mRNA Revolution: SiSaf case study

SiSaf's Bio-Courier® technology uses bioabsorbable silicon to improve nucleic acid delivery. The company licenses the technology and develops its own RNA therapeutics, with a focus on rare genetic disorders and oncology. The mRNA Revolution: A new generation of medicine report highlights the effectiveness, safety, and versatility of SiSaf's sshLNPs compared to conventional LNPs.

What does the company do?

SiSaf is an RNA delivery and therapeutics company. Its proprietary Bio-Courier® technology addresses the limitations of other nucleic acid delivery technologies through the hybridisation of organic materials with inorganic bioabsorbable silicon. The company’s business model is to maximise the potential of its technology by licensing to industry partners and by developing an in-house pipeline of RNA therapeutics. SiSaf’s most advanced programmes are RNA treatments for rare genetic disorders, but the company has the strategic ambition to expand its focus to other therapeutic areas, including oncology.

How does the technology work (simply)?

Lipid nanoparticles (LNP) have become the standard delivery system for mRNA. Bio-Courier® silicon stabilised lipid nanoparticles (sshLNP) are the next generation of lipid nanoparticles combining organic material – lipids – with inorganic material – bioabsorbable silicon. The silicon matrix stabilises both the lipid components and the RNA payload, reducing the need for ionisable or cationic lipids, PEGylated lipids, and cholesterol. This improves safety, targeting, and transfection. Unlike conventional lipid nanoparticles, sshLNP can be manufactured empty and loaded with the RNA later, at the desired point and time of use.

How is this an improvement on existing delivery technologies?

The stabilisation of both lipid components and RNA payload through silicon, as well as the ability to manufacture the carrier without RNA, overcome the key limitations of conventional LNP delivery systems for nucleic acid.

In conventional LNPs, the nucleic acid payload must be introduced early in the production process during the initial formation of LNPs prior to subsequent purification and fill/finish steps. This restricts batch sizes in commercial manufacturing due to the chemical lability of RNA, it affects the quality of the product that ultimately reaches the patient and requires an ultra-cold chain for storage and shipping.

In Bio-Courier sshLNPs, the nucleic acid can be introduced after the manufacture of the sshLNP particles. As a result, RNA encapsulation and fill/finish operations can be separated from carrier manufacture by considerable time and distance, readily permitting on-demand preparation of customised RNA-loaded LNPs on any scale.

In addition, Bio-Courier technology offers significant advantages over conventional LNP technology regarding stability, safety, targeting, and transfection.

• Stability

The use of the positively charged silicon matrix to bind and stabilise the RNA payload reduces the need for cationic/ionisable lipids, avoiding the risk of premature leakage of RNA from the nanoparticles as the positive charge from the lipids decays. The improved physical stability also translates into improved transfection efficiency.

• Safety

Existing approved LNPs rely on PEGylated lipids to protect RNA against enzymatic degradation, however, PEGylated lipids can induce anti-PEG antibodies and provoke an immune response. Due to their silicon-stabilised design, Bio-Courier sshLNPs are less reliant on PEGylated lipids than conventional LNPs, to the extent that some formulations are entirely free of PEGylation.

• Targeting

LNPs have a strong tendency to accumulate in the liver. Biodistribution studies with Bio-Courier sshLNPs have demonstrated minimal accumulation in the liver and Bio-Courier formulations can be customised to provide controlled release and targeting of specific cells and tissues.

What are your challenges?

Opportunities for RNA medicines have advanced hugely in recent years. That being said, RNA remains a new modality with all of the associated development, manufacturing and regulatory challenges. SiSaf believe delivery technology helps move the field forward positively.

The patent landscape in RNA therapeutics including delivery platforms is complicated. However, SiSaf are confident of the strength of our IP (Intellectual Property) portfolio and both our freedom to operate and our ability to license our technology to others.

As a small but ambitious company, SiSaf needs to focus its resources on demonstrating the power of its technology and to attract external partnerships and investment to progress clinical programmes. We are proud that our lead programme SIS-101-ADO, an siRNA therapeutic for patients with Autosomal Dominant Osteopetrosis Type 2 (ADO2), has been granted both Orphan Drug Designation and Rare Pediatric Disease Designation by the U.S. FDA (Food and Drug Administration). There are currently no approved treatments for Osteopetrosis ADO2 and no other treatments currently in clinical trials.

If approved, SiSaf’s SIS-101-ADO would thus be the first treatment for Osteopetrosis ADO2 and could provide life-altering benefits for those who suffer from this debilitating disease. Their fast follower programme, SIS-102-ACH, would offer the first treatment of Achondroplasia that targets the genetic root cause of the condition. SiSaf also have partnered programmes to treat Type II Corneal Dystrophy and an undisclosed programme using Bio-Courier for topical delivery.

SiSaf have raised significant funding to date. They are committed to take their lead programmes through early clinical development, and thus anticipate a series C in due course.

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