Grant: Master's Award: Canada Graduate Research Scholarships - Master's program

Chronic kidney disease (CKD) affects about 4 million Canadians, costing the Canadian healthcare system over $40 billion each year. CKD reduces the body’s ability to make creatine (Cr), a molecule that powers muscles and the brain. CKD destroys kidney cells that produce the enzyme L-arginine:glycine amidinotransferase (AGAT), which initiates the Cr-making process. Without enough Cr, CKD patients develop severe fatigue, muscle weakness, and cognitive impairment, which reduce independence and quality of life. Oral Cr supplements are unsuitable for CKD because they (1) suppress the remaining AGAT activity, (2) overload already weakened kidneys with Cr’s waste product: creatinine (3) are unable to effectively cross the blood–brain barrier, (4) confound creatinine-based biomarkers, and (5) contribute to polypharmacy. This novel study tests a one-time gene-replacement therapy in a sex-balanced mouse model of adenine-induced CKD. Adeno-associated virus serotype 9 (AAV9) delivers functional copies of two Cr-producing enzymes, AGAT and guanidinoacetate methyltransferase (GAMT). A minimally invasive injection into the spinal fluid allows the treatment to spread through the nervous system and the body. This re-establishes natural Cr synthesis lost in CKD. The AAV9’s effects will be evaluated by tracking the mice's weight, water and food intake, heart and kidney function, and blood and urine markers. Additional tests of muscle strength, movement, and memory will be complemented by measurements of Cr levels, cellular energy production, and how widely AAV9 spreads across the body. If successful, this therapy is expected to improve strength, energy, and cognitive function, reducing the health and economic burden of CKD in Canada.