fast, encompassing medical treatments for Gaucher disease, Fabry disease, and some of the dozens of other inherited metabolic disorders categorized as lysosomal storage diseases.

One thing in common for all of these diseases is the absence or deficiency of an enzyme that’s needed for healthy metabolic functions. Without the proper level of certain enzymes in the body, toxic materials build up in the patients’ cells, leading to critical health issues. Depending on the specific disease, different areas of the body are affected—sometimes it’s the skeleton or brain, other times it’s the skin, heart or central nervous system. In all cases, it can be life threatening if not treated.

Enzyme replacement therapy (ERT), a pharmaceutical category with $4 billion in annual sales, has shown to work well in keeping many of these metabolic disorders under control. For example, in individuals with Gaucher disease type 1, an injected therapy known as Cerezyme is able to replace glucocerebrosidase, the enzyme that individuals with Gaucher lack.

But for all of the progress of ERT, there’s a whole class of enzyme-based disorders that these drugs will never be able to treat—diseases in which the enzyme is required within individual cells to perform a key metabolic function.

We see this most clearly in urea cycle disorders, a grouping of four inherited liver diseases with limited therapeutic options today. “Urea cycle” is the term for a series of biochemical steps in which nitrogen, a waste product of protein metabolism, is transformed into a compound called urea and removed from the blood. It’s a process that occurs within the cell.

In healthy people, the urea is naturally removed from the body through urine. However, people born with a urea cycle disorder are lacking one of the enzymes that make the urea cycle possible. As a result, nitrogen builds up in patients’ blood in the form of ammonia, a highly toxic substance. Even a small amount of ammonia presents a serious danger. If it’s not removed, ammonia can reach the brain through the blood, where it can cause irreversible brain damage, coma, or even death.

For urea cycle diseases, a traditional ERT simply isn’t an option, as the enzymes cannot access the intracellular area where it’s needed to be active. However, there may be a different way to treat these patients more effectively than the burdensome and not always reliable “ammonia scavenger” treatment that’s currently the only option. In fact, messenger RNA (mRNA) seems to be built for this very purpose.

A Potential Solution for Intracellular Enzyme Replacement

For the last five years, the biotechnology industry has stirred with excitement over the potential of mRNA to mature into a new class of drugs capable of treating a broad range of diseases, particularly single-gene disorders that result in debilitating health problems.

Whereas such a prospect seemed impossible at the dawn of biotech in the 1980s, today mRNA is seen as one of the next major revolutions of medicine. When delivered to the problematic organ or tissue, mRNA molecules can be introduced into cells—providing the missing genetic information to create the deficient protein, without actually becoming part of the patient’s DNA. However, achieving this vision has been difficult, even for pharma’s best research and development teams.

Stability has been a key problem, as has delivery. Compared with small-molecule drugs, which are typically 500 daltons or smaller and can assimilate easily into the bloodstream, mRNA drugs are enormous—weighing in at hundreds of thousands of daltons. They’re also negatively charged, highly unstable, and easily degraded by nucleases. Further, mRNAs are typically not found circulating in the blood stream; if they are, they are usually associated with a virus such that the body recognizes the mRNA as being part of a foreign entity and mounts an immune response targeting them for destruction. 

For urea cycle disorders, which are based in the liver, developing mRNA formulations that protect the mRNA, while minimizing the potential to activate the immune systems and are specific to hepatocytes is the goal. 


Once the mRNA is delivered inside the cell, the cell’s own machinery is used to produce normal functioning enzyme.

A Safe Shuttle to the Intended Destination

Recent efforts to deliver mRNA to target cells have focused on encapsulating mRNA in a vessel that will protect the nucleic acid until it reaches its intended destination.      

For example, a hybrid lipid-polymer mRNA delivery technology, developed at the University of Washington and advanced more recently at biopharmaceutical company PhaseRx, has been optimized to take advantage of the liver’s inherent ability to filter the blood and remove unwanted material. The lipid-polymer nanoparticles are able to circumvent some of the previously mentioned delivery issues by optimizing their targeting to the liver cells and triggering the endosomal release of mRNA into the cytoplasm. In preclinical studies, this lipid-polymer nanoparticle system was used to lower blood ammonia and rescue 100 percent of treated mice with a urea cycle disorder, and was safe and well tolerated in non-human primates.

Additional delivery systems that have shown promise recently have borrowed heavily on the fusogenic lipid nanoparticle formulations developed by siRNA companies such as Arbutus (formerly Tekmira) and Alnylam—and are now being developed by companies such as Moderna, Acuitas, and Shire, to name a few. These formulations, which have shown high expression of proteins such as erythropoietin (EPO), are being applied to therapeutic proteins and vaccines.  

Picking Up Where Traditional ERT Falls Short

In the burgeoning field of mRNA therapeutics, going after rare liver diseases makes sense for yet another reason: the mRNA manufacturing technology is still in its infancy. As an industry, we have yet to discover how to make sufficient quantities of mRNA for larger disease indications. However, given that mRNA manufacturing is based on the use of enzymes to perform the transcription reactions, the manufacturing process is highly scalable. As technology advances to a point where large batches of mRNA can be produced, it makes sense to focus on diseases with small patient populations—diseases where we can make an impact today. 

The field of mRNA is brimming with discovery and potential in every respect, from drug delivery technology to manufacturing. We are continuously building on the immense knowledge gained in the RNA drug development field, which took off more than a decade ago.

While current mRNA drug programs focus mainly on vaccines, it won’t be long before technology has improved our delivery capabilities and enabled mRNA as feasible therapies for cystic fibrosis, muscular dystrophy, and other disease areas that hinge on a deficient or missing gene. Until that time, it holds much hope for treating rare liver diseases, where patients are eager to be among the first to benefit from this new wave of innovation. 

Michael Houston, Ph.D., is CSO of PhaseRx.