RNAi is a natural process discovered recently. The scientists who made breakthrough discoveries in understanding this natural process were awarded the Nobel Prize in Physiology or Medicine in 2006. Nobel winners Fire and Mello found that double-stranded RNAs (dsRNAs) caused the gene silencing. Subsequently the mechanism was shown in mammals and further shown that short fragments may be used. These short inhibiting agents were termed small interfering RNAs (siRNAs). Since the late nineties RNAi has not only become a widely used tool to understand how a disease works and to find cures, but synthetic siRNAs are also becoming an exciting and highly promising new class of drugs to treat a variety of diseases. Stability, effectiveness and efficient delivery of the siRNA to the right cells are some of the major hurdles that need to be overcome by the siRNA drug. For our siRNA drugs we have solved these major challenges.

1. Our siRNA drugs have a chemically modified, stabilized structure and properties that offers significant advantages

• Activity - Tested in a variety of in vivo models applying both systemic (iv) and local delivery (such as by inhalation, intravitreal, etc); The activity was found to be equal or better than standard siRNA
• Stability - In vitro and in vivo stability is adequate for the variety of indications tested.
• No non-specific toxicity is associated with our siRNA modification.
• No non-specific toxicity is associated with activation of cellular responses to foreign molecules.
• Safety - In the framework of extensive preclinical studies employing both systemic and local application, Quark drugs had a good safety profile up to dose levels well above the proposed clinical range.

2. High yield large scale GMP manufacturing of siRNA drugs: The modified siRNA structures of our drugs have low manufacturing costs and can be produced at high yields.

3. siRNA drugs focus: For our siRNA drugs we concentrate at present on diseases that originate in various organs of the body following oxidative stress, ischemic injuries. These include diseases of the eyes (wet and dry AMD, diabetic retinopathy, vein occlusion), of the lung (COPD, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS)), kidney (Acute Renal Failure), inner ear (acute hearing loss, presbycusis or age-related hearing loss), spinal cord (spinal cord injury) and skin (pressure sores, diabetic ulcer), In all these organs we have demonstrated, in preclinical studies, delivery of our siRNAs to the target cells in the injured organ by delivery means commonly applied in human medicine.

4. Expertise and access to intellectual property and manufacturing for stabilized, chemically modified siRNAs.

• We are testing novel siRNA molecules with different chemical structures. The ultimate aim is to generate siRNA structures that are patentable and are not covered by intellectual property rights of others.
• We are testing proprietary aptamer-siRNA and antibody-siRNA molecules for targeted delivery of active siRNA drug to the disease cells.
• Quark has the infrastructure to rapidly design (based on Quark’s bioinformatics using proprietary and public domain application ,SIRS), synthesize and test activity of siRNA in vitro and in vivo in clinically relevant models. siRNA activity is assessed by the levels of siRNA, measuring target RNA or protein knockdown by qPCR or immunoblotting, respectively and by attenuation of the pathological phenotype.
• Network of opinion leader collaborators in the US and Europe in specific technological fields indications with expertise in delivery of siRNA and functional analysis in vivo.
• Network of CROs and manufacturers in the US and Europe for a fast turnaround of manufacturing, preclinical studies and clinical supplies production.