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41차 유럽기형학회 보고
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Korean Motherisk
한정열 MD,PhD
Education course : Testing stratiges for BioPharmaceuticals
E-1 : Introduction into BioPharmaceuticals and DART
M. Beekhuizen, Netherland
8. Sept
Aim : Overview of stepwise approach to follow on preclin-ical DART testing for biopharmaceuticals
Definition biopharmaceuticals Biotechnology-derived pharmaceuticals
A scientific-based case-by-case approach is considered the most appropriate for nonclinical safety assessment of biopharmaceuticals.
There is not one standard approach applicable per biopharmaceutical subclass
The stepwise approach is similar for general toxicity as for DART, however DART specifics need to be considered
Conclusions :
8. Sept
Why test vaccines for developmental toxicity?
– possible specific risks to reproduction
8. Sept
Goal : To enhance the ability of course participants to approach NHP DART study design and implementation in an effective, case-by-case manner.
9. Sept. ETS presidents Award Lecture: A Ornoy, Israel
Diabetic embryopathy: from clinical to molecular studies in experimental animals and man – some his-torical perspectives
Before discovery of insulin : 1921 Severe fertility problem, Sp. Abortions, fetal death
Slight neurobehavioral development problems( mainly inat-tention, slight gross and fine motor delay) : PGDM, GDM
hyperglycemia, embryonic malnutrition, oxidative stress
maternal diabetes induced change in embryonic gene ex-pression (heart, CNS, and gene related to oxidative stress and hy-poxia)
Diabetic embryopathy and fettopathy etiologies : embryonic metabolic/nutritional/endocrine disturbance/hypoxia/epige-netic changes
Symphosium 1:
Developmental toxicity of nanoparticles-effects, issues and di-rections for future research
S1-0 : Introduction: Light and Ultrastructural Morphology and Permeability of placenta barrier
nanoparticles : one of most challenge research target in toxicol-
ogy
nanoparticles : 1-100nm dimension
accumulate cellular organelles , damage to cellular cytoplasm
capacity to placental barrier , pass to embryonic/fetal tissue and
organ
<100nm – go to cell by passing cellular membrane
<40nm – go to cellular nuclei
<35nm – go to brain by passing BBB
- so, brain is target
Placenta barrier : very strong like BBB
( coherent endothelium, basement membrane, surrounded by
syncythiotrophoblast cells with tight epitheliag junctions)
9. Sept.
S1-1: Prenatal exposure to nanoparticles effects and potential mechanisms
Differ compared to that of bulk materials Interfere with intrauterine development Effects of gene expression, function of CNS system, immune system, and male reproductive system.
Generate oxidative stress and inflammation Interfere placental vasculizationLung inflammation- mediators cross placenta – interfere fetal development
For study - particle size, chemistry, surface area, route of exposure
9. Sept.
S1-2: Nanoparticles and early human placenta – sophisti-cated Matter meets Sophistigated Tissues
Pharmaceutical industry Concern due to size Identification of “nano-thalidomid before marketing
S1-3: Knocking at the door of the unborn child: issues in developmental and placental nanotoxicology and di-rection for the future research a variety applications Concern - 18nm particle were transferred to embryos 24 hr after IV Nanotoxicology 3 principles 1. nanomaterial uptake 2. surface effects 3. material properties Basis for understanding of specific reaction & interactions between nanoparticles and transplacental transfer
9. Sept.
9. Sept. ETS/TS Exchange lecture : Myth or Merit : The use of a second species in Develop-mental Toxicity Testing
ETS subtitles : More safe drugs by less in vivo testing?
Issue & limitation are highlighted
Small molecule pharmaceuticals: tested in rats and rabbits
for
toxicity of embryo in 1960 following thalidomide tragedy
Two species has sufficient power
False positive : discontinuation valuable drugs & limit full po-
tential
use
So, Q?
New paradigm need
Evidence based holistic hazard identification & risk assess-
ment
together with less traditional animal testing for more safe
drug
9. Sept.
TS subtitle : Screening environmental agents
1960 thalidomide disaster : rodent & non-rodent toxicity
testing
Reliable information on developmental hazard and dose re-
sponse
Not yet norm: genomic metabolomics/proteomic profilling/in
vitro
predictive models(eq. whole embryo culture, embryonic
stem
cells)/testing non-mammalian species (eq. Zebra fish)
More common approach : laboratory animal test ( rat and
rabbit)
Q of Rat vs Rabbit – neither species is predictive of risk to
human
More thoughtful, directed, chemical specific approach is
needed
9. Sept.
Symphosium 2:
Cross industry data survey of the value of rabbit developmen-tal toxicity data in the risk of assessment for pharmaceutics
--- used as the 2nd species of developmental toxicity
S2-1: ICH origins of the “2nd species” project UK
S2-2: Scientific background
S2-3: Emerging data
S2-4: Industry perspective
S2-5: Regulatory perspective
10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disruptors in wildlife
and
humans –scientific criteria for regulatory decision making in the
EU
-- risk factor for human fertility
S3-2: Exposure to ED in humans: assessing biomarkers of effect
S3-3: The screening of everyday life chemicals for endocrine activity
–
data interpretation and impact
S33-4: Species difference in susceptibility to inhibition of fetal testis
steroidogenesis
10. Sept.
Symposium 3 : Reproductive toxicity –endocrine mechanisms
S3-1: Identification and assessment of endocrine disruptors in wildlife
and
humans –scientific criteria for regulatory decision making in the
EU
S3-2: Exposure to ED in humans: assessing biomarkers of effect
S3-3: The screening of everyday life chemicals for endocrine activity
–
data interpretation and impact
S33-4: Species differece in susceptibility to inhibition of fetal testis
steroidogenesis
10. Sept.
Symposium 4 : Reproductive toxicity- epigenetics
S4-1: System and genome wide adaptation of the epigenome to gestational stress
Hypothesis that system wide DNA methylation changes early
in life in response to social stress occur in both animal and hu-
mans.
“Adaptive genomic” mechanism that prepares life-long
genome
programming to the anticipated life long environment based on
stress
signal received during gestation and early life.
Glucocorticoids: act as “integrators” that translate the social
stress
signals during gestation to genome wide methylation changes
across
multiple systems
10. Sept.
S4-2: Sex-specific transcriptional and epigenetic signatures
associated
with peripheral leptin-resitance
Non-communicable disease(NCDs) : 60% of worldwide deaths Next decade : 17% increase Fundamental misconception : Obesity, NCDs Paradime shift : DOHaD Early nutritional events: influence on later life health through epigenetic process Evidence : maternal obesity and Type 2 diabetes at conception, gestation & lactation promote development of obesity and diabetes of offspring in their adulthood 2 generation mice model : Obese and diabetic with CD during periconceptional/ gestational/lactation period led to sex specific shift form susceptibility to resistance to HFD in female offspring only Sex specific liver disease risk : unsuspected role of Lepr gene
in peripheral sex specific leptin resistance
10. Sept.
S4-3: Diabetic embryopathy : the role of epigenetics Epigenetic information : silencing or activation of genes heritable change in gene expression without changes in DNA sequence Hyperglycemia affects epigenome
Oxidative stress/ apoptosis/hypoxia 에 반응하는 유전자의 epigenetic changes
eq. NRF2-mediated oxidative stress response pathway
Endoplasmic reticulum pathway
Maternal diabetes seems to cause long lasting changes in
the embryonic epigenome by different mechanism.
These changes might be responsible to the diabetes induced
teratogenicity
11. Sept.
Symposium 5 : Regulatory acceptance of alternative/in vitro methods
S5-1: Bottlenecks for the implementation of alternative
methods in
regulatory reproductive and developmental toxicity
testing
: Alternative method in regulatory method not easily accepted
whole embryo culture/zebrafish embryotoxicity/ embryonic
stem cell
S5-2: Validation- an intrinsic part of safety assessment sci-ence
: reliability / relevance
S5-3: Science for or science based regulation: is there a missing link? : Yes
Abstract
Characterization of phosphatidylethanol blood concentra-tions for screening alcohol consumption in early pregnancy
Termination rate in Korean pregnant women who received counseling in a teratology information service in the first
trimester of pregnancy due to exposure
Abstract
Effects of ß-carotene in cultured mouse embryos exposed to nicotine Cunmei Lin, Sang-Yoon Nam Chung-buk natioanal University
Evaluation of human embryonic stem cell to screen devel-opmental Toxicants EM Jung Chung-buk natioanal University
Diet and Autism spectrum disorders(ASD)
Yasmin H. Departmenet of Human nutrition, The University of Alabama, USA
No clear etiology or cure for ASDNutritional factor may play a role in Tx of ASD restriction of food allergens, probiotics, ketogenic diet, yeast free diet, gluten and casein free diet
Methods: literature review ; 3 types of diet casein free –gluten free diet(GFCF), ketogenic and antioxidant diet
Results: GFCF diet show the most promise of efficacy however, inconvenience and limitation
Conclusion : GFCF requires further safety studies.
Synergistic use of ex vivo and in vitro placenta model systems to study various aspects of
nanomaterial behavior at the placental barrier Tina BT.
NP(fluorescent polystyrene) is increasing production. Major potential for the development of novel theara-peutic strategies to treat specifically either the mother or the developing fetus. So issue is for trans-placental transfer or placental effects
NP 50, 80, 240, 500nm Ex vivo human placental perfusion system 2 novel placenta system(for mechanistic study): a perfused transwell co-culture system a 3D placental microsphere model
240nm : taken by placenta cross placental barrier without affecting the viability of placental explant Established systems for mechanistic study
Biopharmaceuticals & DART
Nanoparticles
2nd species of developmental toxicity
Endocrine disruptor
Epigenetics
Regulatory acceptance of alternative/in vitro methods
Summary
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