via Channel 5

Researchers have been able to identify and treat a genetic mutation responsible for a medical case unsolved for 30 years. The novel treatment method may also be able to help treat other problems within the immune system, both genetic and as a result of transplant or illness. The work was published in the Journal of Allergy and Clinical Immunology.

The patient in question was Steven Francis, who had suffered from sinus and fungal infections, colon inflammation, shingles, renal and respiratory problems, and impeded growth throughout his life. The doctors and specialists that he had seen suspected that the problem was genetic in nature but they’d not been able to prove it or to identify the exact cause.

Eventually things changed in 2012, when Francis was transferred to Donald Vinh, M.D., principal author of this study and researcher at the Research Institute of the McGill University Health Centre (RI-MUHC). “When this patient was referred to me, I went over his entire file in detail, covering some 30 years and literally filling two large cardboard boxes,” Dr. Vinh said. “I also looked at his family history. Since the 1980s, many new immune deficiencies have been identified, and I was able to apply the knowledge from these advances to solve the case.”

Dr. Vinh managed to identify a genetic mutation in Steven’s DNA that impacted a gene called ZAP70, which is known to be critical for correct functionality of the immune system. The gene codes for the synthesis of a protein of the same name, which is involved in the activation of T-cells. Without it, the immune system cannot react effectively against infections and the patient is susceptible to a range of illnesses. One of the reasons this has been so difficult to identify is that the gene cannot be studied within mice, the usual model for these sorts of investigations.

“A mutation on this gene is known to be fatal, and the only treatment available up until now has been a bone marrow transplant that must take place before the age of five. With this new discovery, we have found out that genetic mutations of this kind are also found in adults, which could lead to tremendous advances in research. Solving this mystery has opened a new door into the way that the scientific community will look at immune system deficiencies,” said Dr. Vinh.

The team found that Steven’s mutation wasn’t affecting the amino acid sequence of the ZAP70 protein, but was instead altering the slicing of the gene. To try to counteract the problem, Dr. Vinh adapted an uncommon treatment for hypercholeresterolaemia to block the mutation while maintaining protein synthesis.

“In the laboratory, we demonstrated that a molecule called Morpholino Antisense Oligonucleotide could correct this kind of genetic anomaly and allow the patient’s immune system to function properly,” explained Dr. Vinh.

Not only has this treatment plan been able to help Steven, it has the potential to work in other immune system deficiencies. However, while the research is very promising, Dr. Vinh has stressed that there is still more work to be done. “There are definitely more steps to take before we can test this treatment,” he said. “For one thing, we have to convince the industry to support us. When Steven can finally get the benefit of the treatment, I’ll be able to count this as a victory.”