Personal reflections of my 20-year odyssey during the early stages of the evolution of this now successful field of synthetic DNA and RNA therapeutics.

1. Automated Synthesis of Phosphorus-
Modified Antisense Oligodeoxynucleotides:
The Early Years
Personal Reflections of My Odyssey
by
Gerald Zon, PhD FRSC
10/6/2020 1

2. Outline
• Abstract
• Introduction
• Automated Syntheses of P-Modified ODNs
• Antisense Studies of P-Modified ODNs: Three Collaborations
1. HIV
2. Chloramphenicol Acetyl Transferase
3. ras p21
• Commercialization, Scale-up, and Clinical Studies
• Antisense Studies of Stereopure PS-ODNs
• Concluding Comments
• References
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3. Abstract
As a young organic chemist having “zero” knowledge of oligodeoxynucleotide (ODN) synthesis in
1982, circumstances arose for the need to quickly learn how to use the then prevailing P(V)
phosphotriester chemistry to manually synthesize a 17-mer ODN for my gene-cloning colleagues in a
US Food & Drug Administration (FDA) lab located on the campus of the National Institutes of
Health (NIH).
After successfully accomplishing that not-so-easy task, I chanced upon a 1983 report in J Amer Chem
Soc by Adams et al. that described a highly efficient, manual version of P(III) phosphoramidite
chemistry pioneered by Prof. Marvin Caruthers:
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4. 10/6/2020 4
Sparked by this breakthrough paper, I obtained a
“beta test” automated synthesizer developed by
Applied Biosystems Inc. (ABI) based on
phosphoramidite chemistry.
In addition to synthesizing natural
phosphodiester ODNs for molecular biology, the
P(III) phosphite intermediate was viewed as a
synthon to obtain novel alkylphosphonate,
phosphotriester, and phosphorothioate (PS)
analogs of DNA.
These nuclease-resistant ODN analogs would
enabled biophysical studies and, moreover,
antisense mRNA investigations, then a new
application with great promise.
This account provides personal recollections about my
20-year “odyssey” in automating and scaling-up this
chemistry, with a focus on PS analogs, culminating in
clinical trials of PS-modified antisense agents.

5. Introduction
In 1982, I was the only organic chemist in the FDA Division of Biochemistry & Biophysics, which
was located on the NIH campus in Bethesda, Maryland. Quite frankly, I knew very little about DNA,
let alone its chemical synthesis. Consequently, when the Division Director—my boss’s boss—asked
me if I could help his research team by synthesizing “mixed-base hybridization probes and primers
for cloning a gene” I neither understand that methodology nor appreciated the challenge of such
synthesis. But I could hardly refuse and took on the task. I was provided a small empty lab with a
fume hood, assigned a visiting medical scientist as summer helper, and then asked “when will the
probe would be ready?” to which I replied “as soon as possible, after I scope out the literature.”
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Reading the literature led to borrowing a solid-phase peptide synthesis reaction vessel, buying
commercially available reagents, and plunging ahead with phosphotriester methodology reported
in 1981 by Itakura [1], but adding 31P-NMR (one of my specialties) to study model reaction
kinetics, especially the required mixed-coupling steps.
After a long summer of hard work—and smelling more pyridine than I care to remember—collection
of the slowest-eluting “tiny” peak in a complex mixture of ODNs separated by ion-exchange HPLC
led to 32P-labeled material that appeared to be the desired 17-mer by gel analysis. Successful
cloning using this mixed-base 17-mer was published [2] several years later.

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After thus becoming the only “oligo probe and
primer guy” on the NIH campus, requests from
NIH labs came too fast to accommodate in a
timely manner. Fortunately, in early 1983, I
came across a communication in J Amer Chem
Soc by Adams et al. [3] that described
improvements to phosphoramidite
methodology, first described in 1981 by
Beaucage and Caruthers [4], which was used to
synthesize 51-mer ODNs with very high
coupling yields. The chain-extension cycle
required only 8–10 min compared to my 5-h
phosphotriester cycle and, moreover, no noxious
pyridine for solvent and washing was used.
All of this was great news!

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The Adams et al. article indicated that their phosphoramidite approach was far superior to the
phosphotriester method I had struggled with for months. So, I called Steven Adams for more info, and
he suggested calling Prof. Marvin (“Marv”) Caruthers, who I reached that same day. Marv told me that
the phosphoramidite methodology was being commercially developed by Applied Biosystems Inc.
(ABI) in Foster City, California, then a relatively new company.
A visit to ABI led to arranging early access to one of the five beta-test units, and a “sneak preview”
with William (“Bill”) Efcavitch and Curt Becker in ABI R&D, both of whom had worked in Marv’s
lab.
At the end of 1983, a beta-test ABI single-
column Model 380A automated DNA
synthesizer was operating in my FDA lab at
NIH, which began serving as an “oligo core
facility”, the first of its kind. This was
upgraded to a 3-column 1-μmol Model 380A
synthesizer, pictured in this 1984 ABI
advertisement.

9. Automated Syntheses of P-Modified ODNs
The core lab ABI 380A enabled my research aimed at automating synthesis of P-modified ODNs
with chiral internucleotide linkages. I was fortunate to be joined by Prof. Wojciech J. Stec, as an
FDA International Visiting Scientist, because of his expertise in small-molecule organophosphorus
chemistry and stereochemistry, which would be invaluable for this research.
Our initial investigations, published [5] in 1984, focused on automating the incorporation of one or
more PS linkages in ODNs by replacing the conventional I2/H2O solution with a solution of S8 in 2,6-
lutidine, which worked albeit relatively slowly (15 min) even at elevated temperature (60 °C).
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It was thus possible to synthesize a 50-
mer oligo(T) having 49 PS-linkages.
In all cases investigated, a roughly
equimolar ratio of diastereomeric Rp
and Sp linkages were found by HPLC
and/or 31P-NMR, as expected based
on earlier findings reported by others.

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We investigated possible synthesis of stereopure Rp or Sp PS-linkages in ODNs by use of
diastereomerically enriched fractions of the ABI phosphoramidites obtained by reverse-phase
HPLC. But, as we later reported [6], this approach was unsuccessful due to rapid
epimerization at phosphorus by tetrazole, the coupling catalyst (cf. slide 7).
With hopes of synthesizing PMe-modified ODNs more easily and in better yields compared
to the original methodology developed by Miller et al. [7, 8], we investigated the Arbuzov-
type reaction of a dinucleotide OMe phosphite with methyl iodide, first reported by Nemer
and Ogilvie [9] in 1980. This approach failed, as also reported by Caruthers & coworkers [10].
“Plan B” was relatively simple: adapt the Caruthers phosphoramidite
method by replacement of the POMe moiety with PMe in each of the
resultant A, G, T, and C (shown here) phosphonamidite monomers.
This worked well and led to 2D-NOE NMR studies of the effects of
PMe stereochemistry in model duplexes [11].

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Next, phosphotriester (POR) modified ODNs were automatically
synthesized using protected deoxynucleotide 3'-O-ethyl-N,N-
diisopropylphosphoramidite reagents (shown here) prepared by
members of Prof. Stec’s lab. The d(GGAAPOEtTTCC)
diastereomers were separated by HPLC, and the chirality of the
POEt-modified moiety was assigned by a configurational
correlation scheme [12] that was verified by NMR spectroscopic
studies [13].
New 3’-O-isopropylphosphomorpholidite reagents (shown here)
provided by Prof. Stec were used to automatically synthesize
POiPr-modified ODNs as mixtures of P-chiral diastereomers.
These were separated by HPLC for enzymatic digestion studies and
assignment of configuration at phosphorus by chemical correlation
with known PS-modified compounds [14].

12. Antisense Studies of P-Modified ODNs: Three Collaborations
1. HIV
A critical catalyst for beginning this work came from 1983 Congressionally funded AIDS research
and treatment involving the National Cancer Institute (NCI) and the National Institute of Allergy and
Infectious Diseases (NIAID), my “neighbors” on the NIH campus.
At NCI, Jack Cohen introduced me to the Sam Broder lab, which was in touch with the Robert Gallo
lab, and we all began to collaborate on anti-HIV antisense investigations.
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The antisense target was the rev (art/trs) gene, the
importance and sequence of which were provided by Flossie
Wong-Staal in the Gallo group. Rev (art/trs) is essential for
viral replication and regulates the expression of virion
proteins by affecting the splicing of the viral mRNA.

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The intention was to study PMe-modified antisense ODNs; however, there were PMe-ODN
solubility issues, whereas PS-ODNS were freely soluble in biological media and
therefore also tested, along with unmodified (PO-ODN) controls.
The results [15] were quite surprising: two PO-ODNs and one PMe-ODN showed no
inhibitory effects, whereas all of the antisense PS-ODNs, and an intended sequence-
specificity control dC-homopolymer, exhibited significant inhibition of the cytopathic
effect of HIV in an infectivity assay carried out in the Broder lab.
After much work, especially by Makoto Matsukura in the Broder lab, we published [16]
results consistent with sequence-specific suppression of viral expression by PS-ODNs in
cells chronically infected with HIV, as opposed to the original infectivity assay.
Importantly, PS-ODNs can exert two anti-HIV mechanisms: sequence-
nonspecific (non-antisense) AND sequence-specific (antisense).

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2. Chloramphenicol Acetyl Transferase (CAT)
My FDA colleague Carol Marcus-Sekura suggested using ODN transfection in an in vitro CAT
assay to quantitatively compare antisense activity of different types of P-modified ODNs.
PMe, POEt, POiPr, and PS analogs were compared to unmodified
PO-ODNs for inhibition of expression of plasmid-encoded CAT
gene activity in a fibroblast cell-line derived from monkey kidney
cell.
As published [17] in 1987, the CAT gene was transfected in
plasmid DNA containing the simian virus 40 regulatory
sequences, or the HIV enhancer, in the presence of 30 μM
concentrations of analog.
The %-inhibition of CAT activity for a series of 15-mers transfected at a concentration of 30
μM was as follows: alternating PO/PMe = 60%, alternating PO/POEt = 51%, alternating
PO/POiPr = 0%, all PS = 84%, all PMe = 65%, and PO = 35%.
Ribbon
diagram of
CAT trimer
with bound
substrate.

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3. ras p21
This collaboration was with Esther Chang at the Uniformed Services University of Health
Sciences (USUHS), adjacent to the NIH campus and my FDA lab. Chang had been working with
Profs. Paul Ts’o and Paul Miller at Johns Hopkins University on testing PMe-ODNs as antisense
inhibitors of the proto-oncogene ras p21 protein (shown here), and was interested in
comparisons with other analogs.
The results were published in 1989 [18]. Briefly, a rabbit reticulocyte lysate translation assay
was used to quantitatively compare a series of antisense ODNs targeting the start codon and
downstream bases of ras p21 mRNA.
At concentrations of 12.5 - 25 μM, the PS analogs were
the most potent inhibitors of p21 protein synthesis;
however, a sequence non-specific effect for these
oligomers was dominant at higher concentrations of
oligomer (100-200 μM).

16. Commercialization, Scale-Up, and Clinical Studies
Antisense experiments were limited by the amount
of ODNs available from ABI 10-μmol synthesis
columns. Scale-up involved mechanical and
electrical reengineering of the then existent ABI
Model 433A Peptide Synthesizer.
The resultant ABI 390Z DNA Synthesizer
featured a flow-through/vortexed reaction vessel,
200-μmol synthesis on controlled-pore glass
(CPG) solid-support, and sulfurization with
tetraethylthiuram disulfide (TETD),
Et2NC(S)SSC(S)NEt2 in acetonitrile [19].
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In November 1986, I moved from FDA at NIH to ABI, and soon wrote the ABI DNA
Synthesizer User Bulletin for PMe-ODN synthesis and purification, followed by the Bulletin
for PS-ODNs.

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Soon, early antisense startup companies were
founded, notably Oligogen (1987) (now Gilead)
by Michael Riordan, Isis Pharmaceuticals
(1989) (now Ionis) by Stanley Crooke, Genta
(1989) by Paul Ts’o, and Hybridon (1989) by
Paul Zamecnik.
ABI formed the ABI Therapeutics (ABIT) group
in 1989, which spun-out as Lynx Therapeutics
(Hayward, CA) in 1992. Lynx used the ABI
Model 390Z to synthesize a 20-mer PS-ODN,
designated OL(1)p53, as GMP material for a US
FDA-approved physician-sponsored single-
patient (“compassionate use”) study at the
University of Nebraska Medical Center, Omaha,
NE.

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As reported by Bayever et al. [20] in
an article titled Systemic Human
Antisense Therapy Begins, OL(1)p53
was administered systemically to a
patient with leukemia on June 19,
1992—the first-ever administration
of any type of experimental
antisense ODN. This young man
(“Chris,” pictured here) with acute
myeloblastic leukemia (AML)
received slow infusion of OL(1)p53
by means of an indwelling catheter.
This single-patient study was
followed by a Phase 1 clinical trial of
16 cancer patients [21].

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Chemistry innovations included (1.)
replacement of tetrazole with 5-
ethylthiotetrazole activator; (2.)
sulfurization with bis(O,O-diisopropoxy
phosphinothioyl) disulfide (S-Tetra),
(iPrO)2P(S)SSP(S)P(OiPr)2 [22] in place
of TETD; and (3.) replacement of the
conventional capping reagent mixture
(tetrahydrofuran/2,6-lutidine/acetic
anhydride) with isopropyl phosphite and
1-adamantanecarbonyl chloride.
The Model 390Z system led to Lynx’s development of a GMP manufacturing prototype
(pictured here) with a vortexing reaction vessel (~500 mL) at 10-mmol scale using TentaGel, a
high-loaded amino-PEG polystyrene solid-support (Rapp Polymere GmbH, Tubingen, Germany).

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The manufacturing prototype and chemistry improvements were used for FDA-approved GMP
production of ~60 g of the PS-ODN 15-mer designated as LR-3280, sterile packaged as a
lyophilized solid.
LR-3280, targeted to c-myc mRNA, was designed for treatment of post-angioplasty coronary
restenosis by means of transcatheter local delivery. Following a clinical safety and
pharmacokinetic study in 78 patients in Buenos Aires, Argentina [23], a pilot-efficacy clinical
trial took place in Rotterdam, The Netherlands [24].
Patients (n = 85) received either 10 mg of
LR-3280 or saline vehicle by local delivery
after coronary stent implantation by means
of a dual balloon system similar to the
device depicted here.
There were no differences in angiographic
restenosis rates (38.5 and 34.2%; p 0.81;
placebo vs. ODN) or clinical outcome in this
pilot efficacy study.

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A third clinical trial supported by Lynx followed preclinical studies [25] by Dr. Alan Gewirtz
(Univ. Penn. Medical School) of human leukemia in a mouse model with LR-3001, a 24-mer c-
myb antisense PS-ODN. LR-3001 in 50-mg sterile-filled vials (pictured here) was provided, and
the findings were published by Luger et al. [26] in 2002.
Briefly, CD34+ marrow cells were purged with LR-3001 ex vivo for either 24 h (n = 19) or 72 h (n
= 5). Myb mRNA levels declined substantially in ~50% of patients, and bcr/abl expression
suggested that purging was accomplished in >50% of patients.
Day-100 cytogenetics were evaluated in surviving
patients who engrafted (n = 14). Whereas all
patients were 100% Philadelphia chromosome–
positive (Ph+) before transplantation, 2 had
complete cytogenetic remissions; 3 had 33% Ph+
metaphases; and 8 remained 100% Ph+. One
patient’s marrow at ~18 mo. revealed ~45%
bcr/abl+ cells. Thus, 6-of-14 patients had obtained
a major cytogenetic response.

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Attempted stereoselective synthesis using conventional P(III) phosphoramidites failed due to
tetrazole-catalyzed epimerization at phosphorus (cf. slide 10). Prof. Stec bypassed this
problem by the development of novel P(V) reagents, namely, 5'-O-DMT-nucleoside 3'-O-(2-
thio-1,3,2—oxathiaphospholane (OTP) monomers depicted here [27]. These were used by
Lynx to obtain NIH/NIAID Small Business Innovative Research (SBIR) funding in 1992 for
the first-ever evaluation of stereopure PS-ODNs as antisense agents.
Model System: LR-3280 antisense to c-myc mRNA for inhibiting growth
of vascular smooth muscle cells [28] to treat restenosis following
coronary angioplasty (cf. slide 20). The all-Rp PS-ODN was superior:
all-Rp random-Rp/Sp all-Sp
Tm (PS-ODN/RNA) 55.2 °C 50.7 °C 48.3 °C
%-inhibition 68 ± 4 % 30 ± 2 % 20 ± 10 %
Antisense Studies of Stereopure PS-ODNs

23. Concluding Comments
As suggested by these reflections on my 20-year “odyssey” involving P-modified ODNs as potential
antisense therapeutics, the “winner” was the PS linkage. Other early candidates synthesized in my
lab, namely, PMe and POR, encountered problems that limited utility in biological systems.
However, the early promise of PS-ODNs soon encountered problems that we (and others) found:
• sequence-independent toxicity in mice [29];
• immune stimulation and massive splenomegaly in mice [30];
• profound hypotension in nonhuman primates following bolus intravenous injections [31]; and
• nonspecific binding to cell-surface proteins [32].
Fortunately, these were eventually dealt with by the systematic application of medicinal chemistry
strategies, for which much credit goes to Stanley Crooke and his many coworkers over the years at
Ionis Pharmaceuticals. Chief among these strategies were the development of 2'-O-(2-
methoxyethyl)-modified (MOE) RNA moieties, optimization of chimeric RNA/DNA/RNA “gapmer”
design, and strategic incorporation of PS-linkages [33].
Antisense ODN therapy is now a reality!
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24. “The journey is the reward”
- Steve Jobs
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One more final reflection about my odyssey
is total agreement with this notable quote:

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27. The End
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