Target Disease: Retinal Diseases
The retina is a neuronal tissue located at the back of the eye. Its primary function is the perception of light, the processing of light induced stimuli, and the transmission of light-dependent information to the brain.
Retinal diseases like wet age-related macular degeneration (wet AMD), diabetic retinopathy (DR) and geographic atrophy (GA) can lead to permanent vision loss. VEGF is a protein produced by cells which stimulates the formation of new abnormal blood vessels, a process called neovascularization, and induces vascular permeability, leading to leakage and swelling of the retina. Swelling of the retina leads to vision decline and death of the retinal cells, which can irreversibly cause blindness if not adequately treated.
In addition, a large number of hereditary diseases affect the retina and can result in severe vision impairment or blindness.
Retinal diseases like wet age-related macular degeneration (wet AMD), diabetic retinopathy (DR) and geographic atrophy (GA) can lead to permanent vision loss. VEGF is a protein produced by cells which stimulates the formation of new abnormal blood vessels, a process called neovascularization, and induces vascular permeability, leading to leakage and swelling of the retina. Swelling of the retina leads to vision decline and death of the retinal cells, which can irreversibly cause blindness if not adequately treated.
In addition, a large number of hereditary diseases affect the retina and can result in severe vision impairment or blindness.
Inherited Retinal Diseases
About Inherited
Retinal Diseases (IRDs)
Grouped under the term “inherited retinal degeneration” diseases such as Retinitis Pigmentosa (RP), Leber’s congenital amaurosis (LCA), and Stargardt’s disease (STGD) often result in the degeneration and loss of the light-sensitive cells in the retina, called photoreceptors, leading to visual impairment and blindness.
Grouped under the term “inherited retinal diseases”, Retinitis Pigmentosa (RP), Leber’s congenital amaurosis (LCA), and Stargardt’s disease (STGD) often result in the degeneration and loss of the light-sensitive cells in the retina, called photoreceptors, leading to visual impairment and blindness.
The most common IRDs are caused by a genetic defect in a single gene, out of more than 280 possible genes, which compromises the viability of photoreceptors and leads to photoreceptor cell death.
Patients with these conditions may develop symptoms in early childhood, including night blindness or the inability to see segments of the world in front of them. They can take abnormally long periods of time to adjust to changes in lighting, and some patients may even find lights uncomfortable. Eventually, most individuals with IRD will lose most of their sight.
Normal Retina
Photoreceptors in a healthy retina. There are two general types of photoreceptors, called rods and cones. Rods are in the outer regions of the retina and allow us to see in dim-light conditions. Cones reside mostly in the central portion of the retina and allow us to perceive fine visual detail and color.
Retina affected by RP
Retina affected by RP shows a degeneration of the rods usually followed by a secondary degermation of cones, eventually leading to complete blindness.
Prevalence of Inherited
Retinal Diseases
Retinal Diseases
Retinitis Pigmentosa
1 / 4,000
ADULTS WILL EVENTUALLY LOSE MOST OF THEIR SIGHT
Among inherited retinal diseases, adult-onset Retinitis Pigmentosa (RP) is the most common, with a worldwide prevalence of approximately 1 in 4,000 people.
Leber’s congenital amaurosis
1 / 30,000
A disease onset already in early childhood
A genetically related disease is Leber’s Congenital Amaurosis (LCA), with a prevalence of around 1 in 30,000 people and a disease onset already in early childhood.
Stargardt’s Disease
1 / 10,000
the most commonly inherited retinal disease in children and adults
Stargardt’s Disease (STGD) is the most commonly inherited retinal disease in children and adults with an estimated prevalence of 1 in 10,000 people in the United States.
Unmet Needs of Patients
with Inherited Retinal
Diseases
The death of photoreceptors due to IRDs results in permanent vision loss or blindness. All but one of these diseases are still untreatable today.
To date, only one drug has been approved to address a single mutation (RPE65), which accounts for a very small fraction of IRDs, leaving the vast majority of patients without therapeutic options.
To date, only one drug has been approved to address a single mutation (RPE65), which accounts for a very small fraction of IRDs, leaving the vast majority of patients without therapeutic options.
The Pipeline
GB-601
GB-601 is being developed as a long-acting formulation of a novel cGMP (cyclical guanosine monophosphate) analog as a potential treatment for hereditary retinal diseases like Retinitis Pigmentosa, a group of rare genetic disorders that involve a loss of photoreceptors in the retina.
A newly discovered cell death mechanism shows that photoreceptors degenerate and eventually die due to excessive cGMP signaling. This principal disease mechanism is caused by a large number of mutations in over 280 genes.
cGMP analogs are a new class of therapeutic compounds that can interfere with excessive cGMP-signaling in photoreceptors. Importantly, excessive cGMP signaling is a phenomenon common to many, if not most, forms of hereditary retinal degeneration.
GB-601 has the potential of blocking the excessive signaling and of treating many of these diseases with the same therapeutic compound.
Graybug acquired a portfolio of novel cGMP analogs, supported by a well-characterized mode of action and preclinical data in established RP disease models, from Mireca Medicines GmbH, a German start-up company. Graybug is developing these cGMP analogs as first-in-class, mutation-agnostic long-acting therapeutics to treat hereditary retinal diseases covering a broad range of mutations. GB-601 is in early-stage development.
cGMP analogs are a new class of therapeutic compounds that can interfere with excessive cGMP-signaling in photoreceptors. Importantly, excessive cGMP signaling is a phenomenon common to many, if not most, forms of hereditary retinal degeneration.
GB-601 has the potential of blocking the excessive signaling and of treating many of these diseases with the same therapeutic compound.
Graybug acquired a portfolio of novel cGMP analogs, supported by a well-characterized mode of action and preclinical data in established RP disease models, from Mireca Medicines GmbH, a German start-up company. Graybug is developing these cGMP analogs as first-in-class, mutation-agnostic long-acting therapeutics to treat hereditary retinal diseases covering a broad range of mutations. GB-601 is in early-stage development.
cGMP ANALOG MECHANISM OF
ACTION
ACTION
This graphic illustrates how GB-601 is thought to inhibit the cGMP cascade leading to photoreceptor cell death.
Genetic defects in many different retinal degenerative (RD) genes lead to high levels of cGMP, which over-activate protein kinase G (PKG) and cyclic nucleotide gated channel (CNG channel). While CNG channel function is required for vision (i.e., normal physiology), over-activation of PKG causes photoreceptor cell death (i.e. pathophysiology). GB-601 reduces excessive PKG activity and increases photoreceptor survival.
Genetic defects in many different retinal degenerative (RD) genes lead to high levels of cGMP, which over-activate protein kinase G (PKG) and cyclic nucleotide gated channel (CNG channel). While CNG channel function is required for vision (i.e., normal physiology), over-activation of PKG causes photoreceptor cell death (i.e. pathophysiology). GB-601 reduces excessive PKG activity and increases photoreceptor survival.
Graybug is developing these cGMP analogs as first-in-class, mutation-agnostic long-acting therapeutics to treat hereditary retinal diseases covering a broad range of mutations. GB-601 is in early-stage development.