Scientists at the Research Institute of the McGill University Health Centre (RI-MUHC) recently solved a medical mystery that endured for more than 30 years.
The team, led by Donald Vinh, an assistant professor of microbiology and immunology, identified the genetic mutation responsible for one patient’s longstanding health problems. Thanks to this discovery, Vinh, BSc’97, MDCM’01, was able to develop a therapy that could also help a lot of people who have problems related to the immune system, whether they are genetic or due to a transplant or an illness.
Steven Francis, the patient at the centre of the discovery, has dealt with health issues his whole life.
Followed at the MUHC since childhood, he has faced sinus infections, fungal infections, inflammations of the colon, shingles, respiratory problems, renal issues, and impeded growth.
Doctors were unable to discover an underlying cause; they suspected that it was genetic, but were unable to prove it. His family consulted specialists in the United States, but without success.
“As a child, I often had to miss school and it was difficult to make friends. It is hard not knowing why you are sick,” says Francis.
The tide finally turned in his favour when Vinh began examining his case in 2012.
“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. I also looked at his family history. Since the eighties, many new immune deficiencies have been identified, and I was able to apply the knowledge from these advances to solve the case,” he explains.
Vinh discovered that Francis had a mutation on a gene that is critical for the proper function of the immune system, called ZAP70. It serves to synthesize a protein of the same name that helps activate our T cells. Without the ZAP70 protein, the body can’t defend itself effectively against most infections.
“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,” says Vinh.
The discovery is all the more remarkable considering this gene, unlike many, cannot be studied in mice.
“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,” says Vinh. He is the principal author of a study chronicling these research results that was recently published in the Journal of Allergy and Clinical Immunology.
Grant is now 35 years old. In his case, Vinh and his team now understand exactly where to find the mutation and how it behaves. Grant’s specific mutation subtly affects the slicing of the gene and doesn’t affect the amino acid sequence that synthesizes the ZAP70 protein. Inspired by a little known treatment used in cases of hypercholesterolemia (a condition characterized by very high levels of cholesterol in the blood), Vinh successfully developed a molecule that exclusively blocks the mutation while allowing the protein to be synthesized.
In the process of helping Grant, the researchers have shown that it is possible to create a molecular therapy that might improve the human immune system.
For Vinh, the battle is still only half won: while all the pieces of the puzzle might be found, they haven’t yet been fully put together.
“There are definitely more steps to take before we can test this treatment. 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.”
Vinh studies genetic defects of the immune system. He seeks to understand why the genetic make-up of certain individuals leaves them more vulnerable to rare, severe or recurrent infections.
He sees patients with complicated health problems that seem to be linked to their immune system. He treats what are called rare and orphan diseases – disorders that affect less than one person in 2,000. Patients are referred to him from all of Eastern Canada.
Vinh is sometimes compared to TV’s Dr. Gregory House. Like House, Vinh has a reputation across the country for his interest in the most atypical medical conditions within his field of practice. “I may have a few things in common with him, but I’d like to think people find me a nicer person than he is!” he jokes.
He has certainly made a difference in Steven Grant’s life. After years of searching for an answer, Grant is relieved to finally have a diagnosis for his disorder.
