L4: preclinical studies in drug development Flashcards
what is the legal requirement for preclinical studies in the US
US federal laws require that animal research occur to show the safety and efficacy of new treatments before any human research is allowed to be conducted
define efficacy
ability of a drug to produce a desired effect under ideal circumstances.
what is translational medicine
- A category of biomedical research
- Interdisciplinary area of study that aims to see the efficacy of drugs by testing mechanisms and processes
- focuses on application
Goals
* create diagnostic tests
* Develop drugs
* Clinical impact
* Venture in different fields of science with collaboration
what are the three R’s in animal research
Animal research is crucial but we must consider the three Rs to ensure the research is justified
Replacement
*Computer models
* Invertebrates instead of vertebrates
- can we use yeast, worms or anything else
Reduction
* Fewer animals, experimental design
- required by law to use least amount of animals
Refinement
* Improved experimental design and husbandry
* Minimize pain and distress
- can we limit the pain as much as possible
what is a xenograft mouse models
- when human tumors are injected in the skin of the mouse.
- we use immunocompromised mice that can accept the xenograft
- the tumour grows and drugs can be applied to see if it works – if it works the tumour will shrink
what is ACVR1
ACVR1 is a receptor that is mutated in childhood brain cancer (DIPG)
M4K Medicine for Kids tried to develop a drug against it
describe the normal and mutated ACVR1 signaling pathway
normally:
- ACVR1 is a cell surface receptor which responds to a ligand and tuns on a cascade of downstream events/genes. this is done by signaling that occurs when the ligand binds to the receptor
mutated:
- however, when the ACVR1 receptor is mutated, there is increased signaling for a longer duration and of greater intensity. this creates a mutant ACVR1 protein which causes more downstream events/ leads to the overgrowth of cells (as seen in DIPG)
describe the results / novel compounds that M4K found when testing drugs against DIPG
“They found that two of the chemicals from the new series were particularly good at blocking signals sent out by ACVR1 and killing ACVR1-mutant cells, while having very little effect on healthy brain cells.”
* evidence of selectivity
After the researchers transplanted human brain cancer cells in mice, they found that the potential new drugs:
* stopped ACVR1 activity
* shrunk tumours and
* extended survival by 25 per cent (from 67 to 82 days).
what is ALS (Amyotrophic lateral sclerosis) disease?
- Progressive and fatal disease
- Causes motor neurons to break down
- Drug development involved preclinical models
- there are still active clinical trials
What did drug development look like for ALS (in the preclinical stages)? what is a possible testing system for ALS?
- in 2022 Canada was the first country to approve an experimental drug treatment for ALS
- a system to treat ALS would be to look at the speed and movement of worms
- one sample with normal worms and measure theur duration and speed
- experimental sample of worms that have been genetically engineered to mimic ALS
- the measurements of both sample would show the model of ALS has decreased movement and speed.
- goal would be to apply drugs to the experimental sample and help restore their motor neurons to that of the healthy sample
how is anxiety modeled in mice?
- Mice prefer dark and enclosed spaces (nocturnal species)
- Open and light spaces are less preferred
- if its a non-anxious mouse it will spend more time in light areas
- Some anxiety tests in mice assess social interactions between mice
- There is no single model system
- Use a combination
how can we test anxiety in mice
open field exploration
- box or maze with light and dark sections.
- record the mice and observe how they act and how much time they spend in each region
what are 4 types of studies researchers did to test for covid vaccines
cell cultures
primary cells
animal models
clinical trials
what is the ACE2 receptor in relation to COVID and how does that relate to preclinical work
they found that the ACE2 receptor is the receptor that allows the SARS-CoV2 protein to enter human cells.
to design a drug that will block this entrance they created mice with humanized ACE2 receptors for COVID preclinical studies
How are humanized mice helpful in modeling drug development? what is it an example of
- we can get human stem cells and inject mice with it to make a humanized mice which is an ideal pre-clinical model
- we can then translate the results to humans and discover drugs that work
- this is an example of translational medicine and research
