Our Science
NEXT GENERATION OF PRECISION
RNAi THERAPIES
Based on the scientific discovery of Switch’s co-founders, the company’s proprietary CASi platform combines advantageous properties of both single and double-stranded RNAs in a single molecule, allowing for efficient self-delivery and uptake as well as potency and durable gene knockdown with cell specificity. Switch is leveraging the unique properties of CASi molecules to develop the next generation of precision RNAi therapies for central nervous system (CNS) diseases.
CASi MOLECULES: A NOVEL CLASS OF DRUGS
Switch Therapeutics has developed a novel class of drugs called Conditionally Activated siRNAs (CASi). Each CASi molecule contains a small interfering RNA (siRNA) plus a sensor strand designed to dock to a unique RNA sequence in the targeted cell. This structure enables us to activate the siRNA in the cells of choice – “switching” from an inactive siRNA to an active siRNA. The addition of this sensor gives CASi two critical properties:
(1) Efficient self-delivery and uptake, potency, and sustained duration of gene knockdown. The combination of a unique mechanism for effective self-delivery as well as cell selectivity enables new avenues for next generation RNAi therapy.
(2) The unique ability to target RNAi activity to specific cell types with unique expression of biomarker RNAs. By enabling cell selective activation and knockdown of targets by RNAi, CASi has the ability to improve the therapeutic window for existing targets and open the door for numerous therapeutic applications.
The Platform
COMBINING ADVANTAGEOUS PROPERTIES OF SINGLE AND DOUBLE-STRANDED RNAs IN A SINGLE MOLECULE
Modern oligonucleotide medicines for gene knockdown belong to two different categories; short single-stranded molecules, such as antisense oligonucleotides (ASOs), and short, double-stranded molecules called siRNAs. These current gene knockdown modalities have both incredible promise and known limitations. There is no current gene knockdown modality that is highly potent, exhibits good distribution and has cell-selective capabilities.
CASi MOLECULES COMBINE THE BEST OF BOTH APPROACHES
In CASi molecules, the single stranded toehold domain in the sensor can be combined with validated ASO chemistries to impart CASi molecules with self-delivery properties. Once in the cell of interest, the sensor decouples from the siRNA, allowing for efficient gene knockdown. This best-of-both-worlds approach helps substantially improve delivery and activity. As a result, CASi has broad therapeutic applicability with the potential to deliver the next generation of precision RNAi therapies.
OUR PIPELINE
Our CASi platform has broad applicability, with the potential to treat a range of diseases of the central nervous system as well as conditions outside of the CNS.
Internally, our efforts are initially focused on advancing multiple programs for the treatment of neurodegenerative diseases. With these programs, we leverage our ability to achieve high CNS potency, long duration and deep brain distribution. We are advancing towards IND-enabling studies in the near-term.
We also intend to explore opportunities to expand our CASi platform into new areas through potential pharmaceutical and biotechnology collaborations.
Switch is building an extensive CNS pipeline enabled by CASi
APOE
Apolipoprotein E (APOE) is essential for lipid metabolism in all tissues and organs, but some forms can be toxic to normal brain function. Systemic APOE is produced primarily in the liver and CNS APOE is produced primarily in astrocytes, although under diseased condition is upregulated in microglia and neurons. APOE has three distinct isoforms, APOE*ε2, APOE*ε3 and APOE*ε4, and each person has two copies of APOE which may both be the same isoform (e.g., ε4/ε4) or two different isoforms (e.g., ε3/ε4). The APOE*ε4 allele is the greatest genetic risk factor for late-onset Alzheimer’s disease (LOAD). APOE*ε4 not only strongly increases risk but also lowers the age of onset for developing LOAD in a gene dose-dependent manner as compared to the more common ε3 allele.
Two-thirds of AD patients have at least one copy of ε4 and APOE*ε4 homozygosity adds a significant higher probability of early onset AD dementia. APOE*ε4 allele significantly drives disease pathology as measured by increased amyloid and tau pathology and increasing neuroinflammation. Despite the fact, that APOE*ε4 is a driver of AD pathology, APOE*ε4 patients treated with anti-amyloid antibodies have reported a higher incidence of ARIA (amyloid related imaging abnormalities), limiting their use in APOE*ε4 carriers.
The most viable strategy for APOE*ε4 to treat AD is to only block expression in the brain and maintain APOE production in the liver. Switch’s CASi-APOE is the only therapy in development that is capable of blocking expression in brain cells while sparing the liver.
MAPT
The microtubule-associated protein tau (MAPT) gene encodes for the protein tau, that is involved in the assembly and stabilization of microtubules in neurons. Hyperphosphorylation and post-translation modifications cause tau to detach from microtubules to form intracellular neurotoxic tangles leading to Alzheimer’s disease (biological and clinical). Alzheimer’s disease is a form of secondary tauopathy. In addition, several other neurogenerative disorders such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are caused solely due to a tau pathology called primary tauopathies. Most therapies in development to prevent tau tangles depended on either targeting different epitopes of tau by antibodies or targeting post-translational modifications by small molecules. Another approach is to target the production of tau by targeting the MAPT transcript. This can only happen within the cell, and antibodies are generally unable to enter cells. CASi-002 is being developed as an anti-tau siRNA capable of blocking cellular tau production.
C1q
C1q is the first component of the classical pathway of the complement system, which is the body’s first line of defense against pathogens. C1q binds directly to antibodies and pathogens, activating the complement system; as such C1q has been studied extensively in the context of autoimmune disease and host defense.
Within the CNS, C1q is expressed exclusively in microglia and plays a role in neuroinflammation and maintaining synaptic health. Activated microglia release C1q that ‘tags’ neurons as an ‘eat me’ signal to microglia causing microglia to prune synapses. Cell-selective knockdown of C1q by targeting microglial C1QA using Switch’s proprietary siRNA platform is advantageous to target pathological role of microglial C1q without affecting normal functions of C1q and systemic immunity.