Rare disease research can take many forms, and each drug development platform offers specific advantages researchers can leverage to address elements of these conditions. Earlier this month, we began to discuss research within the field of rare disease (read the article here). We reviewed an article from Nature (you can access it here) and went in detail about specific types of rare disease research in subsequent articles. At this point, we have covered small molecules (click here) and antibody therapy (read it here). In this article, we are going to take a closer look at protein replacement therapies in rare disease research.
What is Protein Replacement Therapy?
Protein replacement therapy is used when a particular protein stops functioning in the body. It involves replacing the actual protein. To illustrate this in practice, imagine a person with hemophilia being administered a factor so that his or her blood clots. By receiving that factor, the hemophiliac’s blood will not be able to clot whereas it was unable to before because particular proteins were not functioning properly. Another example of protein therapy in action is the use of insulin in the treatment of diabetes.
Protein therapy is often called Enzyme Replacement Therapy or ERT when the protein features enzymatic activity. For instance, using factors to treat Hemophilia involves ERT. In many cases, enzymes therapy has focused on lysosomal storage diseases and disorders (LSDs).
Note: Protein replacement therapy is different from antibody-based therapy in that the latter is focused on gaining the function of a protein as opposed to replacing it.
Clinical Success in Protein Replacement Therapy Research
Protein replacement therapy as an area of research has boomed in recent years as technology has allowed researchers to determine protein function (or lack thereof) has improved. Furthermore, plasma-derived products, which traditionally were the foundation of protein replacement therapy are being replaced by recombinant engineered proteins.
These recombinant engineered proteins are growing in popularity because the protein is more stable than those derived from other methods and it is easier to ensure purity. They also tend to be more potent. There are approximately 130 recombinant proteins that have received FDA approval for clinical and roughly 10 of them are for the treatment of LSDs. The numbers rise to over 170 and 11 respectively when considered on a worldwide basis. In many cases, these drugs are lifesavers for people with conditions such as Hunter disease, Pompe disease, and Wolman disease – and more are in development.
Strengths and Limitations of the Platform
The biggest issue in ERT is the costs involved. Keep in mind that manufacturing drugs that leverage proteins or enzymes can be very expensive. Ensuring the purity of the proteins or enzymes takes extra efforts and they translate into extra costs. In addition, drugs developed from this therapeutic platform are often administered as injections or infusions. Patients often seek alternatives. In addition, the technology used to develop ERT is well-developed and the costs of production are improving, but they are still significantly higher than many other drug manufacturing costs.
However, ERT is extremely effective when it is delivered to the right location in the correct dose. As long as a drug developed through this platform can be administered before there is any major damage to organs, the results tend to be good. This drug class is also incredibly safe. Very few people experience reactions to ERT although hypersensitivity may occur and can impact the efficacy of this treatment. Ultimately, ERT continues to have a role, particularly in the treatment and management of LSDs.
Answering the Challenge of Rare Disease Research
Protein replacement therapy and ERT plays an important role in rare disease. While there are limitations and downsides to leveraging this drug class, efficacy and patient health realistically prohibit the exclusion of protein therapy. Alternatives to ERT and other protein replacements are an option, but the technology has to be considered in the development of treatments for conditions that involve a lack of protein functionality.
- Tambuyzer, E., Vandendriessche, B., Austin, C.P. et al. Publisher Correction: Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-019-0059-7
- Science Direct, Enzyme Replacement Therapy. https://www.sciencedirect.com/topics/neuroscience/enzyme-replacement-therapy
- National Gaucher Foundation, What Are Lysosomal Storage Diseases and Disorders? https://www.gaucherdisease.org/about-gaucher-disease/what-is/lysosomal-storage-disorders/
- Science Direct, Recombinant Proteins. https://www.sciencedirect.com/topics/neuroscience/recombinant-proteins