SiSaf Exercises Option to License Gene Therapy for Rare Bone Disease

SiSaf, a company developing RNA therapeutics for rare genetic skeletal disorders, said that it has exercised its option under its collaboration with the University of L’Aquila, Italy to license a gene therapy for a rare bone disorder.

Photo: Suzanne Saffie-Siebert, founder and CEO of SiSaf

The license enables SiSaf to develop small interfering RNA (siRNA) targeted via its Bio-Courier next generation silicon stabilized hybrid lipid nanoparticles (sshLNP) to regulate the expression of a mutant gene expressed by osteoclasts and other cell types responsible for causing the therapeutically neglected rare autosomal dominant disorder type 2 Osteopetrosis (ADO2) in adults.

Autosomal dominant osteopetrosis type 2 (ADO2), also known as marble bone disease or Albers-Schönberg disease, affects one in every 20,000 individuals. It is marked by increased bone density due to a defect in bone resorption by osteoclasts, a type of bone cell that breaks down bone tissue. This process is critical to maintaining healthy bone and the defect leads to bone that is brittle and susceptible to fracture, which is often accompanied by bone pain and skeletal abnormalities significantly impairing the patient’s quality of life. At present, there is no effective medical treatment.

“ADO2 is a severe and debilitating disease for which there is no treatment. We are very encouraged to have made positive progress in demonstrating that our technology can overcome the inherent constraints of both viral delivery systems and lipid nanoparticles, especially in recurrent systemically delivered autosomal dominant disorders, an area with huge potential,” said Suzanne Saffie-Siebert, founder and CEO of SiSaf. “Our lead program to substantially alleviate autosomal dominant osteopetrosis type 2 would be life changing for patients with this incurable condition and we are excited to be developing the siRNA therapy towards clinical trials.”

SiSaf and the University of L’Aquila entered into the research collaboration and licensing agreement last year. The exercise of its option follows 12-months of intensive preclinical collaborative research between the parties to demonstrate that Bio-Courier targeting addresses the drawbacks seen with viral vectors, the current standard in gene therapy delivery to date.

The company said results from the preclinical studies demonstrated that SiS-101-ADO2, an ADO2-specific siRNA combined with SiSaf’s Bio-Courier platform, downregulates the expression of the mutant CLCN7 gene and rescues bone mass and quality to nearly normal levels. The treatment was well tolerated, inducing no adverse events.

SiSaf is now committed to developing SiS-101-ADO2 for the treatment of autosomal dominant osteopetrosis type 2 and is preparing data for its IND package with the aim of submitting an application to the U.S. Food and Drug Administration during the second half of 2022. Given the urgent medical need in autosomal dominant osteopetrosis type 2 patients and the lack of any existing therapies, SiSaf intends to file for Orphan Drug designation for its therapy.

“The translation of positive preclinical results into a clinical reality has been impeded by the requirement to repeatedly eliminate the mutant copy of the mRNA without affecting the healthy copy, a challenge in all autosomal dominant disorders,” said Anna Maria Teti, leader of the team at the University of L’Aquila and a recognized leader in genetic bone disorders.

Teti’s team had demonstrated that a siRNA-based experimental treatment for adult Osteopetrosis type 2 is feasible in human cells and transgenic mice. The study suggested that 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.

“The formulation of an ADO2-specific siRNA with SiSaf’s Bio-Courier next generation sshLNP technology has enabled repeated safe systemic administration, sufficiently stabilizing and protecting the siRNA in the circulatory system to demonstrate sustainable transfection and phenotypic reversion to restore healthy bone architecture,” Teti said.

SiSaf has an ongoing collaboration with Teti’s group and is working to extend its pipeline of Bio-Courier targeted siRNA therapies to cure other genetic skeletal disorders. Its strategy is to develop its pipeline of novel therapies through clinical studies and then seek collaborative partnerships with marketing expertise in genetic skeletal disorders and rare diseases.

Author: Rare Daily Staff