My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To
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Transcript of My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To
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My Long Journey To
Antisense Oligos[ 1968 to 1993 ]
And The Remaining Journey To
Antisense TherapeuticsIncluding
Fountain of Youth[ 1993 to 2013 ? ]
James Summerton, Ph.D. (Biochemistry)GENE TOOLS, LLC
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Academic Phase
1968 Joined Chris Mathews lab in Tucson Conceived gene-blocking strategy for viruses1970
1972 Ph.D. in biochemistry: Chris Mathews1974 Gene-blocking agents begun at Berkeley
1976 Gene-blocking agents continued in Denver
1978 First gene-blocking patent issued (sequence-specific crosslinking) Joined Chris Mathews lab, OSU, Corvallis1980 Switched to major-groove gene-blocking agents Left OSU, founded first gene-blocking company
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Academic Phase
1968 Joined Chris Mathews lab in Tucson Conceived gene-blocking strategy for viruses1970
1972 Ph.D. in biochemistry: Chris Mathews1974 Gene-blocking agents begun at Berkeley
1976 Gene-blocking agents continued in Denver
1978 First gene-blocking patent issued (sequence-specific crosslinking) Joined Chris Mathews lab, OSU, Corvallis1980 Switched to major-groove gene-blocking agents Left OSU, founded first gene-blocking company
![Page 5: My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To](https://reader035.fdocuments.in/reader035/viewer/2022062423/56814710550346895db447ab/html5/thumbnails/5.jpg)
First Scheme (1974-1978)
H
B
B
NN
O
NH2
HN
O
O
NN
O
N
N
NN
NN
O
H
H
H
H
HN
O O
Cl
NN
O
NHHN
NH2
O
O O
ClB
B
B
B
B
B
B
Antisense strand(carrier)
N
N
HNN
H2N
O
B
Sense strand(target)
Cross-linked carrier-target
Sequence-Specific Crosslinking Agents
Activated antisense strand
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Academic Phase
1968 Joined Chris Mathews lab in Tucson Conceived gene-blocking strategy for viruses1970
1972 Ph.D. in biochemistry: Chris Mathews1974 Gene-blocking agents begun at Berkeley
1976 Gene-blocking agents continued in Denver
1978 First gene-blocking patent issued (sequence-specific crosslinking) Joined Chris Mathews lab, OSU, Corvallis1980 Switched to major-groove gene-blocking agents Left OSU, founded first gene-blocking company
![Page 7: My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To](https://reader035.fdocuments.in/reader035/viewer/2022062423/56814710550346895db447ab/html5/thumbnails/7.jpg)
Second Scheme (1979-1982)
Major-Groove Binding Agents
BindingGCpair
BindingCGpair
BindingTApair
BindingATpair
AntiVirals, Inc.
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Anti-Genes (1979-1982) AntiVirals, Inc.
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AntiVirals, Inc.Commercial Phase
Antisense Oligos (1980-1993)
1980 Founded first gene-blocking company: ANTIVIRALS, Inc.
1982 Funding from private investors, NIH (SBIR) Switched to nucleic-acid-analog gene-blocking agents1984 Dupont funding Devised Morpholino structural type1986 “Won” Oregon lottery1988
1990 Near-final Morpholino structural type
1992 Confirmed excellent properties1993 Discovered delivery problem
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AntiVirals, Inc.Commercial Phase
Antisense Oligos (1980-1993)
1980 Founded first gene-blocking company: ANTIVIRALS, Inc.
1982 Funding from private investors, NIH (SBIR) Switched to nucleic-acid-analog gene-blocking agents1984 Dupont funding Devised Morpholino structural type1986 “Won” Oregon lottery1988
1990 Near-final Morpholino structural type
1992 Confirmed excellent properties1993 Discovered delivery problem
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AntiVirals, Inc.Third Scheme (1982-1993)
OHO B
OH
OH2N B
OH
OHN B
O
OHN B
O
O
Homopolymer binds
Heteropolymer does not bind
Heteropolymer binds
ON I
O
ON G
O
O
H
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Competing structure
OO B
O
OO B
O
PO N
DNA analog
Cheap
Good activity
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AntiVirals, Inc.Commercial Phase
Antisense Oligos (1980-1993)
1980 Founded first gene-blocking company: ANTIVIRALS, Inc.
1982 Funding from private investors, NIH (SBIR) Switched to nucleic-acid-analog gene-blocking agents1984 Dupont funding Devised Morpholino structural type1986 “Won” Oregon lottery1988
1990 Near-final Morpholino structural type
1992 Confirmed excellent properties1993 Discovered delivery problem
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Morpholinos From Ribonucleosides
Analogs derived from ribonucleosides
OHO B
OH OH
N
OO B
N
OO B
O
N
N
OO B
N
OO B
SO O
N
OO B
N
ON B
SO O
NH
OHO B
N
OO B
N
OO B
O
Binds DNAbut not RNA
Modeling suggested need for more flexible intersubunit link
Best
AntiVirals, Inc.
N
OO B
N
OO B
PO NR1
R2
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Morpholino phosphorodiamidate structural types
=
B = A C G U
N
OO B
N
OO B
PO N
Near-final structure
Final structure
U T
T improves RNA binding affinityT allows sequencing by mass spectrometry
AntiVirals, Inc.
N
OO B
N
OO B
PO NR1
R2
NR1
R2
NH2
NH
N
N
N
O
NH
Morpholinos From Ribonucleosides
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AntiVirals, Inc.Commercial Phase
Antisense Oligos (1980-1993)
1980 Founded first gene-blocking company: ANTIVIRALS, Inc.
1982 Funding from private investors, NIH (SBIR) Switched to nucleic-acid-analog gene-blocking agents1984 Dupont funding Devised Morpholino structural type1986 “Won” Oregon lottery1988
1990 Near-final Morpholino structural type
1992 Confirmed excellent properties1993 Discovered delivery problem
![Page 17: My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To](https://reader035.fdocuments.in/reader035/viewer/2022062423/56814710550346895db447ab/html5/thumbnails/17.jpg)
MP S-DNA2’-O-Me
RNA PNAMorphsiRNA
efficacy
specificity
stability
in vivo delivery
cost of material
ease of assembly
splice modification
solubility
+ + + + + + + + + +
+ +
+ +
+ +
+ +
+ +
+ +
-
-
-
--
--
- - -
-
-
-----
+ ++ +
+ ++ +
+ +
+ ++ ++ +
+ +
+ + +++
+
+
++
+ -
+ +
O BO
O
O BO
O
PO
O BO
O
O BO
O
PO S
O BO
O
O BO
O
PO O
O
O
O BO
O
O BO
O
PO O
OH
OH N
O BO
N
O BO
PO N
NH
NO
B
O
N
NO
B
O
N
H
H
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Antisense Therapeutics ( 1993 – 1997 )
1993 Discovered delivery problem Delivery: molecular transport engine (1)
1995 Delivery: scrape delivery (2)
1997 AVI went public Left to start GENE TOOLS, LLC
AntiVirals, Inc.
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Antisense Therapeutics ( 1993 – 1997 )
1993 Discovered delivery problem Delivery: molecular transport engine (1)
1995 Delivery: scrape delivery (2)
1997 AVI went public Left to start GENE TOOLS, LLC
AntiVirals, Inc.
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The Delivery ChallengeCell entry of oligomeric drugs
oligomerdrug
lateendosome
pH 5.5
lysosomepH 4.5
extracellularmedium pH 7.4
cytosolpH 7.5
degradedoligomer
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Antisense Therapeutics ( 1993 – 1997 )
1993 Discovered delivery problem Delivery: molecular transport engine (1)
1995 Delivery: scrape delivery (2)
1997 AVI went public Left to start GENE TOOLS, LLC
AntiVirals, Inc.
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watersoluble
watersoluble
lipidsoluble
EARLYENDOSOME
pH 7
LATEENDOSOME
pH 5
ENDOSOMALMEMBRANE
CYTOSOLpH 7
pH-Mediated Solubility Transition of Weak Acid Moieties
Molecular EngineFor Transporting Drugs Across Cell Membranes
James Summerton, Ph.D.ANTIVIRALS, Inc.
Delivery system 1: Molecular Engine AntiVirals, Inc.
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Delivery system 1: Molecular Engine AntiVirals, Inc.
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Octanol / Water Partitioning
Delivery system 1: Molecular Engine AntiVirals, Inc.
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Molecular Engine: not enough power for Morpholinosso adapted for targeting acidic areas of tumors
Delivery system 1: Molecular Engine
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Antisense Therapeutics ( 1993 – 1997 )
1993 Discovered delivery problem Delivery: molecular transport engine (1)
1995 Delivery: scrape delivery (2)
1997 AVI went public Left to start GENE TOOLS, LLC
AntiVirals, Inc.
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Delivery system 2: Scrape Delivery
culture plate
adherent cell
scrapedcell
cargo molecules in medium
AntiVirals, Inc.
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Antisense Therapeutics ( 1993 – 1997 )
1993 Discovered delivery problem Delivery: molecular transport engine (1)
1995 Delivery: scrape delivery (2)
1997 AVI went public Left to start GENE TOOLS, LLC
AntiVirals, Inc.
![Page 29: My Long Journey To Antisense Oligos [ 1968 to 1993 ] And The Remaining Journey To](https://reader035.fdocuments.in/reader035/viewer/2022062423/56814710550346895db447ab/html5/thumbnails/29.jpg)
Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Morpholino
PEG-600
high-osmolarity sugar
release step
wash
Delivery system 3: Osmotic Delivery
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Delivery system 4: Microinjection
Microinjection Into Eggs & Embryos
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Morpholino
EPEI
Delivery system 5: Special Delivery
DNA
Delivery system
Rel
ativ
e m
agni
tude
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Delivery system 6: Endo-Porter
Figure 1: Probable Endo-Porter mechanism
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Delivery system 6: Endo-Porter
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Delivery system 6: Endo-Porter
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Delivery system 7: Vivo-Morphlinos
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Delivery system 7: Vivo-Morphlinos
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Delivery system 8: Receptor/Transport System (in progress)
Design objectives
cell levelhigh-affinity receptor on nearly all cellsefficient endocytosisefficient sortingefficient transport to cytosol
organ levelefficient transcytosis across blood-brain barrier
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Commercial Phase
Antisense Therapeutics ( 1997 – 2013 ? )
1997 Started GENE TOOLS, LLC Delivery: Osmotic delivery (3)1999 Delivery: Microinjection, egg & early embryo (J Heasman, S Ekker) (4)2001 Delivery: Special Delivery (5) 2003 Delivery: Endo-Porter (6)
2005 2007 Delivery: Vivo-Morpholinos (Yongfu Li) (7)2009 Delivery: Receptor/transport system devised (8) 2011 2013 Delivery: Receptor/transport system completed (2013 ?) “Fountain of Youth” application pending delivery
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Fountain of YouthHutchinson-Gilford Progeria Syndrome
Nuclearmembrane:normal
Nuclearmembrane:HGPS
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Fountain of Youth
Scaffidi P, Gordon L, Misteli T (2005) The cell nucleus and aging: Tantalizing clues and hopefulpromises. PLoS Biol 3(11): e395.
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My Long Journey To
Antisense Oligos[ 1968 to 1993 ]
And The Remaining Journey To
Antisense TherapeuticsIncluding
Fountain of Youth[ 1993 to 2013 ? ]
James Summerton, Ph.D. (Biochemistry)GENE TOOLS, LLC