Most laypeople haven't heard of protein replacement therapy, but the world of molecular medicine is abuzz with interest in this promising medical treatment. A chief aim for those working in the field of molecular medicine is to develop an efficient way to reliably replace missing proteins in diseased cells. Gene therapy is one possible method for achieving that, but according to the U.S. National Library of Medicine, a database overseen by the National Institutes of Health (NIH), this experimental approach comes with considerable risks and significant advances will need to be made before it becomes safe. Other methods of protein replacement therapy, however, do not require the transfer of genetic material into cells, which eliminates some of the most significant issues that arise with gene therapy while still allowing for the delivery of missing or deficient proteins.
Read on to learn more about protein therapy and its potential treatment applications.
The Science of Protein Replacement Therapy
So far, most of the research into protein replacement therapy has been focused on its use for the treatment of rare monogenic diseases. These conditions occur because of a single defect in a single gene found in human DNA. Though these diseases are considered rare, experts estimate there are over 10,000 of them and that they affect millions of individuals around the globe.
Supporting Research Into Treatments for Rare Diseases
Developing treatments for rare diseases can be quite challenging, in part because companies are less likely to make a profit off such treatments, and therefore less likely to fund research into potential treatments and cures. In an effort to address this, several countries have passed legislation to encourage companies to develop drugs to treat "orphan diseases," a classification applied to "diseases with a prevalence of less than 200,000 affected individuals in the United States and less than approximately 250,000 affected individuals in the European Union (EU)," per an article titled "Protein Replacement Therapies for Rare Diseases: A Breeze for Regulatory Approval?" that was published in Science Translational Medicine in 2013.
The U.S. Orphan Drug Act, passed in 1983, extends regulatory, commercial, and tax incentives to companies investigating drugs designed to treat orphan diseases. In 2000, the EU passed a similar piece of legislation and multiple other countries have since followed suit. Currently, genetic diseases (along with rare types of cancer and drugs with pediatric indications) rank among the top three in terms of approved orphan drug treatments. And protein replacement therapies for monogenic diseases is a popular subcategory within that realm.
Justifying the Use of Monogenic Protein Replacement Therapies
Blood factors and enzyme replacement therapies for lysosomal storage disorders were two of the first monogenic protein replacement therapies (MPRTs) to receive regulatory approval with orphan drug classification in the United States and EU. When these drugs went to market, manufacturers introduced what's known as "orphan pricing," a system in which high premiums are charged to compensate for limited demand. According to the Science Translational Medicine article, the cost of MPRTs, a category that includes drugs like Fabrazyme, Elaprase, and Naglazyme, tops $200,000 annually while sales come in at over $100 million.
Given those numbers, it's hardly surprising how much attention has been paid to the prices charged for orphan drugs, and, subsequently, the difficulties faced by health care systems when it comes to reimbursement. Determining which patients should be approved for these costly treatments requires complicated calculations, and not everyone agrees on which criteria should be used.
The paradigm so far has been that the use of MPRTs can be reimbursed in the United States, most member countries of the EU, and Japan. It's also common practice for these drugs to be provided at no cost in countries with low average household income levels and underdeveloped health care systems.
The authors of the Science Translational Medicine article argue that in order to justify the high prices charged for orphan drugs and the rates at which health care systems reimburse for their use, manufacturers must demonstrate that they are, in the long-term, cost-effective treatments. While clinical trials have shown that long-term use of MPRTs can be safe, clinically effective, and lead to health-related improvements in terms of quality of life, more research is needed to conclusively prove that their use leads to net reductions in health care costs.
Potential Applications for Protein Replacement Therapy
Clinical trials have investigated the use of protein replacement therapy for a variety of conditions, including:
- Blood components
- Lysosomal enzymes
- Metabolic disorders
Two of the most promising applications to date are for the treatment of recessive dystrophic epidermolysis bullosa and heart failure.
Protein Replacement Therapy for Recessive Dystrophic Epidermolysis Bullosa
Studies conducted on the use of protein replacement therapy to treat recessive dystrophic epidermolysis bullosa have yielded highly promising results.
This disease belongs to the epidermolysis bullosa family, a collection of genetic disorders related to structural proteins in the skin. Individuals with these disorders have atypically fragile skin and mucous membranes that are prone to splitting and blistering. To compound matters, the underlying gene defect compromises wound healing. If wounds do manage to heal, extensive scarring is typical.
Recessive dystrophic epidermolysis bullosa (RDEB), one of the most severe iterations, happens when the gene coding for type VII collagen protein either does not function properly or is absent. This protein helps the two primary layers of the skin—the epidermis and the dermis—adhere to each other. Without it, the skin often separates, leading to blisters and a higher risk of infection.
The NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases highlighted research done with mice that indicated protein replacement therapy could be the key to treating this debilitating genetic condition.
The research, published in Molecular Therapy and the Journal of Investigative Dermatology, examined two techniques for replacing absent or defective type VII collagen with the goal of improving wound healing and reversing both structural and molecular defects in the skin of individuals with RDEB.
The first technique involved topically applying human recombinant type VII collagen (rC7) to the backs of mice with normal collagen genes. After 2 weeks, the team of researchers led by David T. Woodley, M.D., and Mei Chen, Ph.D., of the University of Southern California discovered that the rC7 had been stably incorporated and sped up the skin's healing process. It also decreased scarring compared to untreated mice. The beneficial effects lasted for 2 months.
Next, the researchers tried topical applications of rC7 on RDEB skin grafts attached to the backs of mice. When rC7 was applied to broken skin, it was successfully incorporated and improved wound healing. However, when it was applied to intact skin, it was not incorporated. The researchers concluded that this limits the use of topical rC7 as it can only help to increase the rate of healing for existing wounds and cannot prevent the formation of wounds or blisters.
The second technique was intravenous administration of rC7. The research team began by wounding the skin on the backs of mice with normal collagen genes and injecting rC7 into their tail veins. They discovered that the rC7 traveled to the wounds where it was successfully incorporated. Again, it appeared to accelerate healing. They found no evidence of rC7 in healthy, wound-free skin or internal organs.
Subsequently, the team examined the effects of administering rC7 intravenously to mice with RDEB skin grafts. The injected rC7 traveled to the skin grafts where it "created new anchoring fibril structures, which hold the epidermis together."
According to study authors Drs. Woodley and Chen, "Intravenous delivery of rC7 opens up new prospects for more systemic treatment of the disease. Our data suggest that intravenous rC7 not only improves the healing of multiple RDEB-related wounds simultaneously, but it can also prevent new blisters from developing in RDEB skin."
Protein Replacement Therapy for Heart Failure
While much of the excitement about protein replacement therapy has to do with its use for the treatment of rare genetic disorders, it shows promise as a treatment for more common health conditions too.
Myocardial infarction (heart attack) and heart failure are among the top causes of death in the United States and other countries. A myocardial infarction occurs when blood flow to a segment of heart muscle drops below adequate levels. The greater the length of time before treatment to restore blood flow takes effect, the greater the loss of cardiac muscle cells, or cardiomyocytes. Because the adult heart has little capacity for regeneration, the cardiomyocytes lost in the aftermath of a myocardial infarction get replaced by different types of cells, resulting in scarring and, frequently, heart failure.
To develop an efficacious means of promoting heart regeneration, researchers must find solutions to a multitude of quandaries. It appears that protein replacement therapy utilizing modified mRNA (modRNA) may avoid many common pitfalls. "Modified mRNA (modRNA) is a safe, non-immunogenic, efficient, transient, local, and controlled nucleic acid delivery system," noted the authors of a 2019 article published in Molecular Therapy.
Increased understanding of the molecular pathways and genes involved in heart disease has led scientists to believe protein replacement therapy could be used to target signaling pathways involved in heart disease progression. Per the Molecular Therapy article cited above, delivering replacement proteins to the myocardium (the muscle tissue of the heart) can encourage the regeneration of cardiomyocytes.
Some approaches have fallen into the subcategory of gene therapy, which involves placing a defined gene into a cell to either replace a defective gene or to increase the amount of a certain gene in a specific cell or tissue in order to increase production of a needed protein. Some examples of work in that vein included using viral vectors like adeno-associated virus (AAV) to mediate the delivery of either FGF1 and p38 MAP kinase proteins or periostin.
However, the use of viral vectors comes with the risk of viral genome insertions. While preclinical studies have returned encouraging results, namely, "robust and consistent gene expression," there has also been evidence of adverse effects, including immune responses to the viral vectors.
Direct Delivery of Proteins
As experts continue probing how best to use gene therapy to treat cardiac disease, a consensus is growing that the most practical way to change the expression of a protein of interest is to deliver the corresponding protein directly to the myocardium. This circumvents problems associated with other delivery methods, such as the potential immune responses triggered by viral vectors. It's also been linked to benefits such as:
- Higher levels of protein expression
- Improved dose regulation
- Enhanced control
Direct protein comes with some issues of its own, however, including the short half-life and overall instability of injected proteins.
Modified mRNA Therapy
Unlike gene therapy and the direct delivery of proteins, mRNA-based therapies have proven to be highly promising methods of treating heart disease as well as other disorders. One reason for that is its overall safeness, because mRNA does not integrate into the genetic code.
The first successful use of direct mRNA transfer occurred in the late 1980s in mouse models. Then, in 2008, a team of researchers from the Department of Neurosurgery and Department of Medicine at the University of Pennsylvania in Philadelphia, the Laboratory of RNA Molecular Biology at The Rockefeller University in New York, and the Department of Host Defense at the Research Institute for Microbial Diseases in Osaka discovered how mRNA therapy could be used in genetic and regenerative medicine. Essentially, by modifying mRNA with a naturally occurring modified nucleoside pseudouridine to produce modified mRNA (modRNA), researchers changed its structure so that the body was better able to utilize it to address issues related to protein defects or deficits.
According to the authors of the Molecular Therapy article, modRNA "allows rapid, transient, and efficient gene expression to a specific time window after cardiac injury." They further state that modRNA protein replacement therapy could be "an excellent therapeutic agent to address experimental and clinical needs to induce cardiac regeneration and promote cardiac function in ischemic heart disease."
Key Takeaways About Protein Replacement Therapy
Protein replacement therapy offers a way to treat diseases by transporting missing or deficient proteins to cells, thereby correcting the dysfunction that results in disease. Other techniques for doing this involve transferring genetic material into cells, which comes with a higher level of risk.
At this time, one of the most pertinent applications for protein replacement therapy is as a treatment for rare monogenic diseases, which fall into a category called "orphan diseases" because manufacturers are less likely to develop drugs to treat them due to the limited financial incentive for doing so. While some experts view protein replacement therapy as a much-needed option in a realm with a dearth of viable potential treatments, others feel manufacturers still need to do more work to show that using these treatments ends up being a cost-effective decision for health care systems.
It's important to note, too, that the promise of protein replacement therapy is not limited to rare diseases. Clinical trials have shown it can also be used to overcome one of the central challenges of treating myocardial infarction and preventing heart failure.
As researchers continue to explore applications for protein replacement therapy, it seems likely that they'll uncover an even broader swathe of diseases and conditions it can be used to treat.