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Tod Mitchell Woolf, Ph.D.

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Biography
Havard University , Cambridge, MassachusettsPh.D. 01/1992Biology
University of Michigan , Ann ArborBS06/1986Cellular and Molecular Biology

Overview
TECHNOLOGY TRANSFER
I have served as the Executive Director of the Technology Ventures Office at BIDMC since 2019, where my team manages intellectual property and technology commercialization activities. In addition to supporting investigators in the development of novel technologies, I work with the TVO team to identify and pursue opportunities for pre-clinical strategic alliances. We also present seminars and provide mentoring in new venture formation and technology development to faculty, trainees and staff.

BIOTECHNOLOGY INDUSTRY EXPERIENCE
More than 25 years of prior experience at biotechnology companies. Founded Sequitur in 1996, which was acquired by Invitrogen (now Thermo Fisher). Co-founded and took RXi Pharmaceuticals public in 2006. Served as CBO and CTO at X-Body BioSciences, which was acquired by Juno, and co-founded ETAGEN Pharma in 2014. My research teams and I developed Modified mRNA Therapeutics, STEALTH RNAi, Self-Delivering RNAi and Therapeutic Genome and mRNA Editing platforms.

CURRENT RESEARCH
My current research focuses on developing highly specific chemical modification patterns to optimize the mechanism, specificity, cellular uptake, bio-distribution and potency of RNA Therapeutics.

Summary of Prior Research
Antisense:
In my thesis work in Doug Melton’s laboratory at Harvard, I collaborated with Charles Jennings to demonstrate that seed sequence hybridization to partially matched sequences causes off-target effects with antisense oligonucleotides (Woolf et al., PNAS 1992). This off-target mechanism was later found to be a critical challenge in siRNA and CRISPR-Cas9. My teams developed reporter gene targets with mismatch cross over controls to differentiate between on-target and off-target effects. These reporter gene targets allowed for optimization of chemical modification patterns for antisense, siRNA and editing. I subsequently developed kinetic modeling which predicted that the steric blocking antisense mechanism could be as potent as the cleaving antisense mechanism in certain cases (Woolf Antisense Research and Development 1995). This prediction was validated by the observed potency of the approved splice modulating antisense drug Spinraza for Spinal Muscular Atrophy.

I extended my graduate thesis work on gapmer antisense by developing reduced toxicity three-component antisense oligonucleotides which have been commercialized for target validation and gene function analysis by several companies. At Sequitur this technology was deployed by our customers Amgen and Pharmacia to identify the Alzheimer’s beta-secretase as described in their 1999 Nature and Science publications.

siRNA
My research team at Sequitur, Inc. was the first to commercialize chemically modified STEALTH RNAi (also known as dicer substrates), which is now being pursued by Dicerna for therapeutic applications. Over 4,000 publications have employed STEALTH RNAi as a research tool. At RXi Pharmaceuticals, my team and I developed the first oligo delivery conjugate to enter clinical trials in 2008. These lipophilic self-delivering siRNA compounds are currently being employed by RXi (now Phio), Anastasia Khvorova’s Laboratory at UMASS Medical School, Atalanta Therapeutics & Advirna.

Therapeutic Editing
My research group at Ribozyme Pharmaceuticals, Inc. (RPI) was the first to demonstrate therapeutic mRNA editing in a model system, which is now being employed by ETAGEN, ProQR, Beam, and Locana & Korro (Woolf, et al. PNAS, 1995). This work was the first demonstration of therapeutic editing by chemical modification of a mutant nucleobase (now called BASE editing). I then published a review article that described a general model for mRNA and genome editing (Woolf, Nature Biotech 1998). I founded ETAGEN in 1998, where we designed 3rd generation chemically-modified editing oligonucleotides that could be employed with or without programmable nucleases (Woolf et al. Nature Reviews Drug Discovery, 2017). ETAGEN’s issued patent covers the use of CRISPR guides sequences that also act as donor DNA. This technology has recently been shown by other groups to substantially increase the efficiency of genome editing.

Chemically Modified mRNA Therapeutics and Vaccines
I was an inventor on the first patent application focused on Modified mRNA (now called MOD mRNA) for protein replacement & vaccines (Woolf, et al. “Sense mRNA Therapeutics” US Pat App 60-059371 1997). This work led to the first biotech alliance focused on chemically modified mRNA Therapeutics and Vaccines between Sequitur and Inex Pharmaceuticals (now Arbutus) in 1998. Our patent application described the use of mRNAs depleted of unmodified uridines by using redundant codons with fewer uridines or by using chemically modified uridines. This approach was cited as “prior art” in the patent estates of Moderna, BioNTech (patent owned by University of Pennsylvania) & CureVac, and the background technology disclosed in my patent application was used in the Moderna, BioNTech (Pfizer) and CureVac COVID-19 vaccines.

Research
The research activities and funding listed below are automatically derived from NIH ExPORTER and other sources, which might result in incorrect or missing items. Faculty can login to make corrections and additions.
  1. Corporate Funding (Tod Woolf) Dec 4, 2014
    ETAGEN Pharma
    Genome and mRNA Editing with Chemically-Modified Oligonucleotides that Act as Donor and Guide
    Role Description: CRISPR Donor Guides: Adding donor DNA sequences to the termini of trRNA can in principle enhance precision editing with CRISPR-Cas (twoolf patent issued). This concept has been confirmed in cell culture by third parties. We have also disclosed a design in which the strand invading portion of the trRNA is substituted with DNA residues and the sequence is made to correspond to the desired editing sequence, so it can act as the guide and template for DNA repair enzymes.
    Role: Principal Investigator
  2. Corporate Funding (Tod Woolf) Dec 1, 2014
    ETAGEN Pharma
    Self-Delivering Chemically-Modified Oligonucleotides for Genome Editing without Programmable Nucleases
    Role Description: Self-Delivering Chemically-Modified Oligonucleotides can achieve Genome Editing without Programmable Nucleases, by acting both as the donor DNA and guide.
    Role: Principal Investigator

Featured Content

    Bibliographic
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
    Newest   |   Oldest   |   Most Cited   |   Most Discussed   |   Timeline   |   Field Summary   |   Plain Text
    PMC Citations indicate the number of times the publication was cited by articles in PubMed Central, and the Altmetric score represents citations in news articles and social media. (Note that publications are often cited in additional ways that are not shown here.) Fields are based on how the National Library of Medicine (NLM) classifies the publication's journal and might not represent the specific topic of the publication. Translation tags are based on the publication type and the MeSH terms NLM assigns to the publication. Some publications (especially newer ones and publications not in PubMed) might not yet be assigned Field or Translation tags.) Click a Field or Translation tag to filter the publications.
    1. Tod Woolf. Improved methods for genome editing with programmable nucleases and genome editing without programmable nucleases. 2021. View Publication.
    2. WOOLF TW , RIVERA-TORRES N , HOGREFE R AND KMIEC E. GENOME EDITING WITH THIRD-GENERATION CHEMICALLY MODIFIED OLIGONUCLEOTIDES. 2021. View Publication.
    3. Woolf TM, Gurumurthy CB, Boyce F, Kmiec EB. To cleave or not to cleave: therapeutic gene editing with and without programmable nucleases. Nat Rev Drug Discov. 2017 04; 16(4):296. PMID: 28303022.
      Citations: 5     Fields:    Translation:HumansAnimals
    4. Woolf TM, Lebedev AV, Hogrefe RI. . Compositions and Methods of Treatment of Disease Using Editing Oligonucleotides. 2016. View Publication.
    5. Lapierre J, Salomon W, Cardia J, Bulock K, Lam JT, Stanney WJ, Ford G, Smith-Anzures B, Woolf T, Kamens J, Khvorova A, Samarsky D. Potent and systematic RNAi mediated silencing with single oligonucleotide compounds. RNA. 2011 Jun; 17(6):1032-7. PMID: 21493786.
      Citations: 7     Fields:    Translation:HumansCells
    6. Woolf, TM, Samarky, DA. and Cardia, JP. . Self-Delivering RNAi Compounds. Drug Delivery Technology. 2010; 16(17):1-5.
    7. Salomon W, Bulock K, Lapierre J, Pavco P, Woolf T, Kamens J. Modified dsRNAs that are not processed by Dicer maintain potency and are incorporated into the RISC. Nucleic Acids Res. 2010 Jun; 38(11):3771-9. PMID: 20167638.
      Citations: 12     Fields:    Translation:HumansAnimalsCells
    8. Hough SR, Wiederholt KA, Burrier AC, Woolf TM, Taylor MF. Why RNAi makes sense. Nat Biotechnol. 2003 Jul; 21(7):731-2. PMID: 12833082.
      Citations: 7     Fields:    Translation:Humans
    9. Woolf, TM, Wiederholt, KA and Taylor, MF. Sense mRNA Therapeutics. 1998. View Publication.
    10. Woolf TM, Taylor M. Variations on the theme of genomics. Functional genomics: from identifying proteins to faster drug discovery, Westin City Center Hotel, Washington, DC, USA, 10-11 March 1998. Trends Genet. 1998 Jun; 14(6):219-20. PMID: 9635403.
      Citations:    Fields:    Translation:Humans
    11. Woolf TM. Therapeutic repair of mutated nucleic acid sequences. Nat Biotechnol. 1998 Apr; 16(4):341-4. PMID: 9555723.
      Citations: 9     Fields:    Translation:HumansCells
    12. Miao N, Wang M, Ott JA, D'Alessandro JS, Woolf TM, Bumcrot DA, Mahanthappa NK, Pang K. Sonic hedgehog promotes the survival of specific CNS neuron populations and protects these cells from toxic insult In vitro. J Neurosci. 1997 Aug 01; 17(15):5891-9. PMID: 9221786; PMCID: PMC6573190.
      Citations: 28     Fields:    Translation:AnimalsCells
    13. Jarvis TC, Wincott FE, Alby LJ, McSwiggen JA, Beigelman L, Gustofson J, DiRenzo A, Levy K, Arthur M, Matulic-Adamic J, Karpeisky A, Gonzalez C, Woolf TM, Usman N, Stinchcomb DT. Optimizing the cell efficacy of synthetic ribozymes. Site selection and chemical modifications of ribozymes targeting the proto-oncogene c-myb. J Biol Chem. 1996 Nov 15; 271(46):29107-12. PMID: 8910566.
      Citations: 10     Fields:    Translation:HumansAnimalsCells
    14. Woolf T. It's not the size, it's the potency. Nat Biotechnol. 1996 Jul; 14(7):824. PMID: 9630999.
      Citations:    Fields:    Translation:Cells
    15. Woolf TM, Chase JM, Stinchcomb DT. Toward the therapeutic editing of mutated RNA sequences. Proc Natl Acad Sci U S A. 1995 Aug 29; 92(18):8298-302. PMID: 7545300.
      Citations: 28     Fields:    Translation:HumansAnimalsCells
    16. Woolf TM. To cleave or not to cleave: ribozymes and antisense. Antisense Res Dev. 1995; 5(3):227-32. PMID: 8785479.
      Citations: 5     Fields:    Translation:HumansAnimals
    17. Dohrmann CE, Hemmati-Brivanlou A, Thomsen GH, Fields A, Woolf TM, Melton DA. Expression of activin mRNA during early development in Xenopus laevis. Dev Biol. 1993 Jun; 157(2):474-83. PMID: 8500654.
      Citations: 15     Fields:    Translation:AnimalsCells
    18. Woolf TM, Melton DA, Jennings CG. Specificity of antisense oligonucleotides in vivo. Proc Natl Acad Sci U S A. 1992 Aug 15; 89(16):7305-9. PMID: 1380154; PMCID: PMC49698.
      Citations: 52     Fields:    Translation:AnimalsCells
    19. Thomsen G, Woolf T, Whitman M, Sokol S, Vaughan J, Vale W, Melton DA. Activins are expressed early in Xenopus embryogenesis and can induce axial mesoderm and anterior structures. Cell. 1990 Nov 02; 63(3):485-93. PMID: 2225062.
      Citations: 81     Fields:    Translation:AnimalsCells
    20. Woolf TM, Jennings CG, Rebagliati M, Melton DA. The stability, toxicity and effectiveness of unmodified and phosphorothioate antisense oligodeoxynucleotides in Xenopus oocytes and embryos. Nucleic Acids Res. 1990 Apr 11; 18(7):1763-9. PMID: 1692405; PMCID: PMC330594.
      Citations: 42     Fields:    Translation:AnimalsCells
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    Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.