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