Alport Syndrome: clinical advances

Dr. Cecil Alport's 1927 report on a family experiencing hematuria and deafness marked the early recognition of what would later be identified as Alport syndrome. The discovery of collagen in 1966 proved pivotal in understanding the disorder, now recognized as a monogenetic condition caused by variants in COL4A3, COL4A4, or COL4A5 genes. Though its prevalence remains uncertain, estimates range from 1 in 5000 to 1 in 50,000 in the United States and Europe. Alport syndrome affects the kidneys, auditory system, and eyes. The natural history of Alport syndrome is well-documented in males with X-linked Alport syndrome. Current therapeutic approaches primarily involve angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to manage kidney disease and slow progression.
Recent years have seen increased interest in drug development for chronic kidney diseases, including Alport syndrome, with several investigational drugs in various stages of development. While existing therapeutics aim to manage symptoms, emerging approaches like gene replacement therapies and CRISPR/Cas9 genome editing target the underlying genetic cause. However, these approaches are still in preclinical stages, with gene replacement therapies focusing on restoring gene function to produce functional proteins. CRISPR/Cas9 editing, though promising, has shown nearly 40% correction of pathogenic variants and the occurrence of undesired effects like insertions and deletions.