RNAi is a natural process, the discovery of which in 1998 was awarded the Nobel Prize in 2006. Nobel laureates Fire and Mello found that double-stranded RNAs (dsRNAs) induced gene silencing in C. elegans (1998 Nature 391:806-11). Subsequently, Tuschl et al (2001 Nature 411:494-8). demonstrated that the RNAi pathway could be safely activated in mammals using short, synthetic dsRNAs called small interfering RNAs (siRNAs). Since its discovery in 1998, RNAi has been utilized extensively to interrogate gene function and to identify new therapeutic targets. In addition, synthetic siRNAs are emerging as an exciting and highly promising new class of therapeutics to treat a variety of diseases. Stability, potency, abrogation of off-target effects and efficient delivery of synthetic siRNAs are some of the major challenges for successful application of this technology in the clinic. Quark focuses its efforts on designing and optimizing synthetic siRNAs for therapeutic applications:

1. Our siRNA drugs are selected and chemically modified to confer properties necessary for successful application in the clinic, including:

• Potency 
• Stability 
• Reduced hybridization-dependent off-target activity 
• Abrogation of innate immune activation 
• Safety - Quark drugs exhibit good safety profiles at dose levels well above the proposed clinical range

2. siRNA drug focus:

Our strategy is to first assess which organs/tissues/cells effectively take up our synthetic siRNAs via various routes of administration, and we concentrate on diseases that originate in those tissues/cells. Areas that we initially focused on include diseases of the eye (e.g., wet, diabetic macular edema, diabetic retinopathy, NAION, glaucoma etc.), lung (e.g., acute lung injury, primary graft dysfunction in lung transplantation), kidney (acute kidney injury, delayed graft function), inner ear (e.g. acute hearing loss, ototoxicity and Ménière’s disease), and spinal cord (spinal cord injury).

3. Expertise in:

• Bioinformatics and proprietary algorithms to identify the best target sequences for our unique siRNA compositions to ensure adequate potency and specificity. We also design our siRNAs to function in relevant species used for efficacy and toxicology studies.
• siRNA characterization, including: 
• In situ detection and quantification of synthetic siRNAs in tissues and organs to assess distribution and uptake.
• Assays for molecular detection and quantification of RNA targets and cleavage products to evaluate RNAi activity in animal models.
• Full capabilities, including systems and assays, to assess for potential off-target effects and for possible innate immune activation.
• In vivo evaluation and animal proof of concept studies in-house and in collaboration with leading scientists and opinion leaders.
• Fully-integrated research and development teams to insure that optimal drug design starts at the stage of conception.
• Expert regulatory, medical and preclinical and clinical development teams to efficiently progress drug candidates through preclinical studies to IND and clinical trials.