Developing RNA therapeutics for rare genetic disease

SiSaf has developed a broad product pipeline based on the fundamental features of its proprietary Bio-Courier RNA delivery platform: durable stabilization of RNA, non-immunogenic, efficient transfection, and no accumulation.

We focus on rare, and as yet, incurable diseases to provide first-in-class therapeutics within an expedited time frame, under the orphan drug designation program.

We work in close collaboration with renowned academic experts to generate in vivo validated therapeutic sequences. This removes the heavy lifting of internal sequence discovery and further accelerates the process of making safe and effective drugs available to patients.

Our in-house pipeline is currently focused on rare Genetic Skeletal Disorders including Osteopetrosis, and Achondroplasia which require:

  • repeated systemic administration to target multiple organs in the body
  • the ability to target the mutant gene without affecting the healthy gene
  • safety and efficacy at any age, without accumulation over time

Our Bio-Courier siRNA complexes can achieve these exacting demands and similar strategies could be applied to other autosomal-dominant bone diseases, opening an avenue for wider use of RNA interference therapy in rare genetic disorders.

We are partnered with a leader in ophthalmic genetic disease, Avellino Labs USA, to develop the world’s first eye drop RNA interference therapy and CRISPR cas 9 gene editing cure for Corneal Dystrophy.

AUTOSOMAL DOMINANT OSTEOPETROSIS (ADO2)

SIS-101-ADO is a systemic Bio-Courier siRNA designed to inhibit the dominant-negative mutations of the Clcn7 gene and rescue the phenotype of Autosomal Dominant Osteopetrosis (ADO2). ADO2 is a genetic bone disease affecting 5.5 in 100,000 people. The mutated gene causes a defect in bone reabsorption by osteoclasts resulting in increased bone density. This leads to an accumulation of bone with a defective architecture, making them brittle and susceptible to fracture. In the most severe forms, patients present with extensive osteosclerosis, especially of the skull base, pelvis, and vertebrae, and experience multiple fractures, osteomyelitis, hematologic failure, and sensorial symptoms, including impaired vision and hearing. Currently, there is no cure for AD02 so SIS-101-ADO represents a first-in-class treatment to reverse the bone phenotype to normal.

ACHONDROPLASIA

SIS-102-ACH is a systemic Bio-Courier siRNA designed to inhibit mutated Fibroblast Growth Factor Receptor 3 gene (FGFR3), a negative regulator of bone growth, and rescue the phenotype of patients with Achondroplasia. About one in 25,000 people are born with Achondroplasia, a disorder of bone growth that prevents the changing of cartilage (particularly in the long bones of the arms and legs) to the bone. It is characterized by dwarfism, limited range of motion at the elbows, large head size (macrocephaly), and small fingers. Achondroplasia can cause health complications such as interruption of breathing (apnea), obesity, recurrent ear infections, and an exaggerated inward curve of the lumbar spine (lordosis). More serious problems include a narrowing of the spinal canal that can pinch (compress) the upper part of the spinal cord (spinal stenosis) and a build-up of fluid in the brain. SIS-102-ACH will be the first RNA therapeutic that addresses the root cause of Achondroplasia, directly inhibiting the mutated FGFR3 gene without affecting its healthy copy.

TYPE II CORNEAL DYSTROPHY

SIS-201-CD is a topical BIO-COURIER siRNA designed to inhibit the mutated Transforming Growth Factor Beta I (TGFBI) to prevent the overproduction and aggregation TGFBI protein in patients with Type II Corneal Dystrophy. Corneal Dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophy can cause watery eyes, dry eyes, sensitivity to light, pain, corneal erosion, and significant visual impairment, but to date there is no cure and treatment focuses on alleviating symptoms. SIS-201-CD represents a 1st in class treatment to target the mutated TGFBI gene and inhibit protein accumulation in the cornea with the ease and convince of eye drop administration.

SIS-202-CDC is a topical Bio-Courier CRISPR-Cas 9 designed to permanently edit the mutated Transforming Growth Factor Beta I (TGFBI) gene using double-cut CRISPR Cas 9 and stop the overproduction and aggregation TGFBI protein in patients with type II Corneal Dystrophy. SIS-202-CDC represents the First-in-class cure for patients with type II Corneal Dystrophy with the ease and convince of eye drop administration.