Chandra Vargeese

Chief Technology Officer, Wave Life Sciences

Smiling woman in purple top

My career has been dedicated to the research and development of genetic medicines. I am a Senior Research and Development Scientist with over 33 years of experience in research and development of nucleosides and nucleic acid-based therapeutics.  I have developed a deep understanding of these technologies, diseases, and associated disease mechanisms. I am an internationally recognized thought leader in the application of various nucleic acid platform technologies from basic research and discovery to commercial products, with a strong track record of numerous patents and publications. Areas of expertise include: 

•    Pioneer in the research and development of stereopure oligonucleotides and advanced six clinical programs
•    Developing various nucleic acid-based therapeutics 
•    Co-invented Macugen, FDA approved aptamer drug for Age Related Macular Degeneration (AMD)     
•    Oligonucleotide design, nucleic acid modification, synthesis and large scale production of drugs to support clinical trials
•    Invented and developed nucleic acid delivery technologies including lipid nanoparticles and targeted delivery
•    Pharmaceutical process research and development
•    Communicating effectively and working collaboratively across a broad range of functions
•    Recruiting and leading high-performance multidisciplinary organizations

 

Publications

As a post-doctoral research associate with Prof. Elie Abushanab, synthetic expertise was developed in the areas of chiral acyclic nucleosides and nucleotides.  A practical synthesis of 2’,3’-didehydro-2’,3’-dideoxythymidine (D4T), a potential antiviral agent against HIV was achieved starting with D-glucose.

  • Chandra Vargeese & Elie Abushanab (1992) A Practical and Stereospecific Approach to the Synthesis of 3′-Deoxy-2′,3′-didehydrothymidine (D4T), Nucleosides and Nucleotides, 11:8, 1549-1559. doi: 10.1080/07328319208021195

Contributions to nucleic acid Aptamers

As an associate director, I was responsible for establishing high throughput, medium and large-scale oligonucleotide synthesis facility and fully supported NeXstar’s drug discovery group by providing various unmatched high-quality aptamers in a very short period. To increase the stability of RNAs, I designed and synthesized various 2’ modified pyrimidines and their triphosphates, for incorporation into oligonucleotides. Worked with the discovery team using SELEX technology to Co-invent Macugen, a pegylated VEGF aptamer which was approved for the treatment of Age Related Macular Degeneration.  This is the first fully chemically modified, pegylated aptamer designed for therapeutic applications.  Subsequently I was responsible for the development of various aptamer conjugates designed to improve their pharmacological properties for therapeutic applications. In collaboration with other groups in the company, I was involved in developing microtiter plates for laying protein or aptamers for SELEX technology development.

  • Danny P. C. McGee, Chandra Vargeese, Yansheng Zhai, Gary P. Kirschenheuter, Alecia Settle, Colleen R. Siedem & Wolfgang A. Pieken (1995) Efficient Synthesis of 2′-Amino-2′-deoxypyrimidine 5′-Triphosphates, Nucleosides and Nucleotides, 14:6, 1329-1339, doi: 10.1080/15257779508010694

siRNAs and miRNAs

I played an important role in the formation of Sirna Therapeutics in 2003.  I headed the siRNA chemistry and delivery group in the development of siRNA based therapeutics including optimization of siRNA chemistry to improve potency and stability; Responsible for the invention of rationally designed Lipid Nanoparticle (LNP) technology to efficiently deliver siRNAs by systemic and local administration. My inventions resulted in the filing of over 20 patents in various aspects of nucleic acid chemistry including siRNA delivery, chemical modifications, oligonucleotides synthesis process and bioanalytical methods.  The early work on siRNAs resulted in the filing of the first IND for Sirna-027, a chemically modified siRNA designed to target VEGF to treat AMD patients.  Besides managing discovery efforts, my responsibilities included making numerous presentations to potential investors and pharma partners like Allergan and GSK; generating and implementing highly focused research strategies; I also played an important role in the acquisition of Sirna Therapeutics by Merck & Co., Inc. for $1.1 B in 2007.

Perhaps my most significant contribution in siRNA efforts has been the discovery of a novel avenue for delivery of siRNAs/miRNAs. In response to the need for robust delivery techniques that allow the application of these therapeutics to increasingly complex disease and organ systems, my efforts were focused on siRNA conjugates and degradable LNPs for delivery to liver and tumors.  I identified important characteristics for LNPs to effectively deliver to liver across species. The same LNP delivery was used to deliver siRNAs very effectively to tumors by changing the size of the particles and fine tuning the lipid compositions. These findings resulted in several patent filings on LNPs and nano particle based delivery.  

  • Morrissey, D. V., Lockridge, J. A., Shaw, L., Blanchard, K., Jensen, K., Breen, W., Hartsough, K., Machemer, L., Radka, S., Jadhav, V., Vaish, N., Zinnen, S., Vargeese, C., Bowman, K., Shaffer, C. S., Jeffs, L. B., Judge, A., MacLachlan, I., & Polisky, B. (2005). Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs. Nature biotechnology, 1002–1007. doi:10.1038/nbt1122.
  • Shen, J., Samul, R., Silva, R. L., Akiyama, H., Liu, H., Saishin, Y., Hackett, S. F., Zinnen, S., Kossen, K., Fosnaugh, K., Vargeese, C., Gomez, A., Bouhana, K., Aitchison, R., Pavco, P., & Campochiaro, P. A. (2006). Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene therapy,  225–234. doi:10.1038/sj.gt.3302641.

Stereopure Oligonucleotides

As a Chief Technology officer at Wave Life Sciences, I am currently leading our efforts to establish unique platform capabilities in nucleic acid therapeutics by controlling the chemistry and stereochemistry of oligonucleotides.  These scientific advances over the last several years have brought major breakthroughs in the application of nucleic acid therapies to treat serious, genetically-defined diseases. Investigation of the interplay of sequence, chemistry and stereochemistry of the backbone along with the introduction of novel PN backbone chemistry enabled us to rationally design and optimize the various nucleic acid therapeutics and successfully transition several oligonucleotides for clinical development. These platform advances are widely applicable across all nucleic acid modalities including silencing, splicing, and editing and the next generation oligonucleotides show dramatic improvements in the pharmacology of our compounds. In addition, we have developed proprietary chemistries for the synthesis of stereopure oligonucleotides and established GMP manufacturing capabilities to ensure seamless transitions from preclinical and clinical development.

  • Iwamoto, N., Butler, D., Svrzikapa, N., Mohapatra, S., Zlatev, I., Sah, D., Meena, Standley, S. M., Lu, G., Apponi, L. H., Frank-Kamenetsky, M., Zhang, J. J., Vargeese, C., & Verdine, G. L. (2017). Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nature biotechnology, 845–851. doi:10.1038/nbt.3948.
  • Svrzikapa, N., Longo, K. A., Prasad, N., Boyanapalli, R., Brown, J. M., Dorset, D., Yourstone, S., Powers, J., Levy, S. E., Morris, A. J., Vargeese, C., & Goyal, J. (2020). Investigational Assay for Haplotype Phasing of the Huntingtin Gene. Molecular therapy. Methods & clinical development, 162–173. doi:10.1016/j.omtm.2020.09.00