1. Genome editing
The regulatory landscape
N Ferry
Department of cell therapy
Hopital Saint Louis, Paris
Eurordis Workshopon genome editing
Paris, Friday 4th November 2016

2. • Classificationof gene editing
• Orphan similarity
Agenda

3. Overview of the present regulation
The definition of ATMPs (Advanced Therapy Medicinal
Products) is laid down in Reg 1394/2007 modifying Dir
2001/83
Four Different types of ATMPs:
1. Gene Therapy medicinal products
2. Cell Therapy medicinal products
3. Tissue engineered products
4. Combined ATMPs

4. Gene therapy medicinal product means a biological medicinal
product which has the following characteristics:
(a)it contains an active substance which containsor consists of
a recombinant nucleic acid used in or administered to human
beings with a view to regulating, repairing, replacing, adding or
deleting a genetic sequence;
(b) its therapeutic, prophylactic or diagnostic effect relates
directly to the recombinant nucleic acid sequence it
contains, or to the product of genetic expression of this
sequence.
Gene therapy medicinal products shall not includevaccines
against infectiousdiseases.
Gene therapy medicinal product

5. Classification of ATMPs
ATMP classification is a procedure performed by the Committee
for Advanced Therapies
• open to all applicants
• scientific recommendationfrom CAT on the regulatory
classification of their ATMP (non binding)
• 60-day procedure (often shorter)
• publication of summary information on classification
• >150 procedures finalised
• list accessible on EMA web site

6. How to classify gene editing?
Prom gene pA
Prom gene pA
1. Modificationof the coding sequence: additionor deletion
Initialgenome
Prom gene pA
2. Modificationof non coding sequence: promoter or polyA
Prom gene pA
3. Modificationof regulatory sequences or splice sites

7. Ex vivo
Gene editing
Therapeutic gene
Therapeutic gene
In vivo
Gene editing
Gene edited cells
Two types of gene editing applications

8. ex vivo gene editing
The product is the modified
cells
in vivo gene editing
The product is a biologic
YES the product is the
modified cells
The product containsor
consists of a recombinant
nucleic acid
YES
The therapeuticeffect
relates directly to the
recombinantnucleic acid
sequence
YES (coding sequences)/
NO (non coding sequences)
Does gene editing meet the requirement of a
gene therapy product?

9. Regulation of globin genes

10. Re-expression of fetal globin after gene editing of the SOX6
regulatory protein
Direct effect of the recombinant nucleotide sequence?

11. ex vivo gene editing
The product is the modified
cells
in vivo gene editing
The product is a biologic YES YES usually
The product containsor
consists of a recombinant
nucleic acid
YES YES or NO
The therapeuticeffect
relates directly to the
recombinantnucleic acid
sequence
YES (coding sequences)/
NO (non coding sequences)
Does gene editing meet the requirement of a
gene therapy product?

12. Recombinant DNA (Wikipedia)
• Recombinant DNA (rDNA) molecules are DNA
molecules formed by laboratory methods of
genetic recombination (such as molecular
cloning) to bring together genetic material
from multiple sources, creating sequences
that would not otherwise be found in the
genome.

13. ZFN and TALEN are proteins acting
directly on the genome

14. Delivery of proteins can be achieved
with virus like particles without DNA

15. ex vivo gene editing
The product is the modified
cells
in vivo gene editing
The product is a biologic YES YES usually
The product containsor
consists of a recombinant
nucleic acid
YES YES or NO
The therapeuticeffect
relates directly to the
recombinantnucleic acid
sequence
YES (coding sequences)/
NO (non coding sequences)
NO if no nucleic acid
Does gene editing meet the requirement of a
gene therapy product?

16. Conclusion (1)
• Gene editing cannot always be classified as
gene therapy medicinal product
• It could also be a biological product which
should comply with different guidelines

17. • Classificationof gene editing
• Orphan similarity
Agenda

18. The present regulation

20. According to the present regulation:
• Two related cell therapy products
• Or two polynucleotide substances when the
differences are in the vector or transfer system
Should be considered as orphan similar

21. Gene therapy results in addition of a therapeutic sequence:

22. Gene edited cells vs genetically transduced cells
CD 34+ cell
transduced with a
retroviral vector
expressing ADA
protein
CD 34+ cell
transduced with
a lentivirall
vector expressing
ADA protein
CD 34+ cell with
ADA gene edited
expressing ADA
protein
The therapeutic nucleic acid sequence is the same

23. Conclusion (2)
Orphan similarity regulation should be modified
to take gene editing in consideration
EMA issued a Consultationdocument (until
November 4, 2016):
CONCEPT OF ‘SIMILAR MEDICINAL PRODUCT’ IN THE
CONTEXT OF THE ORPHAN LEGISLATION: ADAPTATION
TO TECHNICAL PROGRESS

24. Conclusion (2)
An active substance is not considered similar in cases of:
(aa) ATMPs for which principal molecular structural features cannot be fully
defined and the similarity between two active substances needs to be
assessedon the basis of biological and functional characteristics.
(bb) Two gene therapy medicinal products when there are differences in the
therapeutic sequence, viral vector, transfer system or regulatory sequences
that significantly affect the biological characteristics and/or activity relevant
for the intended therapeutic effect of the product. Minor differences in the
therapeutic sequence without a significant impact on the intended
therapeutic effect are not sufficient to support the claim that two gene
therapy medicinal products are non-similar.
(cc) Genetically modified cells. The considerations under (aa) and (bb) apply.

25. Thank you