Gene Therapy for Rare Eye Disease to Advance to Human Trial

The Vision Center at Children’s Hospital Los Angeles has received a $4.7 million grant from the California Institute for Regenerative Medicine to study a gene therapy to treat blue cone monochromacy (BCM), a rare, inherited vision disorder linked to the X chromosome that occurs in boys. Children with blue cone monochromacy experience severe vision loss and color blindness, extreme sensitivity to light, and involuntary eye movements.

Blue cone monochromacy is caused by mutations in the red and green opsin gene cluster OPN1LW and OPN1MW. Opsin proteins are light-sensitive pigments in the cones of the retina at the back of the eye. The disorder affects fewer than 1 in 100,000 people and is usually diagnosed in infancy. Currently, there is no treatment for this disease.

Aaron Nagiel, M.D., Ph.D., an investigator conducting ophthalmology and neuroscience research at Children’s Hospital Los Angeles, will lead efforts on research of a gene therapy that aims to slow the progression of disease and restore vision loss. Nagiel is also an assistant professor of Clinical Ophthalmology at Keck School of Medicine of USC.

The gene therapy, BGTF-027 (formerly ADVM-062), was developed by Adverum Biotechnologies and licensed to Blue Gen Therapeutics Foundation (BGTF), a nonprofit organization developing gene therapies for rare inherited retinal diseases. Blue Gen Therapeutics Foundation was co-founded by John Cavitt, who has three children affected by blue cone monochromacy.

BGTF-027 is an intravitreal gene therapy that encodes a functional copy of the long-wavelength-sensitive opsin protein for the treatment of blue cone monochromacy. It can be administered by intravitreal injection, which is placed in the space in the back of the eye.

Nagiel noted in a news release that intravitreal injection requires less time for treatment and recovery than other therapies. For example, a currently available gene therapy for an inherited retinal dystrophy caused by a mutation in the RPE65 gene, Luxturna (voretigene neparvovec), is given as a surgical injection beneath the retina.

“This treatment [BGTF-027] is designed to reach the cells of the retina from the vitreous, which is the inner cavity of the eye. If they’re old enough, patients may be able to have the injection awake, in an outpatient setting,” he said.

Once administered, the gene therapy is designed to restore the function of the patient’s central cone photoreceptors.

Over the next 18 months, the Children’s Hospital Los Angeles and the Blue Gen Therapeutics Foundation will conduct the work to prepare for clinical trials for BGTF-027, including developing a protocol for a phase 1 clinical trial and preparing the investigational new drug application for submission to the FDA.

Blue Gen Therapeutics Foundation also licensed ADVM-082, an intravitreal gene therapy that encodes a functional CNGB3 gene for the treatment of achromatopsia, another rare disease that leads to vision that has no color. This gene therapy is in nonclinical development.

Both programs use Adverum’s AAV.7m8 capsid, which encodes retinal cells to become biofactories that provide sustainable amounts of therapeutic proteins throughout the retina. Modification of the adeno-associated virus (AAV) used as a vector in these gene therapies allows it to bypass the inner limiting membrane (ILM) to efficiently deliver transgenes to target retinal cells