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TITLE
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Genetic Engineering
2 Physician Led | Therapeutically Focused
“…the process of making targeted modifications to
the genome...
Zinc-Finger Nuclease (ZFN)
3 Physician Led | Therapeutically Focused
Transcription Activator Like Effector Nuclease (TALEN):
Application in Duchenne Muscular Dystrophy
4 Physician Led | Thera...
CRISPR: Clustered Regularly Interspaced
Short Palindromic Repeats
5 Physician Led | Therapeutically Focused
o First descri...
CRISPR Basics
Physician Led | Therapeutically Focused6 Physician Led | Therapeutically Focused6
Spacer
DNA
cas Spacer
DNA
...
cas Protein and crRNA Produced
Physician Led | Therapeutically Focused7 Physician Led | Therapeutically Focused7
Spacer
DN...
Physician Led | Therapeutically Focused8 Physician Led | Therapeutically Focused8
Spacer
DNA
cas Spacer
DNA
Spacer
DNA
Spa...
Bacteriophage Denied!!
New Spacer DNA Incorporated into Bacterial Genome for Next Time…
Physician Led | Therapeutically Fo...
Physician Led | Therapeutically Focused10
The Breakthrough
Jinek et al, Science, 2012
Physician Led | Therapeutically Focused11
Next?
Physician Led | Therapeutically Focused
o Transcription
interference
o Co-...
Clinical Human Applications of CRISPR
12 Physician Led | Therapeutically Focused
o Viral infections: HIV, HSV, VZV
 Inser...
Clinical Human Applications of CRISPR?
13 Physician Led | Therapeutically Focused
o Genetic diseases
 Remove or add the s...
Human Experience
14 Physician Led | Therapeutically Focused
o Liang et al using human
tripronuclear zygotes cleaved the
HB...
Cancer Studies
15 Physician Led | Therapeutically Focused
Source: Clinicaltrials.gov, Sept 2016
The NIH Recombinant Advisory
Committee has Approved the First US Trial
16 Physician Led | Therapeutically Focused
The Univ...
Limitless Applications…
Physician Led | Therapeutically Focused17
• Drug development – optimize
biotech manufacture
• Dise...
Regulatory and
Ethical Implications
Clinical Development Considerations for
Gene Editing Technology
19 Physician Led | Therapeutically Focused
o Therapies may...
Physician Led | Therapeutically Focused
o Most likely to be largest
area of clinical
development using
CRISPR technology
o...
Ethical Concerns
o International Summit on Human Gene Editing (Dec 2015)
 Concerns over germ line editing – need for an o...
Regulatory Challenges
o CRISPR/Cas-based gene editing of
somatic cell therapies will use in vivo or
ex vivo strategies
o C...
o Off-target effects/genotoxicity
 Improvements in targeting of CRISPR/Cas9 system
• Methods to assess genome-wide off-ta...
Physician Led | Therapeutically Focused
o Complex manufacturing processes
o Release testing
o Shelf-life may be short (hou...
o Role of RAC in the US
 Recent revisions to streamline the process
o Review of gene therapy studies in EU
 Additional t...
Regulatory Pathways to the Market
o EU, Japan and US recognize the importance of
faster transit through the current regula...
Cost and Reimbursement
o CRISPR-based therapy that provides a one-off
lifetime cure will come at a high development
cost
...
Future Direction of Clinical Development
o CRISPR/Cas9-based gene editing of cells and tissues will be an
exciting and rap...
Physician Led | Therapeutically Focused29
“Genome editing holds great promise to provide a
precise set of tools for counte...
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Gene Editing - Challenges and Future of CRISPR in Clinical Development

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In this presentation, Medpace experts discuss the unique opportunity of evolving gene editing technology as it applies to human diseases

Published in: Health & Medicine
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Gene Editing - Challenges and Future of CRISPR in Clinical Development

  1. 1. CLICK TO EDIT TITLE Click to edit subtitle
  2. 2. Genetic Engineering 2 Physician Led | Therapeutically Focused “…the process of making targeted modifications to the genome, its contexts (e.g., epigenetic marks), or its outputs (e.g., transcripts)” (Hsu et al, 2014).
  3. 3. Zinc-Finger Nuclease (ZFN) 3 Physician Led | Therapeutically Focused
  4. 4. Transcription Activator Like Effector Nuclease (TALEN): Application in Duchenne Muscular Dystrophy 4 Physician Led | Therapeutically Focused X Y DMD gene Xp21 • DMD gene: 79 exons, deletions, duplications or loss can lead to lack of functional dystrophin protein • Large size renders traditional AAV based gene editing difficult • Li et al. (2015) used TALEN to correct in iPSCs via exon knockin and demonstrated proof of principle • TALEN can have off target mutagenesis Li et al, Stem Cell 2015
  5. 5. CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats 5 Physician Led | Therapeutically Focused o First described in E. coli and determined to be part of the bacterial innate immune system versus bacteriophages o Consists of short segments of DNA that are palindromes interspaced with spacer DNA o The spacer DNA is identical in sequence to viral (bacteriophage) DNA o There are additional CRISPR associated proteins: cas proteins that are typically helicases or nucleases Spacer DNA cas Spacer DNA Spacer DNA Spacer DNA
  6. 6. CRISPR Basics Physician Led | Therapeutically Focused6 Physician Led | Therapeutically Focused6 Spacer DNA cas Spacer DNA Spacer DNA Spacer DNA Bacteria Cell Wall
  7. 7. cas Protein and crRNA Produced Physician Led | Therapeutically Focused7 Physician Led | Therapeutically Focused7 Spacer DNA cas Spacer DNA Spacer DNA Spacer DNA cas protein /crRNA complex Bacteria Cell Wall
  8. 8. Physician Led | Therapeutically Focused8 Physician Led | Therapeutically Focused8 Spacer DNA cas Spacer DNA Spacer DNA Spacer DNA cas Protein A New Bacteriophage Arrives Bacteria Cell Wall
  9. 9. Bacteriophage Denied!! New Spacer DNA Incorporated into Bacterial Genome for Next Time… Physician Led | Therapeutically Focused9 Physician Led | Therapeutically Focused9 New Spacer DNA Spacer DNA cas Spacer DNA Spacer DNA Spacer DNA Bacteria Cell Wall
  10. 10. Physician Led | Therapeutically Focused10 The Breakthrough Jinek et al, Science, 2012
  11. 11. Physician Led | Therapeutically Focused11 Next? Physician Led | Therapeutically Focused o Transcription interference o Co-activation and interference o Transcription activation o Epigenetic modifiers 11 Dominguez et al., Nature Reviews: Molecular Cell Biology, 17, 5-15, Jan 2016
  12. 12. Clinical Human Applications of CRISPR 12 Physician Led | Therapeutically Focused o Viral infections: HIV, HSV, VZV  Inserted viral genome could be removed by altering immune cells  Human embryos: Kang and colleagues inserted the CCR5Δ32 allele into early human 3PN embryos o Cancer  Mutation driven cancers Kang, X. et al. J Assist Reprod Genet 33, 581, 2016
  13. 13. Clinical Human Applications of CRISPR? 13 Physician Led | Therapeutically Focused o Genetic diseases  Remove or add the sequence that is causing the disease o Transplantation  Gene editing of mismatched human or even non-human mammals as potential organ donors  Editing will reduce risk of immune responses and rejection when using mismatched organs/tissues/cells
  14. 14. Human Experience 14 Physician Led | Therapeutically Focused o Liang et al using human tripronuclear zygotes cleaved the HBB gene with a CRISPR/Cas9- mediated system  Low efficiency and edited embryos were mosaic with off target cleavage o Other clinical trials forthcoming:  Editas  CRISPR Therapeutics  Caribou Biosciences  Intellia Therapeutics Liang et al, Protein and Cell 2015
  15. 15. Cancer Studies 15 Physician Led | Therapeutically Focused Source: Clinicaltrials.gov, Sept 2016
  16. 16. The NIH Recombinant Advisory Committee has Approved the First US Trial 16 Physician Led | Therapeutically Focused The University of Pennsylvania: combination of PD-1 and NY-ESO-1 and LAGE-1 in human cancer Time, 2016
  17. 17. Limitless Applications… Physician Led | Therapeutically Focused17 • Drug development – optimize biotech manufacture • Disease models • Ecological vector control – mosquito sterilization • Biofuels • Agriculture – modification of crop strains or animals
  18. 18. Regulatory and Ethical Implications
  19. 19. Clinical Development Considerations for Gene Editing Technology 19 Physician Led | Therapeutically Focused o Therapies may provide life-long cure through a single treatment o CRISPR technology has made gene-editing much more accessible and has broadened the range of targets o Regulatory and ethical frameworks o Bring new therapies to the clinic via a safe and rapid pathway
  20. 20. Physician Led | Therapeutically Focused o Most likely to be largest area of clinical development using CRISPR technology o Regulations available to govern these applications o No new ethical concerns/issues o Research permitted o Therapies being developed o Considered for some indications – would alter the genome in all cells and become heritable o Ethical concerns o Inconsistent and variable guidelines and regulation o Limited research permitted o Development of therapies may be restricted Somatic Cell Therapy Germ Line Therapy 20
  21. 21. Ethical Concerns o International Summit on Human Gene Editing (Dec 2015)  Concerns over germ line editing – need for an ongoing forum o NAS/NAM Meeting (April 2016)  All aspects of human germline editing, consequences, regulation and potential applications  Committee assembled to perform a year-long in-depth study o EU CT Directive (2001/20/EC) does not allow germ line editing (Article 9) o NIH RAC will not review proposals on germ line editing o Eugenic practices prohibited:  Oviedo Convention  Convention on Human Rights and Biomedicine (1997)  Article 3(2) of the Charter of Fundamental Rights of EU prohibits eugenic practices Non-Therapeutic Use / Enhancement Physician Led | Therapeutically Focused21
  22. 22. Regulatory Challenges o CRISPR/Cas-based gene editing of somatic cell therapies will use in vivo or ex vivo strategies o Current regulations for gene therapy and cell therapy will regulate CRISPR-based therapies o Regulators will need to stay up to date with rapid technology advances o Pathways to market will need to be flexible and allow timely patient access to therapies Somatic Cell Therapies Physician Led | Therapeutically Focused22
  23. 23. o Off-target effects/genotoxicity  Improvements in targeting of CRISPR/Cas9 system • Methods to assess genome-wide off-target effects • Need to ensure there is no detectable germ line modification o Efficacy  Single administration may be sufficient but need to consider multiple treatments  Control of CRISPR/Cas editing o Animal models  Significant area for regulators and companies Safety and Efficacy Physician Led | Therapeutically Focused23
  24. 24. Physician Led | Therapeutically Focused o Complex manufacturing processes o Release testing o Shelf-life may be short (hours) o Stability and transportation logistics are important considerations Quality/Manufacturing and Administration 24 o Patients may be treated in specialized centers o Manufacture based at site of administration o Patients to be localized at these sites – international travel for treatment will become more common
  25. 25. o Role of RAC in the US  Recent revisions to streamline the process o Review of gene therapy studies in EU  Additional time for review, may involve expert committees  Use of modified viral vectors requires authorisation for use of GMOs o Regulators gain experience with gene editing therapies (quality, safety, efficacy)  Increased focus on review by ECs/IRBs may raise additional questions and impact the start-up process for CTs Clinical Trial Considerations 25 Physician Led | Therapeutically Focused
  26. 26. Regulatory Pathways to the Market o EU, Japan and US recognize the importance of faster transit through the current regulatory pathways  EU – Adaptive pathways (conditional approvals), PRIME (PRIority MEdicines), accelerated assessment  Japan –PMD Act, expedited approval system for regenerative medicine products  US – fast track, breakthrough therapy, accelerated approval, priority review Timely and Flexible; Faster Access to Developing Therapies Physician Led | Therapeutically Focused26
  27. 27. Cost and Reimbursement o CRISPR-based therapy that provides a one-off lifetime cure will come at a high development cost  Rare diseases will only have a small number of potential patients o Single high-cost therapy treatment could remove a lifetime’s cost of existing treatment and be more effective The Market Challenge Physician Led | Therapeutically Focused27 o Health Technology Assessment bodies (HTAs) may need to consider new approaches to pricing  Strimvelis (GSK) - pay for performance agreement in Italy (AIFA)
  28. 28. Future Direction of Clinical Development o CRISPR/Cas9-based gene editing of cells and tissues will be an exciting and rapid area of development in the coming years  Anticipate that rare genetic diseases, mutation-driven malignancies and cardiovascular indications will be key areas of development  Recognize that the potential is vast and applications may be limitless o Flexible approach to the regulatory pathways is essential  Developers, ethicists and regulators should be discussing collaboratively at an early stage and throughout the development pathway o Long term efficacy and safety will demonstrate the value of this technology and demonstrate its potential to treat complex and challenging diseases Physician Led | Therapeutically Focused28
  29. 29. Physician Led | Therapeutically Focused29 “Genome editing holds great promise to provide a precise set of tools for counteracting genetic diseases. But as Spiderman cautions, ‘With great power, there must come great responsibility’ Moving these methods to clinical applications must proceed judiciously….(and) under appropriate regulatory oversight” Kohn et al, Blood (2016, 127: 2553 - 2560)
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