Harvard Catalyst Profiles

Havard University , Cambridge, Massachusetts	Ph.D.	01/1992	Biology
University of Michigan , Ann Arbor	BS	06/1986	Cellular and Molecular Biology

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.

• Technology Transfer Antisene siRNA RNA interference, mRNA Therapeutics, genome editing, BASE editing