Palo Alto, CA — Bietti Crystalline Dystrophy (BCD) is a rare inherited eye disease responsible for vision loss due to crystal buildup in the retina. It is caused by changes in the CYP4V2 gene, which helps the body process fats. Stanford researchers are investigating how gene mutations cause retinal degeneration, their effects on other organs beyond the eye, and how advanced retinal imaging can detect unhealthy cells—critical steps toward enabling human gene therapy trials.
Vinit Mahajan M.D., Ph.D., Stanford professor and vice chair of ophthalmology research, said, “We are in the planning stages of a phase-3 BCD gene therapy trial here in the US, and that brings new hope for patients. Research to support BCD is more important than ever as we move closer to being able to provide a life altering therapeutic to patients.”
To highlight important BCD discoveries, Mahajan pointed to his research team’s recent publication in the American Journal of Ophthalmology Case Reports, “Enhanced genotype-phenotype analysis using multimodal adaptive optics and 3D protein structure in Bietti Crystalline Dystrophy.” The team was the first to use AI-generated models of the CYP4V2 protein to understand how mutations damage the protein.
“These models help reveal at the molecular level whether a gene mutation is the likely cause of BCD and whether patients should be enrolled in a clinical trial,” Mahajan said.
In collaboration with Professor Alf Dubra, a Stanford physicist in the department of ophthalmology, researchers used powerful Adaptive Optics cameras to image the retina at the single cell level.
Dubra said, "The AO images not only confirmed the typical crystal deposits at the highest resolution to date, but they also showed new, cyst-like structures in the retina—possibly revealing an overlooked feature of the disease that may be important in how patients respond to treatment."
BCD was thought to affect only the eyes. But new findings from the team suggest otherwise.
Mahajan said, “We noticed that our BCD patients had abnormal liver enzyme tests. Working with our colleagues in pathology, we identified crystals in the liver, establishing that BCD is not just an eye disease.”
These findings are in a separate study, “Crystalline Hepatopathy Associated With Bietti Crystalline Dystrophy: A Striking Manifestation of Disordered Fatty Acid Metabolism,” published in the American Journal of Surgical Pathology. Researchers described three BCD patients who had unusual crystal-like spaces and inflammation in their liver tissue. All had abnormal fat or cholesterol levels, and other potential causes of liver damage were ruled out. These liver crystals resembled the ones found in the eye, suggesting BCD may affect more of the body than previously recognized.
“Since CYP4V2 is active in several organs, including the liver and brain, BCD could be a broader metabolic condition. These discoveries not only change how we think about this rare disease but could also help scientists better understand fat-related disorders like metabolic liver disease,” Mahajan said.
Because BCD progresses quickly in the eye and has no current cure, researchers are turning to gene therapy—a method that delivers healthy copies of a gene into cells. The CYP4V2 gene is small enough to fit into adeno-associated virus (AAV) vectors, which are commonly used in gene therapy. These vectors can target and treat the cells affected in BCD, making it a promising candidate for this kind of therapy.
“We are excited to be working with Liping Yang M.D., Ph.D., Professor of Ophthalmology at Peking University, one of the world’s foremost experts in BCD. She developed a gene therapy for BCD that showed promising results in a phase-2 clinical trial,” Mahajan said.
Led by Dr. Yang’s team, with contributions by Mahajan, the researchers wrote a comprehensive, up-to-date review on BCD in the journal Progress in Retinal and Eye Research. The article, “Unravelling CYP4V2: Clinical features, genetic insights, pathogenic mechanisms and therapeutic strategies in Bietti crystalline corneoretinal dystrophy,” explains the symptoms, genetics, and biological mechanisms behind BCD.
Mahajan said, “By highlighting both the scientific advances and ongoing challenges, the article shows how gene therapy for BCD could soon become a real treatment and could also pave the way for treating other genetic eye diseases in the future.”
BCD is one of the most frequently inherited retinal diseases in East Asia but also affects over 100,000 people across all continents and races.