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2014- MChem, Chemistry, University of Southampton, United Kingdom

2019- PhD, Chemistry, McGill University, Canada

2020-2024 Postdoctoral Fellow, RNA Therapeutics Institute, University of Massachusetts Chan Medical School, USA

Oligonucleotides are now the third class of therapeutics, alongside biologics and small molecules.  It's an exciting time in the field with>20 FDA-approved oligonucleotides and many more in clinical trials. Oligonucleotides have a vast therapeutic potential, with applications including gene silencing (antisense and siRNA), altering epigenetics, modulation of splicing (antisense), gene editing (CRISPR guides), protein expression (mRNAs), vaccination (mRNAs), vaccine adjuvants and protein binding (aptamers).

The O’Reilly lab is passionately dedicated to creating oligonucleotide therapeutics for rare and ultra-rare diseases. This mission requires empathy and support for patients and their families.

The six research areas of the O'Reilly lab are:

1. Develop novel chemical modifications to enhance the therapeutic potential of oligonucleotides.  Altering the natural structure of RNA to enhance therapeutic properties, such as nuclease resistance and cellular uptake, has been a critical advance for the successful development of therapeutics.  Non-natural structures, such as simple linkers (C6, PEG) have also shown promise in pre-clinical studies. One of the lab's goals is to expand the toolbox of non-natural structures to enhance their therapeutic utility and use them as structural probes for mechanistic understanding. 
2. Mechanistic understanding of the chemical biology of oligonucleotides. For oligonucleotides to effectively function within a cell, they must interact with a variety of biological systems. These interactions include binding to extracellular proteins and being recognized by the immune system. There are still unanswered questions, such as identifying which part of the nucleotide contributes to immune recognition and protein binding and whether oligonucleotides can affect biological processes like epigenetics. To address these questions, we will employ structural probes and mimics.
3. Understanding the delivery of oligonucleotides to different tissues and cell types is essential for advancing medical research and developing targeted therapies. While there is some understanding of how oligonucleotides get into cells via endosomal release, there are still important questions to understand. The first is, do oligonucleotides deliver to all cell types in a tissue but show activity in a fraction?  And how does the chemistry of the oligonucleotide affect delivery? Our lab will answer these questions by utilizing chemical modifications and non-natural linkers as structural probes to answer fundamental questions about delivery. 
4. Creating New Ligands for Precise Tissue Targeting. The delivery issue for hepatic cells in the liver has been solved due to the discovery of GalNac sugar, which binds to the AGCPR receptor to enhance uptake when conjugated to a therapeutic. Six approved therapeutics utilize this approach. However, no highly specific conjugates are available for extrahepatic tissues. One of the primary goals in the lab is to develop novel conjugates to target extrahepatic tissues (using sugars, antibodies, or peptides). 
5. Development of therapeutics for a range of rare diseases.  The O'Reilly lab specializes in creating oligonucleotides for Huntington's disease. These tools can help control the expansion of the CAG repeat, which is a critical factor in the age of onset. Our research also focuses on using these tools to develop treatments for other genetic repeats to determine if expansion mechanisms are similar across different repeats. Additionally, we are exploring the development of treatments for non-neurological diseases, such as heart-related conditions, and currently have active projects in this area.
6. Collaborations. The O'Reilly lab is dedicated to creating a state-of-the-art oligonucleotide synthesis and organic chemistry facility. This facility will be made available to researchers through collaborations, greatly expanding their access and enabling the development of therapeutics for a broader range of diseases.

† = co-first author, *Co- corresponding author

1.   Halle Barber†, Adam Pater†, Keith Gagnon*, Masad J. Damha*, and Daniel O’Reilly*. Chemical engineering of CRISPR-Cas Systems to enhance their therapeutic utility. Nature Reviews Drug Discovery. Under Revisions.

1.   Daniel O’Reilly, Cristina Cabrero, Nicolette Pollock, Elizabeth Epps, Shawn Sharkas, Adam Katolik, John Rossi, Carlos González, and Masad J. Damha. Synergistic effects of RNA and DNA analogues in steric blocking antisense oligonucleotides. Nucleic Acid Therapeutics. Under Revisions. 

   3. Daniel O’Reilly, Willeke van Roon-Mom,  Annemieke Aartsma-Rus,  and on behalf of the N = 1 Collaborative. A guide to chemical considerations for the pre-clinical development of oligonucleotides. Nucleic Acid Therapeutics. Accepted. 

    

   4. Jillian Belgrad, Qi Tang, Sam Hildebrand, Ashley Summers, Ellen Sapp, Dimas Echeverria, Daniel O’Reilly, Eric Luu, Brianna Bramato, Sarah Allen, David Cooper, Julia Alterman, Ken Yamada, Neil Aronin, Marian DiFiglia, Anastasia Khvorova. Nucleic Acid Research. Accepted.

   5. Sarah Engelbeen, Daniel O’Reilly, Davy Van De Vijver, Ingrid Verhaart, Maaike van Putten, Vignesh Hariharan, Matthew Hassler, Anastasia Khvorova, Masad J. Damha, and Annemieke Aartsma-Rus. Challenges of assessing exon 53 skipping of the human DMD transcript with LNA- modified AONs in a mouse model for Duchenne muscular dystrophy. Nucleic Acid Therapeutics. 2023, 33 (6), 348-360.

1.   Sarah M. Davis, Samuel Hildebrand, Hannah J. MacMillan, Kathryn Monopoli1, Jacquelyn Sousa, David Cooper, Socheata Ly, Dimas Echeverria, Nicholas McHugh, Chantal Ferguson, Andrew Coles, Vignesh N. Hariharan, Daniel O’Reilly, Qi Tang, Raymond Furgal, Julianna Buchwald, Ken Yamada, James Gilbert, Emily Knox, Julia F. Alterman, Yamilett Pineda, Caitlyn N. Weston, Christina E. Baer, Athma A. Pai, and Anastasia Khvorova. Guidelines for Designing Therapeutic siRNAs.  Nucleic Acid Research. Revised Manuscript submitted.  

1.   Daniel O'Reilly^†, Jillian Belgrad^†, Chantal Ferguson, Ashley Summers, Ellen Sapp, Cassandra McHugh, Ella Mathews, Julianna Buchwald, Socheata Ly, Dimas Echeverria Moreno, Zachary Kennedy, Vignesh Hariharan, Kathryn Monopoli, X. William Yang, Jeffery Carroll, Marian DiFiglia, Neil Aronin, Anastasia Khvorova. Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease. Molecular Therapy.2023 Jun 7;31(6):1661-1674. 

   8. Vignesh N. Hariharan^†, Minwook Shin^†, Ching-Wen Chang^†, Daniel O’Reilly, Annabelle Biscans, Ken Yamada, Zhiru Guo, Mohan Somasundaran, Qi Tang, Kathryn Monopoli, Pranathi Meda Krishnamurthy, Gitali Devi, Nicholas McHugh, David A. Cooper, Dimas Echeverria Moreno, John Cruz, Io Long Chan, Ping Liu, Sun-Young Lim, Jill McConnell, Satya Prakash Singh, Samuel Hildebrand, Jacquelyn Sousa, Sarah M. Davis, Zachary Kennedy, Chantal Ferguson, Bruno M. D. C. Godinho, Socheata Ly, Manish Muhuri, Karen Kelly, Fiachra Humphries, Alyssa Cousineau, Krishna Mohan Parsi, Qi Li, Yang Wang, René Maehr, Guangping Gao, William M. McDougall, Katherine A. Fitzgerald, Robert W. Finberg, Jennifer P. Wang, Jonathan K. Watts, and Anastasia Khvorova. Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection. Proceedings of the National Academy of Sciences, 2023. 120. e2219523120. doi:10.1073/pnas.2219523120. 

   9. Annemieke Aartsma-Rus, Elizabeth Vroom, and Daniel O'Reilly. The Role of Patient Involvement When Developing Therapies. Nucleic Acid Therapeutics.  2022. 32 (2), 118-122.

   10. Tim Yu and Daniel O'Reilly. Oligonucleotides and N = 1 Therapeutics: From the Patient Perspective to Chemistry, Manufacturing, and Control.  Nucleic Acid Therapeutics.  2022. 32(2):81-82. (Editorial)

   11. C. L Barkau, D. O’Reilly, S.B. Eddington, M.J. Damha, K. T Gagnon. Small Nucleic Acids and the Path to the Clinic for Anti-CRISPR. Biochemical Pharmacology, 2021. 189, 114492.

   12. J. D. Thorpe^†, D. O’Reilly^†, T. Friščić and M. J. Damha. Mechanochemical synthesis of short DNA fragments. Chemistry-a European Journal. 2020. 26, 8857-8861.

   13. A. J. Debacker, V. K. Sharma, P. M. Krishnamurthy, D. O’Reilly, R. Greenhill, J. K. Watts. Next-generation PNA chimeras exhibit high affinity and potent gene silencing. Biochemistry. 2019, 58 (6), 582-589.  (undergraduate work)

   14. C. L. Barkau, D. O’Reilly, K. J. Rohilla, M. J. Damha, and K. T. Gagnon. Rationally designed Anti-CRISPR nucleic acid inhibitors of CRISPR-Cas9. Nucleic Acid Therapeutics. 2019, 29 (3), 136-147

   15. D. O'Reilly^†, Z. J. Kartje^†, E. A. Ageely, E. Malek-Adamian, M. Habibian, A. Schofield, L. B. DeRossett, A. T. Weigle, M. J. Damha, and K. T. Gagnon. Extensive CRISPR RNA modification reveals chemical compatibility and structure-activity relationships for Cas9 biochemical activity.  Nucleic Acids Research. 2018, 47 (2), 546-558.

   16. D. O’Reilly, R. S. Stein, M. Burai Patrascu, S. K. Jana J. Kurian, N. Moitessier and M. J. Damha. Exploring atypical fluorine-hydrogen bonds and their effects on nucleoside conformations. Chemistry-a European Journal. 2018, 24 (61), 16432-16439. 

   17. X. Shen, A. Kilikevicius, D. O’Reilly, T. Prakash, F. Rigo, M.J. Damha, and D.R. Corey (2018). Activating Frataxin expression by single-stranded siRNAs targeting the GAA repeat expansion. Bioorganic & Medicinal Chemistry Letters. 2018, 28 (17), 2850-2855.

   18. L. Li, X. Shen, Z. Liu, M. Norrbom, T.P. Prakash, D. O’Reilly, V. Sharma, M.J. Damha, J.K. Watts, F. Rigo, and D.R. Corey. Activation of Frataxin expression by antisense oligonucleotides targeting the mutant expanded repeat. Nucleic Acid Therapeutics. 2018, 28 (1), 23-33.

    

   Link to my NCBI bibliography:

   https://www.ncbi.nlm.nih.gov/myncbi/daniel.o'reilly.3/bibliography/public/