PIPELINE / RETINITIS PIGMENTOSA
EXTENSIVE THERAPEUTIC POTENTIAL
Inherited Retinal Dystrophies (IRDs) are a group of rare diseases characterized by the progressive loss or dysfunction of photoreceptors. Different forms of IRD differ in onset, severity, and progression of the disease depending on the type of mutation and cells affected.
Vision loss may occur at birth or later in life. Currently, there are over 270 genes that have been associated with IRDs.
Retinitis Pigmentosa (RP) is the most common form of IRDs, with a reported prevalence of 1 in 3,000-4,500 individuals worldwide. It is the first cause of irreversible blindness in developed countries for people under 70 years of age.
RP has a highly heterogeneous genetic basis. Most cases of retinitis pigmentosa are monogenic, with mutations in more than 80 genes identified to date. These genes play essential roles in the structure and function of the two types of photoreceptors in the retina, rods and cones.
Mutations in any of these genes lead to the gradual loss of these cells, manifesting with initial night blindness followed by a gradual narrowing of the visual fields over the patient’s life, tunnel vision or complete vision loss will result.
CURRENT STANDARD OF CARE IS UNSUITABLE FOR MANAGING MOST RP PATIENTS
DIAGNOSIS
RP symptoms significantly differ in terms of severity and rate of progression.
Thus, it is difficult to establish a standard diagnosis, counselling, and therapeutic strategy to all RP patients. RP clinical diagnosis relies upon a complex combination of clinical history examinations, visual field testing and retinal imaging to evaluate photoreceptor function, and molecular genetic testing.
TREATMENT & MANAGEMENT
Symptomatic treatment:
There are some proposed treatments for RP, although they are not specific and cannot cure RP.
Curative treatment:
The first ocular gene therapy and the only marketed treatment is Luxturna (approved in the US in 2017 and in the EU in 2018), indicated for RPE65 mutation (<1% of all RP patients).
PATHOGENIC MECHANISM
Multiple genes are involved in the expression and regulation of enzymes, transporters and channels controlling the visual function in photoreceptors.
Intracellular calcium transients are key mediators of phototransduction signals regulated by such genes.
Mutations in many of these genes lead to intracellular calcium dysregulation that damages photoreceptors and ultimately triggers the death of rods and cones.
So, a common mechanism activated by changes in intracellular calcium appears to be shared by several forms of RP and, thus, restoring calcium ions homeostasis should be evaluated as a new therapeutical avenue.
THERAPEUTIC TARGET
RyR2 as a New Therapeutic Target for RP
RyR2 calcium channels play a central role in photoreceptor calcium homeostasis.
In the retina, RyR2 is expressed in the endoplasmic reticulum, with expression also reported in the disk rim of the outer segments.
RyR2 channels play a key role in calcium homeostasis and photoreceptor survival in a mouse model of inherited retinal dystrophy:
- RyR2 is upregulated in cGMP/PKG signaling-induced ER stress and photoreceptor degeneration.
- Deletion of RyR2 reverses ER stress and suppresses photoreceptor apoptosis in a mouse model of achromatopsia and cone dystrophies.
MP-004
The new standard for RP
- Potential therapy for all RP patients (agnostic to mutations).
- Stand alone therapy or combinable with other therapeutic approaches.
- Reaches retina after topical administration.
- Results confirm absence of MP-004 in untreated contralateral eye
- Optimized physicochemical and ADME properties
- Easily scalable synthesis and low manufacture cost
- Improves rods and cones’ structure and function
- Low toxicity due to specific mechanism of receptor defects (does not alter physiological function)