DROSHA

Currently, 6 siRNA drugs have been approved globally, including Patisiran, Inclisiran, and Amvuttra, which have demonstrated significant therapeutic effects in fields such as genetic diseases, cardiovascular diseases, and infectious diseases. Furthermore, according to statistics from Patsnap Synapse, at least 150 siRNA drugs are in clinical trials, covering a wide range of therapeutic areas. According to Maximize Market Research, the siRNA therapeutics market is expected to grow substantially from $12.7 billion in 2022 to $39.2 billion by 2029, with a compound annual growth rate (CAGR) of 25.3%. siRNA drugs are synthesized chemically and typically consist of 21-23 nucleotides. They are composed of a guide strand (antisense strand) and a passenger strand (sense strand). Inside the cell, the generation of siRNA begins with long double-stranded RNA (dsRNA). These dsRNAs can originate from exogenous RNA viruses, transgenes, or transcription products of endogenous genes. Dicer, an RNA enzyme from the RNase III family, recognizes and cleaves long dsRNA to generate siRNA duplexes approximately 21-23 nucleotides in length. Dicer is responsible not only for cleaving dsRNA but also for processing and maturing the siRNA duplexes. The resulting siRNA duplexes are then loaded into the RNA-induced silencing complex (RISC). RISC is a multiprotein complex containing various proteins, with the most crucial component being the Argonaute protein, especially Ago2. Within RISC, the passenger strand (sense strand) is typically degraded or expelled, while the guide strand (antisense strand) is retained as the functional component of RISC. RNAi biogenesis and mechanism1The RISC complex, loaded with the guide strand, searches for mRNA in the cytoplasm that is complementary to the guide strand. The guide strand binds to a specific region of the target mRNA through base pairing. This complementarity is typically perfect, ensuring high specificity of siRNA for the target mRNA. The recognition site for target mRNA is usually located in the 3' untranslated region (3' UTR), but it can also be in the coding region or other areas. RISC recognizes the target mRNA through precise base pairing, a process that depends on the complementarity between the guide strand and the mRNA. Extracellular and intracellular barriers for siRNA therapeutics1Once the guide strand in the RISC complex successfully binds to the complementary sequence of the target mRNA, the Argonaute protein in RISC (especially Ago2) exerts its endonuclease activity and catalyzes the cleavage of the mRNA. Ago2 protein cleaves the mRNA at specific sites, causing mRNA fragmentation. The cleaved mRNA fragments are then further degraded, typically through other RNA degradation pathways within the cell, such as the action of exonucleases. This process completely disrupts the integrity of the mRNA, preventing it from being translated into protein, thereby inhibiting the expression of the target gene. Through mRNA degradation, siRNA effectively blocks the expression of the target gene, a process known as post-transcriptional gene silencing (PTGS). PTGS is widely present in both plants and animals and serves as an important mechanism for cells to regulate gene expression. After completing one round of mRNA degradation, the RISC complex does not immediately become inactive but can be released and reused to search for new target mRNAs for further degradation. This recycling mechanism allows siRNA to continuously exert its effect within the cell, enhancing the efficiency and persistence of gene silencing. The levels of siRNA in the cell and the activity of RISC are in a dynamic equilibrium. Newly generated siRNA constantly replenishes RISC, while older siRNAs are gradually metabolized or degraded, ensuring the continuity and effectiveness of gene silencing. Types of Modifications in siRNA Drugs and Their Effects1. Phosphodiester Backbone ModificationsPhosphodiester backbone modifications in siRNA drugs primarily include thio-phosphodiester (PS) modifications and 5’-(E)-vinylphosphonate (5’-(E)-VP) modifications. Thio-phosphodiester modification replaces the phosphodiester bond in siRNA with a thio-phosphodiester bond, significantly enhancing the stability of siRNA and its resistance to nucleases. This modification also increases the lipophilicity of siRNA, facilitating its penetration through the cell membrane. However, excessive PS modification may reduce the binding affinity of siRNA to the target mRNA, potentially affecting the efficiency of gene silencing. The 5’-(E)-VP modification is a novel phosphate mimic, where a vinylphosphonate group is introduced at the 5’ end of siRNA to enhance its stability in vivo. This modification not only makes siRNA resistant to exonuclease degradation and improves its silencing effect in vivo, but it also increases the binding affinity of siRNA to Ago2 protein, improving its loading efficiency into RISC. The generation of RNA aptamers2For example, Inclisiran, developed by Alnylam Pharmaceuticals, is an siRNA drug for treating hypercholesterolemia that incorporates 5’-(E)-VP modification. This modification significantly improves the in vivo stability and gene-silencing efficacy of Inclisiran. The 5’-(E)-VP modification enables Inclisiran to resist degradation by exonucleases more effectively, maintaining its activity in the body for a longer duration. Additionally, the 5’-(E)-VP modification enhances the binding affinity of Inclisiran to the Ago2 protein, increasing its loading efficiency into RISC and further boosting its gene-silencing efficacy. The successful development and clinical application of Inclisiran demonstrate the significant potential of 5’-(E)-VP modification in enhancing the performance of siRNA drugs. 2. Ribose ModificationsRibose modifications are effective strategies for improving siRNA stability and reducing immunogenicity. Common ribose modifications include 2’-O-methyl (2’-OMe), 2’-O-methoxyethyl (2’-MOE), and 2’-fluoro (2’-F) modifications. The 2’-OMe modification introduces a methyl group at the 2’ position of the ribose, enhancing siRNA stability and nuclease resistance while reducing immunogenicity. This modification has minimal impact on the base-pairing ability of siRNA and does not significantly affect its gene-silencing efficacy. The 2’-MOE modification introduces a methoxyethyl group at the 2’ position of the ribose, further improving siRNA stability and nuclease resistance, significantly reducing immunogenicity, but potentially slightly decreasing its gene-silencing efficacy. The 2’-F modification introduces a fluorine atom at the 2’ position of the ribose, enhancing siRNA stability and nuclease resistance, and reducing immunogenicity, though it may slightly reduce gene-silencing efficacy. For example, Patisiran, developed by Alnylam Pharmaceuticals, is an siRNA drug for treating hereditary transthyretin amyloidosis (hATTR) that incorporates 2’-OMe and 2’-F modifications. By introducing 2’-OMe and 2’-F modifications at specific positions on the sense and antisense strands of siRNA, Patisiran significantly improves its stability and nuclease resistance while reducing immunogenicity. These modifications enable Patisiran to maintain its activity in vivo for a longer duration, effectively degrading the target mRNA and reducing the accumulation of abnormal proteins, thereby alleviating disease symptoms. The successful development and clinical application of Patisiran demonstrate the significant potential of 2’-OMe and 2’-F modifications in enhancing the performance of siRNA drugs. 3. Base ModificationsBase modifications enhance the stability and nuclease resistance of siRNA by altering its nucleotide bases. Common base modifications include locked nucleic acid (LNA) and glycol nucleic acid (GNA). LNA is a unique bicyclic nucleotide derivative containing one or more 2’-O, 4’-C-methylene-β-D-ribofuranose monomers. The methylene bridge between the 2’ oxygen and 4’ carbon atoms of the ribose locks the sugar ring into a rigid bicyclic structure, significantly reducing the flexibility of the ribose and enhancing the local stability of the phosphate backbone. LNA modification markedly improves the thermal stability of siRNA, making it more stable in vivo, while also increasing its binding affinity to the target mRNA, thereby enhancing gene-silencing efficacy. GNA, on the other hand, features an acyclic three-carbon propylene glycol (1,2-propanediol) backbone, replacing the (deoxy)ribose of DNA and RNA to form the simplest chemically stable nucleic acid structure. GNA modification enhances the binding affinity of siRNA, improves its gene-silencing efficacy, reduces immunogenicity, and minimizes immune responses. These base modifications not only improve the stability and degradation resistance of siRNA but also significantly enhance its gene-silencing efficacy, thereby improving the safety and therapeutic effectiveness of siRNA drugs. Nucleotide modifications of siRNA1For example, Givosiran, developed by Alnylam Pharmaceuticals, is an siRNA drug for treating acute hepatic porphyria (AHP) that incorporates LNA modification. By introducing LNA modifications at specific positions on the antisense strand of siRNA, Givosiran significantly improves its thermal stability and nuclease resistance while enhancing its binding affinity to the target mRNA, thereby boosting gene-silencing efficacy. This modification enables Givosiran to maintain its activity in vivo for a longer duration, effectively degrading the target mRNA and reducing the accumulation of porphyrin precursors, thereby alleviating disease symptoms. 4. Terminal ModificationsTerminal modifications enhance the stability and nuclease resistance of siRNA by introducing specific chemical groups at the 5’ or 3’ ends. Common 5’ terminal modifications include 5’-phosphorylation and 5’-methylphosphonate (5’-MP) modifications. The 5’-phosphorylation modification involves introducing a phosphate group at the 5’ end of siRNA, which enhances the binding affinity of siRNA to the Ago2 protein, improves its loading efficiency into the RNA-induced silencing complex (RISC), and thereby enhances gene-silencing efficacy. The 5’-MP modification introduces a methylphosphonate group at the 5’ end, which not only improves siRNA stability but also enhances its resistance to nucleases. Common 3’ terminal modifications include 3’-inverted deoxynucleotide (3’-ddN), which can reduce the immunogenicity of siRNA, minimize immune responses, and improve gene-silencing efficacy. These terminal modifications not only enhance the stability and degradation resistance of siRNA but also significantly improve its gene-silencing efficacy, thereby increasing the safety and therapeutic effectiveness of siRNA drugs. Phosphate-backbone modifications of siRNA1Fitusiran, developed by Alnylam Pharmaceuticals, is an siRNA drug used to treat hemophilia A and B. By targeting the mRNA of antithrombin (AT), Fitusiran reduces its expression in the liver, thereby increasing the levels of clotting factors in the blood and reducing bleeding episodes. Fitusiran incorporates 5’-phosphorylation modification, which introduces a phosphate group at the 5’ end of siRNA, significantly enhancing its binding affinity to the Ago2 protein. This modification enables siRNA to bind more effectively to the Ago2 protein after entering cells, forming the RNA-induced silencing complex (RISC), which specifically recognizes and degrades the mRNA of antithrombin, reducing its expression. The 5’-phosphorylation modification not only improves the gene-silencing efficacy of Fitusiran but also enhances its in vivo stability and degradation resistance, reduces immunogenicity, and minimizes potential side effects. SummaryAs an emerging therapeutic technology, siRNA drugs have demonstrated significant therapeutic effects in areas such as genetic disorders, cardiovascular diseases, and infectious diseases. Through the aforementioned modification strategies, the stability and specificity of siRNA drugs have been significantly improved, while immunogenicity and off-target effects have been reduced, enhancing their bioavailability and therapeutic efficacy in vivo. The development of these modification technologies has provided a solid foundation for the application of siRNA drugs in the treatment of various diseases and has driven the rapid growth of the siRNA therapeutics market. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Reference 1.Ali Zaidi SS, Fatima F, Ali Zaidi SA, Zhou D, Deng W, Liu S. Engineering siRNA therapeutics: challenges and strategies. J Nanobiotechnology. 2023 Oct 18;21(1):381. doi: 10.1186/s12951-023-02147-z. PMID: 37848888; PMCID: PMC10583313.2.Zhou J, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017 Mar;16(3):181-202. doi: 10.1038/nrd.2016.199. Epub 2016 Nov 3. Erratum in: Nat Rev Drug Discov. 2017 Jun;16(6):440. doi: 10.1038/nrd.2017.86. PMID: 27807347; PMCID: PMC5700751.

According to a report by Yole Développement, the CRISPR technology market is projected to reach $5 billion by 2023, marking its rapid global development and widespread application. By 2027, the global CRISPR technology market is expected to grow to $3.94 billion, with a compound annual growth rate (CAGR) of 24.2%. This forecast underscores the sustained growth of CRISPR technology across various fields, particularly in therapeutic applications. Key therapeutic uses of CRISPR include gene editing, gene therapy, and immunotherapy, which hold promise for offering new treatment solutions for numerous genetic disorders and cancers. Mechanism of CRISPR-Cas9The development of CRISPR-Cas9 technology can be traced back to 1987, when Japanese scientists first identified CRISPR sequences in Escherichia coli, though their significance was not realized at the time. In 2005, researchers discovered that CRISPR sequences matched viral DNA infecting bacteria, revealing the relationship between CRISPR and bacterial defense against viruses. By 2007, researchers at Danisco demonstrated that the CRISPR system could function as an adaptive immune mechanism in bacteria, protecting against foreign genetic material. Mechanism of CRISPR/Cas9 system[1]In 2012, Jennifer Doudna, Emmanuelle Charpentier, and their team unveiled the functional mechanism of the CRISPR-Cas9 system. They discovered that the Cas9 protein, guided by RNA molecules, could precisely identify and cleave specific DNA sequences, highlighting its immense potential for precise gene editing. This breakthrough rapidly made CRISPR-Cas9 a prominent tool in scientific research, finding applications in gene function studies, genetic disease treatments, and more. A brief history of CRISPR/Cas9 system development and associated gene editing tools[1]In the CRISPR-Cas system, CRISPR loci are initially transcribed into a long precursor RNA (pre-crRNA). This process occurs within bacterial or archaeal cells in response to the invasion of viruses or other foreign genetic material. CRISPR loci consist of multiple repeat sequences and spacer sequences, the latter of which are derived from fragments of previously encountered viral genes. Typically, CRISPR loci include a leader region rich in AT bases, which acts as a promoter. Following the leader region, alternating repeat and spacer sequences form a pattern of "repeat-spacer-repeat," transcribed under the leader region's regulation into pre-crRNA containing multiple repeats and spacers. Each spacer corresponds to an integrated viral gene fragment. Naturally occurring Cas proteins and the engineered Cas proteins[2]Pre-crRNA requires processing to form mature crRNA, a process aided by trans-activating crRNA (tracrRNA). TracrRNA is a longer RNA molecule that contains a domain binding to Cas proteins and a sequence complementary to the repeat regions of pre-crRNA. Through complementary pairing, tracrRNA binds to the repeat regions of pre-crRNA to form a double-stranded RNA structure. This structure is cleaved by endogenous enzymes like RNase III, producing multiple mature crRNA molecules. Each crRNA includes a spacer sequence complementary to a previously integrated viral gene fragment. Mature crRNA, approximately 20 nucleotides long, specifically recognizes target DNA sequences. Schematic diagram of in vitro or in vivo CRISPR screening[1]The mature crRNA is produced from pre-crRNA and includes a spacer sequence complementary to the integrated viral gene fragment. TracrRNA facilitates the complementary pairing of its sequence to the repeat regions of pre-crRNA, forming a double-stranded RNA structure. Enzymes such as RNase III cleave this structure to produce mature crRNA, which includes a spacer sequence complementary to the target DNA sequence. Mature crRNA pairs with tracrRNA to form a double-stranded RNA complex, structurally resembling a "Y" shape. The spacer sequence of crRNA remains single-stranded, while the remainder forms a double strand with tracrRNA. This double-stranded RNA complex stabilizes the crRNA and provides the necessary structure for subsequent binding to the Cas9 protein. Pooled CRISPR/Cas9 screening approachesCas9 protein is a nuclease capable of cleaving DNA at specific locations. It has two primary domains: RuvC-like and HNH, which cleave the two DNA strands, respectively. The double-stranded RNA complex binds to Cas9, forming a ribonucleoprotein (RNP) complex essential for precise gene editing. The RNP complex is stabilized through Cas9's specific domains binding to tracrRNA. The spacer sequence of crRNA is exposed and pairs complementarily with the target DNA sequence. The RNP complex recognizes and binds to the target DNA sequence through the spacer sequence of crRNA. The target DNA sequence must contain a Protospacer Adjacent Motif (PAM), essential for Cas9 recognition and binding. Once the crRNA pairs with the target DNA sequence, it forms an R-loop structure, a prerequisite for DNA cleavage by Cas9. Cas9 cleaves the double-stranded DNA at specific positions upstream of the PAM sequence, creating double-strand breaks (DSBs). The RuvC-like and HNH domains of Cas9 cleave the non-target and target strands, respectively. DSBs are repaired via non-homologous end joining (NHEJ) or homology-directed repair (HDR). NHEJ introduces random insertions or deletions (indels), leading to gene inactivation or loss of function, while HDR enables precise insertion or replacement of specific DNA fragments for accurate gene editing Market Drivers for CRISPR TechnologyIn recent years, CRISPR technology has seen significant advancements in genome editing platforms, particularly in optimizing Cas9 proteins. For instance, optimized versions like eSpCas9 and SpCas9-HF have significantly reduced off-target effects and improved editing efficiency. These innovations have expanded CRISPR's applications across various fields. In basic research, high-precision CRISPR tools help scientists study gene functions, identify biomarkers, and discover drug targets. In clinical applications, reduced off-target effects enhance therapeutic safety, minimizing adverse reactions and providing more effective treatments. Additionally, optimized Cas9 proteins are useful for complex gene editing tasks such as multi-gene editing and large-scale genomic screening, driving CRISPR's broader adoption in research and medicine. As the understanding of genetic diseases and cancer deepens, the demand for precision medicine and personalized therapies continues to grow. CRISPR technology, with its high efficiency and precision, has become a critical tool to meet these needs. Genetic diseases are often caused by specific gene mutations, and traditional therapies struggle to provide cures. In contrast, CRISPR technology enables precise gene editing to correct pathogenic mutations, offering curative treatment options. For instance, CRISPR has been successfully used in early-stage treatments for genetic disorders such as β-thalassemia and sickle cell disease. In cancer therapy, CRISPR technology allows the editing of immune cells, such as CAR-T cells, enhancing their ability to recognize and eliminate cancer cells, thereby improving the efficacy of immunotherapy. Moreover, CRISPR is being used to develop novel gene therapies, including gene-editing vaccines and gene-drive systems, paving the way for new approaches in disease prevention and treatment. The increasing demand for CRISPR-based solutions not only drives innovation and technological advancement but also fosters the formation of related industrial chains, delivering significant economic and social benefits. Regional Development of CRISPR TechnologyThe United States leads the research and development of CRISPR technology. Prominent institutions and biotech companies, such as Harvard University, MIT, the Broad Institute, CRISPR Therapeutics, and Intellia Therapeutics, are at the forefront of advancing this technology. The U.S. Food and Drug Administration (FDA) has approved several clinical trials for CRISPR-based therapies, targeting conditions such as sickle cell disease (SCD), transfusion-dependent β-thalassemia (TDT), and hereditary blindness. On December 8, 2023, the FDA approved Casgevy (exa-cel), a CRISPR-based gene-editing therapy developed by CRISPR Therapeutics and Vertex Pharmaceuticals, for treating SCD and TDT. The United Kingdom is also at the forefront of CRISPR regulation and approvals. On November 16, 2023, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) approved Casgevy (exa-cel) for treating SCD and TDT. Institutions like the University of Cambridge and Imperial College London have made significant contributions to the basic and applied research of CRISPR technology. Several European Union countries are actively advancing CRISPR research and clinical applications. The European Medicines Agency (EMA) approved Casgevy (exa-cel) for treating SCD and TDT on December 15, 2023. Research institutions and biotech firms in Germany, France, and the Netherlands have achieved notable progress in clinical trials and applications of CRISPR technology. Competitive Landscape of the CRISPR Gene Editing Therapy MarketCRISPR Therapeutics, based in Basel, Switzerland, is a leading gene editing company focused on utilizing CRISPR-Cas9 technology to treat various genetic disorders. Its flagship product, Casgevy (exa-cel), is a gene editing therapy for sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT). This therapy received approval from both the FDA and EMA in 2023. The company is also advancing CTX001, an autologous cell therapy for β-thalassemia and SCD, which has demonstrated promising safety and efficacy in multiple clinical trials. Intellia Therapeutics, headquartered in Cambridge, Massachusetts, specializes in the development and application of CRISPR-Cas9-based therapies. The company is advancing both in vivo and ex vivo gene editing treatments for various genetic diseases. Key products include NTLA-2001, an in vivo gene editing therapy for transthyretin amyloidosis (ATTR), which has shown significant efficacy and safety in clinical trials, and NTLA-2002, an in vivo therapy for hereditary angioedema (HAE), which has received FDA approval for clinical trials and demonstrated positive results in early-stage studies. Editas Medicine, also based in Cambridge, Massachusetts, is a prominent player in the gene editing field, leveraging CRISPR-Cas9 technology to address genetic diseases. Its lead product, EDIT-101, is an in vivo gene editing therapy for Leber congenital amaurosis type 10 (LCA10). Using an AAV5 vector to deliver the CRISPR-Cas9 system, this therapy targets pathogenic mutations in the CEP290 gene to restore photoreceptor function. It has shown good safety and preliminary efficacy in Phase 1/2 clinical trials. Another key product, EDIT-301, treats SCD and TDT by editing hematopoietic stem cells to produce high levels of fetal hemoglobin, reducing or eliminating disease symptoms. EDIT-301 is currently under evaluation in several clinical trials, showing favorable safety and efficacy. Mammoth Biosciences, located in San Francisco, California, was co-founded by CRISPR pioneer Dr. Jennifer Doudna. The company focuses on applying CRISPR technology for disease diagnosis and gene editing. Notable offerings include the DETECTR platform, a CRISPR-based diagnostic tool that leverages Cas enzymes and guide RNA to deliver genetic diagnostic results within 20 minutes. This platform gained prominence during the COVID-19 pandemic through the RADx initiative and collaborations with the U.S. Department of Defense, showcasing its potential in public health emergencies. Mammoth is also developing gene editing therapies for genetic disorders using its proprietary ultra-small Cas enzymes (e.g., Cas14 and Cas12), which are smaller, more thermally stable, and exhibit faster reaction kinetics, enabling efficient delivery and gene editing. Collaborations with companies like Bayer and Regeneron are accelerating Mammoth’s therapeutic development efforts. Beam Therapeutics, headquartered in Cambridge, Massachusetts, is a biotechnology company specializing in base editing technology. This approach enables precise genetic modifications, providing tailored treatments for genetic disorders. Its key products include BEAM-101 and BEAM-102. BEAM-101 is an ex vivo gene-editing therapy designed for the treatment of sickle cell disease (SCD). It works by editing hematopoietic stem cells to increase fetal hemoglobin (HbF) levels, thereby mitigating or eliminating SCD symptoms. BEAM-101 has received FDA IND approval and is currently undergoing the Phase 1/2 BEACON-101 clinical trial. Early data indicate its ability to significantly elevate HbF levels while reducing HbS levels, demonstrating both safety and efficacy. BEAM-102 targets transfusion-dependent β-thalassemia (TDT), similarly using edited hematopoietic stem cells to increase HbF levels and alleviate or eliminate disease symptoms. BEAM-102 is currently in the IND feasibility study phase, laying the groundwork for future clinical trials. SummaryThe market outlook for CRISPR technology is promising, with expanding applications in gene editing, gene therapy, and immunotherapy. Advances in technical optimization, safety improvements, growing market demand, and supportive policies are driving the rapid development of CRISPR technologies. As more clinical trials succeed and regulatory approvals increase, CRISPR holds the potential to offer precise and effective treatments for genetic disorders and cancers. This progress is also expected to stimulate the growth of related industries, delivering positive economic and social impacts. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Reference： 1.Wang, S.W., et al., Current applications and future perspective of CRISPR/Cas9 gene editing in cancer. Mol Cancer, 2022. 21(1): p. 57. 2.Liu, Z., et al., Recent advances and applications of CRISPR-Cas9 in cancer immunotherapy. Mol Cancer, 2023. 22(1): p. 35.

License allows Lepton, with their proprietary Castling Technology, to develop and commercialize products and services using CRISPR/Cas9 technology Dublin, Ireland and Zichron Yakov, Israel, 26 July 2022: ERS Genomics Limited (‘ERS’) is pleased to announce a new license agreement with Lepton Pharmaceuticals LTD (‘Lepton”). This is a non-exclusive licensing agreement granting Lepton access to the ERS CRISPR/Cas9 patent portfolio for certain applications. ERS, co-founded by Dr. Emmanuelle Charpentier, 2020 Nobel Prize winner for gene-editing, provides access to the foundational CRISPR/Cas9 intellectual property. Over 90 patents are held in over eighty countries. Lepton Pharmaceutical LTD is a biotechnology company developing a proprietary, breakthrough technology (Castling Technology) to substantially improve adaptive cell-mediated immune response (T-cells, CAR-T-cells, NK-cells….) Dr. Daniel Zurr, CEO of Lepton said: “We are very pleased to establish this relationship and license agreement with ERS Genomics. It will greatly assist us to develop our innovative Castling technology to significantly improve immune cells efficiency and longevity to fight cancer.” Eric Rhodes, CEO at ERS Genomics added: “Lepton’s Castling technology has great potential to impact the field of immunotherapies and we are pleased to help enable Lepton in pursuing this exciting approach.” The Castling technology is a proprietary, miRNA-based general technology platform, essentially consisting of the manipulation of miRNA expression to achieve enhanced efficacy and longevity (reduced exhaustion) of cell-based therapies. miRNAs are noncoding RNAs that each affects the expression of hundreds of coding genes. The Castling technology allows, in a single gene editing event in the immune cell (either allogeneic or autologous.)to impact the expression of multitude genes in the immune-cells once they penetrate the microenvironment of cancer cells. This technology aims to revolutionize the immune cell cancer therapy field, Financial details of the agreement are not disclosed. About ERS Genomics ERS Genomics is a biotechnology company based in Dublin, Ireland. The company was formed to provide broad access to the foundational CRISPR/Cas9 intellectual property held by Dr. Emmanuelle Charpentier. Non-exclusive licenses are available for research and sale of products and services across multiple fields including: research tools, kits, reagents; discovery of novel targets for therapeutic intervention; cell lines for discovery and screening of novel drug candidates; GMP production of healthcare products; companion animal and livestock health; production of industrial materials such as enzymes, biofuels and chemicals; and synthetic biology. For additional information please visit www.ersgenomics.com About Lepton Pharmaceuticals Lepton Pharmaceuticals LTD. is based in Israel. Lepton focuses on subtle and precise silencing of coding RNA expression by small non-coding RNA molecules, working via the DROSHA/DICER/RISC pathways, small interfering RNA (siRNA), and microRNA (miRNA), to develop products and services to, ultimately, improve therapies for underserved diseases and improve and change patients’ lives. For additional information please visit www.leptonpharma.com