copy pasta
https://www.dropbox.com/s/7qnxwu14udk5w0k/Long-Term-Follow-Up-After-Admin-Human-GT-Products_Jan_2020.pdf?dl=0
Potential Risks of Delayed Adverse Events Following Exposure to
Human
Gene
Therapy
Products
C
hara
cteristics unique to
human GT
product
s that may be associated with delayed
adverse events
include
:
1.
The integration activity of the
GT pro
duct
:
The biological activity of
retroviral vectors
4
(
e.g.,
vectors
derived from
gamma
retrovirus, lentivirus,
foam
y virus etc.
) and
transposon
elements
is imparted
by an integration
event in the genome.
In general, such integration is not directed to
spe
cific sites in the
human
genome,
and this
raises the potential for
disruption of critical host
(human)
genes at the site of integration, or
activation of proto
-
oncogenes near the integration site(s) and, thereby, the
risk for malignancies.
2
“
Testing of Retroviral Vector
-
Based
Human
Gene Therapy Products for Replication Competent
Retrovirus during
Product Manufactur
e and Patient Follow
-
up
; Guidance for Industry”
is available at this website:
https://www.fda.gov/media/113790/download
.
3
This guidance does not apply to vaccin
es for infectious disease indication
s, bacteriophage
products
, live
biotherapeutic products, fecal microbiota
for
transplant
ation
(FMT)
products and allergenic products.
4
See section VIII. Definitions: Vector
.
Contains Nonbinding Recommendations
3
2.
Genome edit
ing activity
:
Genome editing
-
based
GT
products impart their
biological activity through site
-
specific changes in the
human
genome
,
but
may also have off
-
target effects on the genome
(Ref
.
2
)
.
Similar to
integrating vectors,
genome
editing
may
produce
und
esirable changes in
the genome
(
whether
ex vivo
or
in vivo
)
,
with the risk of malignancies,
impairment of gene function
,
etc.
3.
P
rolonged e
xpression: A GT product where the transgene (therapeutic
gene) encodes growth factors
,
such as vascular endothelia
l growth factor
(VEGF) or prot
eins associated with cell division such as p53, may raise
the potential for
unregulated cell grow
th and malignancies due to
prolonged exposure to the therapeutic protein.
Similarly, transgenes
encoding immune recognition fact
ors
may
introduce the risk for
autoimmune
-
like reaction
s
(
to self
-
antigens
) upon prolonged exposure.
For GT products that carry transcriptional regulatory elements
(e.g.
,
mi
cro
RNA
)
or immune
-
modulatory proteins
(
e.g.
,
c
ytokines
)
there is also
the risk of
unknown
pleotropic effects
,
including altered expression of
host
(human)
genes that
could result in unpredictable and undesirable
outcomes
.
4.
Latency:
When the GT
product
has the potential for latency,
such as a
herpesvirus
, there is the
potential for
reactiva
tion from latency
and the risk
of delayed adverse events related to a symptomatic infection
.
5.
Establishment of persistent infections:
GT products that are
replication
competent viruses and bacteria
,
such as listeria
-
based bacterial vectors,
ha
ve the p
otential to establish persistent infections in
immunocompromised patients leading to the risk of developing a delayed
but serious infection