Because proteins provide function, not just structure, to the body, their absence or imperfections can have profound effects on health. Many advances in protein engineering are thanks to the mapping of the human genome completed in 2003, which provided the location for about 19,000 protein-coding genes. Academic, government and industry scientists now explore the functions of these genes in health and disease, which is complex science because some genes code for up to three proteins.
Some rare diseases are caused by genetic mutations that cause a protein deficiency. For example, Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, stems from mutations to a gene on the X chromosome that codes for the iduronate 2-sulfatase, a protein that works as an enzyme to help the body degrade specific large sugars. Shire is developing a replacement enzyme, idursulfase-IT, now in clinical trials, as a potential treatment option for children with Hunter's.
When trying to develop protein replacement treatments, scientists often engineer the therapeutic protein as an optimized, improved version. When effective, such therapies can provide life-changing improvements to the disease’s symptoms, but not the underlying cause. To get at the root of a rare disease and modify its origin, researchers are exploring the use of gene therapy.
“Each year we understand better how the body is functioning at its most basic molecular level, and each year we develop new ways to more precisely influence those functions that cause disease and apply new technologies to proteins. Gene therapy will even go one step further, where instead of giving patients proteins, we may be able to give them the actual missing gene," explained Clark Pan, Ph.D., Vice President, Head of Discovery Therapeutics at Shire. "The convergence of all these different technologies is incredibly exciting. It might have a significant impact in helping people with these diseases.”
Key to gene therapy for a disease is understanding the genetic error involved, which can range from genes missing entirely to defective genes. Genes are collections of nucleic acids in a specific order that together provide the instructions to build the structure of proteins from amino acids. If a nucleic acid is not in the right order or substituted by another, the error creates a "typo" in the instructions and subsequently the alteration of amino acids in protein structure, creating a defect with potential health impact.
“Think of it like a LEGO building set,” Pan explained. “Amino acids are the individual blocks, DNA is the written instruction book, and proteins are small finished parts of a larger building.”
Gene therapies involve inserting a gene into a patient’s cells instead of using drugs or surgery. The insertion can replace a mutated gene with a healthy copy, work to inactivate a mutated gene or introduce a new gene to help modify the disease. The U.S. Food and Drug Administration (FDA) has not yet approved any gene therapy for use in the United States, but many research projects are focused on developing such techniques for use in patients.