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Our Genome-Edited Future:
the Promise
and the Challenge
Fyodor Urnov
Deputy Director
Altius Institute for Biomedical Scien...
Urnov
Gregory
Holmes
Nature 2005
3 2018:
genome editing about to enter its second decade in the clinic
2009:
First subject treated
ZFNs
Sangamo
2015:
First...
4
Leonardo’s flying machine
5
Commercial aviation 2018
Urnov The CRISPR Journal 2018
Genome editing BC (Before CRISPR)
B.C.
A.D.
34 27 19 12 11 10
I-SceI ZFN
Genome editing BC (Before CRISPR)
B.C.
A.D.
34 27 19 12 11 10 9 8 7 6 5 4 3 2
K562
T cell
t
hESC CHO hESC
iPSC
CD34 Liver
...
B.C.
A.D.
34 27 19 12 11 10 9 8 7 6 5 4 3 2 1
K562
T cell
t
hESC CHO hESC
iPSC
CD34 Liver
I-SceI ZFN TALEN Cas9
1
Genome Editing:
the Core Vocabulary
OECD | 27 June 2018
10
DNA: a universally familiar acronym
OECD | 27 June 2018
11
DSB: double-strand break
OECD | 27 June 2018
12
Nuclease: in this context, enzyme engineered to induce a DSB
Zinc Finger Nucleases (ZFNs) TALE Nucl...
OECD | 27 June 2018
13 ZFN: zinc finger nuclease
TALEN: transcription activator like effector nuclease
Cas9: CRISPR-associ...
OECD | 27 June 2018
14
Clustered regularly interspaced short palindromic repeats1
CRISPR: an acronym, the meaning of which...
OECD | 128 June 2018
15
DSB-R: double-strand break repair
OECD | 128 June 2018
16
NHEJ: non-homologous end joining
OECD | 128 June 2018
17
KO: knockout
Santiago et al. PNAS 105: 5809 (2008)
OECD | 128 June 2018
18
DSB-R: double-strand break repair
OECD | 27 June 2018
19
HR (HDR): homology-directed repair
OECD | 27 June 2018
20
Donor: DNA used to repair a nuclease-induced DSB by HDR
OECD | 27 June 2018
21 Knockin: the introduction of new genetic information
(in this case, of a SNP - single nucleotide po...
OECD | 27 June 2018
22 TI: targeted integration - new DNA information COPIED into the
break, but not physically transferre...
OECD | 27 June 2018
23
Genome editing is a fundamentally different way to engineer the genome:
The genome editor itself is...
2
Genome Editing:
the Toolbox
OECD | 27 June 2018
25
The toolbox of genome editing is largely nuclease-type-agnostic
Non-Homologous
End Joining
Homology...
OECD | 27 June 2018
26
Applications of the genome editing toolbox
Non-Homologous
End Joining
Homology Directed
Repair
gene...
OECD | 27 June 2018
27
Genome editing: nucleases, biotechs, CROs
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRIS...
OECD | 27 June 2018
28
Genome editing is a fundamentally new way to engineer living systems:
Putting together the “enginee...
3
Genome Editing:
a Short Aside on IP
OECD | 27 June 2018
30
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRISPR RNA-Guided NucleasesMeganucleases / meg...
OECD | 27 June 2018
30
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRISPR RNA-Guided NucleasesMeganucleases / meg...
OECD | 27 June 2018
30
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRISPR RNA-Guided NucleasesMeganucleases / meg...
OECD | 27 June 2018
30
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRISPR RNA-Guided NucleasesMeganucleases / meg...
OECD | 27 June 2018
30
Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs)
CRISPR RNA-Guided NucleasesMeganucleases / meg...
OECD | 27 June 2018
31
Genome editing redefines the meaning of the word “natural”
it allows you to move a natural form of ...
OECD | 27 June 2018
32
Moving a genetic variant from the warthog to the pig
3
Genome Editing:
Clinical Applications -
HIV
~40 million HIV positive
~8 million have access to ART
Therapy
37 approved drugs

Brand Name Generic Name
Manufacturer
Name* Approval Date Time to Approval
Multi-class Combinati...
OECD | 27 June 2018
37
A historic cure
CCR5!32 

donor
OECD | 27 June 2018
38
Genome Editing for HIV:
CCR5
CCR5 gene disruption
NHEJ
error-prone repair
T cells
Cells returned
to...
OECD | 27 June 2018
39
Berlin patient (BMT) and edited subject
Berlin patient One of the 96
subjects on the
trial
OECD | 28 June 2018
40
Berlin patient (BMT) and edited subject: a paradox
Received his own T cells back with a
knockout of...
OECD | 28 June 2018
41
Genome editing for HIV: status and implications
Implications
There is a path to the clinic for edit...
Genome Editing En Route to the Clinic:

CD34 GMP Cell Manufacturing Process At Clinical Scale
CliniMACS
CD34 enrichment
Da...
Cancer immunotherapy v. 1.0 – 

Carl June (Penn)
http://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-...
2018: the commercial reality of gene therapy
Jack Hogan (luxturna, Spark)Emma Whitelaw (kymriah, Novartis)
OECD | 28 June 2018
46
Gene editing for HIV - a path forward
Genome editing for HIV:
2-3 yrs: continued effort in ex vivo ...
3
Genome Editing:
Clinical Applications -
Cancer
28123068
OECD | 27 June 2018
49
Cells from healthy volunteer
Knock out TCR
Add CAR
Knock out CD52
Patient 1: 11 months old
“The inf...
OECD | 28 June 2018
50
Gene editing for cancer - path forward
Gene editing for cancer:
1-3 yrs: clinical trials with edite...
OECD | 28 June 2018
51
The challenge of access
How about for an off-the-shelf cell
product?
Where you cannot seriously tal...
4
Genome Editing:
Clinical Applications -
hemoglobinopathies
OECD | 27 June 2018
53
Current:

Find a bone marrow donor -> do a bone marrow transplant
Challenge:

Poor donor availabili...
OECD | 27 June 2018
54
β-thalassemia is caused by mutations in β-globin
α
α
β
β
• Point mutations that affect
splicing of ...
OECD | 27 June 2018
55
Sickle cell disease is cause by a mutation in β-globin
“Kind of Blue” – “So What”
Jan van Eyck – The Arnolfini Portrait
Mom: adult hemoglobin (HbA)
Baby: fetal hemoglobin (HbF)
OECD | 27 June 2018
57
Switch in β-globin production
fetal ON adult OFFBaby:
fetal OFF adult ONAdult:
OECD | 27 June 2018
58 A person with β-thalassemia, or with sickle-cell disease, has a
“spare tire” in her/his genome
feta...
59
BCL11A ↓ = fetal globin ↑ = disease ameliorated or eliminated
Disease-Protective Genetic Variation in β-thalassemia
BCL...
OECD | 27 June 2018
60 Clinical strategy: move a natural protective allele into the genome
of a person with disease
fetal ...
OECD | 28 June 2018
61
Gene editing for the hemoglobinopathies - path forward
Path forward:
1-5 years: gene therapy trials...
5
Genome Editing:
Clinical Applications -
hemophilia B and MPS1/2
6
Genome Editing:
health applications
OECD | 27 June 2018
66
Naturally occurring disease protection
OECD | 27 June 2018
67
88%
OECD | 27 June 2018
68 There are TWO approved drugs, both biologics, against PCSK9
($14k/year)
OECD | 27 June 2018
69
… just use genome editing to get rid of the gene in the liver?
Statins were initially approved NOT ...
6
Genome Editing:
enhancement
OECD | 27 June 2018
71
One mutation -> OK on 4 hrs of sleep
Science Vol. 325. no. 5942, pp. 866 – 870.
Genetic enhancement for air traffic
controllers?
OECD | 27 June 2018
73
“The index case for the present study was a ten-
year-old child, well known to the medical service
...
Genetic enhancement for pain-free special-
forces soldiers?
OECD | 28 June 2018
75
The promise and the challenge of genome editing
Challenges:
Approved medicines:
- will be very expe...
OECD | 28 June 2018
76
A word from the Marquis de Condorcet (1743-1794)
Tel est le but de l’ouvrage que j’ai entrepris,
et...
Our Genome-Edited Future: the Promise and the Challenge
Our Genome-Edited Future: the Promise and the Challenge
Our Genome-Edited Future: the Promise and the Challenge
Our Genome-Edited Future: the Promise and the Challenge
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Our Genome-Edited Future: the Promise and the Challenge

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This presentation gives some background of genome editing techniques in the broader context. The focus of the Conference is on agriculture to ensure that one specific sector can be addressed in depth. However, the potential applications of genome editing are much broader than just agriculture and
there are a number of topic areas which cannot be covered thoroughly in the limited time available.

Published in: Science
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Our Genome-Edited Future: the Promise and the Challenge

  1. 1. Our Genome-Edited Future: the Promise and the Challenge Fyodor Urnov Deputy Director Altius Institute for Biomedical Sciences, Seattle, WA, USA
  2. 2. Urnov Gregory Holmes Nature 2005
  3. 3. 3 2018: genome editing about to enter its second decade in the clinic 2009: First subject treated ZFNs Sangamo 2015: First pediatric subject treated TALENs Qasim/Thrasher/Cellectis 2017: First subject treated in vivo ZFNs Sangamo
  4. 4. 4 Leonardo’s flying machine
  5. 5. 5 Commercial aviation 2018
  6. 6. Urnov The CRISPR Journal 2018 Genome editing BC (Before CRISPR) B.C. A.D. 34 27 19 12 11 10 I-SceI ZFN
  7. 7. Genome editing BC (Before CRISPR) B.C. A.D. 34 27 19 12 11 10 9 8 7 6 5 4 3 2 K562 T cell t hESC CHO hESC iPSC CD34 Liver I-SceI ZFN TALEN
  8. 8. B.C. A.D. 34 27 19 12 11 10 9 8 7 6 5 4 3 2 1 K562 T cell t hESC CHO hESC iPSC CD34 Liver I-SceI ZFN TALEN Cas9
  9. 9. 1 Genome Editing: the Core Vocabulary
  10. 10. OECD | 27 June 2018 10 DNA: a universally familiar acronym
  11. 11. OECD | 27 June 2018 11 DSB: double-strand break
  12. 12. OECD | 27 June 2018 12 Nuclease: in this context, enzyme engineered to induce a DSB Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs
  13. 13. OECD | 27 June 2018 13 ZFN: zinc finger nuclease TALEN: transcription activator like effector nuclease Cas9: CRISPR-associated gene number 9
  14. 14. OECD | 27 June 2018 14 Clustered regularly interspaced short palindromic repeats1 CRISPR: an acronym, the meaning of which is not useful
  15. 15. OECD | 128 June 2018 15 DSB-R: double-strand break repair
  16. 16. OECD | 128 June 2018 16 NHEJ: non-homologous end joining
  17. 17. OECD | 128 June 2018 17 KO: knockout Santiago et al. PNAS 105: 5809 (2008)
  18. 18. OECD | 128 June 2018 18 DSB-R: double-strand break repair
  19. 19. OECD | 27 June 2018 19 HR (HDR): homology-directed repair
  20. 20. OECD | 27 June 2018 20 Donor: DNA used to repair a nuclease-induced DSB by HDR
  21. 21. OECD | 27 June 2018 21 Knockin: the introduction of new genetic information (in this case, of a SNP - single nucleotide polymorphism) P229: CCA CCG Urnov et al. 
 Nature 435: 646 (2005)
  22. 22. OECD | 27 June 2018 22 TI: targeted integration - new DNA information COPIED into the break, but not physically transferred into it Moehle, Rock, et al PNAS 2007
  23. 23. OECD | 27 June 2018 23 Genome editing is a fundamentally different way to engineer the genome: The genome editor itself is ABSENT from the resulting organism. Only the desired edit is present. Key message #1
  24. 24. 2 Genome Editing: the Toolbox
  25. 25. OECD | 27 June 2018 25 The toolbox of genome editing is largely nuclease-type-agnostic Non-Homologous End Joining Homology Directed Repair Urnov et al, Nature Reviews Genetics 2010 TALENs Cas9 MegaTAL meganuclease
  26. 26. OECD | 27 June 2018 26 Applications of the genome editing toolbox Non-Homologous End Joining Homology Directed Repair gene knockout introduction, or repair,
 of point mutations targeted introduction
 of transgenes tagging genes study of larger
 genomic regions targeted introduction
 of multiple transgenes Urnov Nature Reviews Genetics 2010
  27. 27. OECD | 27 June 2018 27 Genome editing: nucleases, biotechs, CROs Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird
  28. 28. OECD | 27 June 2018 28 Genome editing is a fundamentally new way to engineer living systems: Putting together the “engineer” - ie the “device” that you will use - is a technically solved challenge. The obstacles to the technology lie outside the technology itself. Key message #2
  29. 29. 3 Genome Editing: a Short Aside on IP
  30. 30. OECD | 27 June 2018 30 Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird
  31. 31. OECD | 27 June 2018 30 Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird Versatile, powerful - IP monopoly
  32. 32. OECD | 27 June 2018 30 Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird Versatile, powerful - IP monopoly Not versatile, powerful - IP monopoly
  33. 33. OECD | 27 June 2018 30 Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird Versatile, powerful - IP monopoly Not versatile, powerful - IP monopoly Versatile, powerful - IP fragmented
  34. 34. OECD | 27 June 2018 30 Zinc Finger Nucleases (ZFNs) TALE Nucleases (TALENs) CRISPR RNA-Guided NucleasesMeganucleases / megaTALs Sangamo Sigma Dow Agro Cellectis Calyxt Recombinetics Thermo Caribou Editas Intellia CRISPR Tx Precision bluebird Versatile, powerful - IP monopoly Not versatile, powerful - IP monopoly Versatile, powerful - IP fragmented Versatile, powerful - IP …
  35. 35. OECD | 27 June 2018 31 Genome editing redefines the meaning of the word “natural” it allows you to move a natural form of a gene from one living organism to another - without adding an extra gene to the recipient (solely by changing the recipients’ own natural gene to a different equally natural form) Key message #2
  36. 36. OECD | 27 June 2018 32 Moving a genetic variant from the warthog to the pig
  37. 37. 3 Genome Editing: Clinical Applications - HIV
  38. 38. ~40 million HIV positive ~8 million have access to ART
  39. 39. Therapy 37 approved drugs
 Brand Name Generic Name Manufacturer Name* Approval Date Time to Approval Multi-class Combination Products Atripla efavirenz, emtricitabine and tenofovir disoproxil fumarate Bristol-Myers Squibb and Gilead Sciences July 12, 2006 2.5 months Complera emtricitabine, rilpivirine, and tenofovir disoproxil fumarate Gilead Sciences August 10, 2011 6 months Stribild elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate Gilead Sciences August 27, 2012 6 months Nucleoside Reverse Transcriptase Inhibitors (NRTIs)       Combivir lamivudine and zidovudine GlaxoSmithKline September 27, 1997 3.9 months Emtriva emtricitabine, FTC Gilead Sciences July 2, 2003 10 months Epivir lamivudine, 3TC GlaxoSmithKline November 17, 1995 4.4 months Epzicom abacavir and lamivudine GlaxoSmithKline August 2, 2004 10 months Hivid zalcitabine, dideoxycytidine, ddC (no longer marketed) Hoffmann-La Roche June 19, 1992 7.6 months Retrovir zidovudine, azidothymidine, AZT, ZDV GlaxoSmithKline March 19, 1987 3.5 months Trizivir abacavir, zidovudine, and lamivudine GlaxoSmithKline November 14, 2000 10.9 months Truvada tenofovir disoproxil fumarate and emtricitabine Gilead Sciences, Inc. August 2, 2004 5 months Videx EC enteric coated didanosine, ddI EC Bristol Myers- Squibb October 31, 2000 9 months Videx didanosine, dideoxyinosine, ddI Bristol Myers- Squibb October 9, 1991 6 months Viread tenofovir disoproxil fumarate, TDF Gilead October 26, 2001 5.9 months Zerit stavudine, d4T Bristol Myers- Squibb June 24, 1994 5.9 months Ziagen abacavir sulfate, ABC GlaxoSmithKline December 17, 1998 5.8 months Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)       Edurant rilpivirine Tibotec Therapeutics May 20, 2011 10 months Intelence etravirine Tibotec Therapeutics January 18, 2008 6 months Rescriptor delavirdine, DLV Pfizer April 4, 1997 8.7 months Sustiva efavirenz, EFV Bristol Myers- Squibb September 17, 1998 3.2 months Viramune  nevirapine, NVP Boehringer Ingelheim June 21, 1996 3.9 months Viramune XR( Extended Release) nevirapine, NVP Boehringer Ingelheim March 25, 2011 9.9 months Protease Inhibitors (PIs)       Agenerase amprenavir, APV (no longer marketed) GlaxoSmithKline April 15, 1999 6 months Aptivus tipranavir, TPV Boehringer Ingelheim June 22, 2005 6 months Crixivan indinavir, IDV, Merck March 13, 1996 1.4 months Fortovase saquinavir (no longer marketed) Hoffmann-La Roche November 7, 1997 5.9 months Invirase saquinavir mesylate, SQV Hoffmann-La Roche December 6, 1995 3.2 months http://www.fda.gov/ForConsumers/ byAudience/ForPatientAdvocates/ HIVandAIDSActivities/ucm118915.htm
  40. 40. OECD | 27 June 2018 37 A historic cure CCR5!32 
 donor
  41. 41. OECD | 27 June 2018 38 Genome Editing for HIV: CCR5 CCR5 gene disruption NHEJ error-prone repair T cells Cells returned to patient
  42. 42. OECD | 27 June 2018 39 Berlin patient (BMT) and edited subject Berlin patient One of the 96 subjects on the trial
  43. 43. OECD | 28 June 2018 40 Berlin patient (BMT) and edited subject: a paradox Received his own T cells back with a knockout of his CCR5 gene. Received an entire foreign bone marrow, bearing 6,000 coding differences plus the delta 32 CCR5 mutation.
  44. 44. OECD | 28 June 2018 41 Genome editing for HIV: status and implications Implications There is a path to the clinic for edited autologous T cells There is a path to the clinic for edited stem cells Status: T cells - 96 subjects treated. Good safety record. Consistent antiviral effect. Tebas NEJM 2014 Hematopoietic stem cells - subjects have been treated treated.
  45. 45. Genome Editing En Route to the Clinic:
 CD34 GMP Cell Manufacturing Process At Clinical Scale CliniMACS CD34 enrichment Day 0 Platelet depletion by centrifugation Day 0 Day 0 Rest cells in culture Formulate and cryopreserve CD34 cells Day 3 Gene modified CD34 cells
 Final Product after QC testing and release (~30 days) ZFN Maxcyte mRNA electroporation Day 1Day 1-3 Static culture step to allow ZFN gene expression 10 Liter apheresis in G- CSF mobilized subjects Day -1 or Day 0
  46. 46. Cancer immunotherapy v. 1.0 – 
 Carl June (Penn) http://www.nytimes.com/2012/12/10/health/a-breakthrough-against-leukemia-using-altered-t-cells.html 23527958
  47. 47. 2018: the commercial reality of gene therapy Jack Hogan (luxturna, Spark)Emma Whitelaw (kymriah, Novartis)
  48. 48. OECD | 28 June 2018 46 Gene editing for HIV - a path forward Genome editing for HIV: 2-3 yrs: continued effort in ex vivo edited autologous T cells and HSPCs shows a good safety 5 yrs: approved gene editing medicine (autologous T cells or HSPCs for HIV) 5-7 yrs: ex vivo gene editing vaccine (autologous) 10 yrs: in vivo gene editing vaccine Chances that a 15 year old girl in South Africa will become HIV-positive in her lifetime: 80%
  49. 49. 3 Genome Editing: Clinical Applications - Cancer
  50. 50. 28123068
  51. 51. OECD | 27 June 2018 49 Cells from healthy volunteer Knock out TCR Add CAR Knock out CD52 Patient 1: 11 months old “The infant is well 18 mo after therapy” Patient 2: 16 months old “The child remains clinically well at home 12 mo after therapy” The “allogeneic” cell product 28123068
  52. 52. OECD | 28 June 2018 50 Gene editing for cancer - path forward Gene editing for cancer: 1-3 yrs: clinical trials with edited cells for leukemia 1-5 years: clinical trials with edited cells for solid cancers 2-5 years: as above, with off-the shelf cells If effective and safe: Off-the shelf edited cell medicines for cancer - this should be MUCH cheaper Approved medicines: Kymriah Yescarta Next-gen products: Cellectis Sangamo, CRISPR, Editas, Intellia, bluebird ….
  53. 53. OECD | 28 June 2018 51 The challenge of access How about for an off-the-shelf cell product? Where you cannot seriously talk about making a generic? Gilead - cure for hepatitis. In US, $84,000 per patient Egypt has a high prevalence of hepatitis They said they’d just make a generic Gilead agreed to make the drug available at <$1,000 a dose
  54. 54. 4 Genome Editing: Clinical Applications - hemoglobinopathies
  55. 55. OECD | 27 June 2018 53 Current:
 Find a bone marrow donor -> do a bone marrow transplant Challenge:
 Poor donor availability; procedure has substantial clinical risk Our plan: 
 each patient can be her/his own donor – take blood stem cells, do genome editing, return cells to patient. Sickle cell disease and beta thalassemia
  56. 56. OECD | 27 June 2018 54 β-thalassemia is caused by mutations in β-globin α α β β • Point mutations that affect splicing of the mRNA • Nonsense mutations • Point mutations in the promoter • Deletions ~200
  57. 57. OECD | 27 June 2018 55 Sickle cell disease is cause by a mutation in β-globin “Kind of Blue” – “So What”
  58. 58. Jan van Eyck – The Arnolfini Portrait Mom: adult hemoglobin (HbA) Baby: fetal hemoglobin (HbF)
  59. 59. OECD | 27 June 2018 57 Switch in β-globin production fetal ON adult OFFBaby: fetal OFF adult ONAdult:
  60. 60. OECD | 27 June 2018 58 A person with β-thalassemia, or with sickle-cell disease, has a “spare tire” in her/his genome fetal ON adult OFFBaby: fetal OFF adult ONAdult: fetal OFF a*ult ON Adult w/ SCD or b-thal: genome editing fetal ON a*ult DOWNAdult:
  61. 61. 59 BCL11A ↓ = fetal globin ↑ = disease ameliorated or eliminated Disease-Protective Genetic Variation in β-thalassemia BCL11A - 2008:
  62. 62. OECD | 27 June 2018 60 Clinical strategy: move a natural protective allele into the genome of a person with disease fetal OFF a*ult ONAdult with disease: Bcl11a Use genome editing to remove the enhancer of BCL11A: BCL11A activity goes down in precursors of red blood cells! Disease symptoms improved! (we hope) fetal ON a*ult DOWN Enhancer- Edited Adult Bcl11a
  63. 63. OECD | 28 June 2018 61 Gene editing for the hemoglobinopathies - path forward Path forward: 1-5 years: gene therapy trials continue Can expect first approval next year. Will be expensive. 1-6 years: genome editing trials continue If safe and effective, can expect approval in 5-7 years. If a way is developed to deliver editor to stem cells in vivo (injection), this could be scaled to Asia and Africa. Current: Advanced-stage gene therapy trials (US and Europe) with conventional gene therapy (bluebird bio) Early-stage genome editing trials - US and Europe
  64. 64. 5 Genome Editing: Clinical Applications - hemophilia B and MPS1/2
  65. 65. 6 Genome Editing: health applications
  66. 66. OECD | 27 June 2018 66 Naturally occurring disease protection
  67. 67. OECD | 27 June 2018 67 88%
  68. 68. OECD | 27 June 2018 68 There are TWO approved drugs, both biologics, against PCSK9 ($14k/year)
  69. 69. OECD | 27 June 2018 69 … just use genome editing to get rid of the gene in the liver? Statins were initially approved NOT as CVD prevention - they were approved to treat a rare genetic form of disease. Only when it was discovered they are safe, did physicians start prescribing them as disease prevention agents. Why not …
  70. 70. 6 Genome Editing: enhancement
  71. 71. OECD | 27 June 2018 71 One mutation -> OK on 4 hrs of sleep Science Vol. 325. no. 5942, pp. 866 – 870.
  72. 72. Genetic enhancement for air traffic controllers?
  73. 73. OECD | 27 June 2018 73 “The index case for the present study was a ten- year-old child, well known to the medical service after regularly performing 'street theatre'. He placed knives through his arms and walked on burning coals, but experienced no pain. He died before being seen on his fourteenth birthday, after jumping off a house roof.” Natural mutation in SCN9A leads to loss of pain sensation
  74. 74. Genetic enhancement for pain-free special- forces soldiers?
  75. 75. OECD | 28 June 2018 75 The promise and the challenge of genome editing Challenges: Approved medicines: - will be very expensive - and will not be easily portable beyond US and Europe ACCESS What about more common disease? Human enhancement - who will regulate, and who will have access? A future of alpha humans and beta humans? “Rogue” germline editing. Promise: The editor leaves, the edit stays Making the editor is a solved problem Can move natural alleles In the clinic for HIV, cancer, hemoglobinopathies, metabolic disease Editing ex vivo and in vivo Clearly on horizon - editing as disease prevention
  76. 76. OECD | 28 June 2018 76 A word from the Marquis de Condorcet (1743-1794) Tel est le but de l’ouvrage que j’ai entrepris, et dont le résultat sera de montrer, par le raisonnement et par les faits, qu’il n’a été marqué aucun terme au perfectionnement des facultés humaines ; que la perfectibilité de l’homme est réellement indéfinie ; que les progrès de cette perfectibilité, désormais indépendante de toute puissance qui voudrait les arrêter, n’ont d’autre terme que la durée du globe où la nature nous a jetés. Sans doute, ces progrès pourront suivre une marche plus ou moins rapide, mais jamais elle ne sera rétrograde ; du moins, tant que la terre occupera la même place dans le système The work which I have undertaken will show, through reasoning and through facts, that nature has assigned no limit to the perfecting of the human faculties, that the perfectability of humans is truly indefinite; that the progress of this perfectability has no limit other than the duration of the globe on which nature has placed us. Doubtless its progress will be more or less rapid; but never will humans retrograde, so long, at least, as the earth occupies the same place in the system of the universe.

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