Lecture 11: Drug Discovery III

Question 1

Drugs of the future

Answer 1

-RNA interference
-mRNA medicine
-Monoclonal antibody and antibody-drug conjugate (ADC)
-gene therapy
-CRISPR
-Stem cell (iPSC) therapy

Question 2

RNA interference (ASO)

Answer 2

-antisense oligonucleotides (ASO)
-reduce mRNA level = less protein made
-Onpattro: RNAi therapeutic for ppl w rare/deadly genetic disorder called hereditary transthyretin-mediated amyloidosis

Question 3

mRNA medicine

Answer 3

-introduce exogenous mRNA into body
=cells can make proteins based on introduced mRNA
-COVID19 vax
-not only vax, will be used for cancer etc

Question 4

mAb and Ab-drug conjugate (ADC)

Answer 4

-type of y shape protein
-affect protein
-binds to target to block function
-or recognize group of cells that express target protein
-PD1 and PDL1 drugs

Question 5

Gene Therapy

Answer 5

-virus as vehicle to deliver gene
-FDA-approved adeno-associated virus (AAV) drug Luxturna to treat rare form of inherited vision loss

Question 6

CRISPR

Answer 6

-trial of CRISPR-Cas9 therapy (CTX001) for blood disorder B-thalassemia has been launched
-targets DNA

Question 7

Stem cell (iPSCs) therapy

Answer 7

-most still being developed
-potential to generate any cell types in the body to replace damaged tissue

Question 8

Multi-level targeting of next gen meds

Answer 8

-DNA: CRISPR
-RNA: mRNA and ASO
-Protein: mAbs
-Transgene: gene therapy
-Cell: stem cell tx

Question 9

ASO treatment

Answer 9

-treat missense gain of function mutations
-not using for loss of function

Question 10

Antisense oligonucleotides (ASO) mech

Question 11

mRNA medicine mech

Answer 11

1. generate mRNA seq that codes for virus spike protein (not whole virus)
2. RNA seq coated in lipid for delivery (VAX)
3. once injected, cells read info in the mRNA seq to produce millions of copies of spike protein
4. protein frags spur immune system to produce Abs that can protect the body when real virus enters body

-must make exogenous mRNA stable
-find right coating
-COVID vax

Question 12

Monoclonal Abs mech

Answer 12

-mAb is type of protein that very specifically binds to target
-often blocks function or tags for destruction

Question 13

Antibody-drug conjugate (ADC) mech

Answer 13

-mAb with drug added attaches to allergen
-endocytosis of mAB-allergen into endosome
-cytosolic drugs release in lysosome
= cell death

Question 14

Gene-therapy with adeno-associated virus (AAV) mech

Answer 14

1. Transgene packed into AAV vectors
2. Delivery by one time IV infusion, AAVs carrying transgene to liver
3. AAV vectors deliver to nucleus of liver cells to enable production of therapeutic protein

-ex: zolgensma

Question 15

Zolgensma (AAV)

Answer 15

-SMA is nueromuscular disorder caused by mutation in SMN1 gene
=dec in SMN protein (needed for survival of motor neurons

-Zolgensma is biologic drug consisting of AAV9 capsids that contain SMN1 transgene along w synthetic promoters

-expensive!!!

Question 16

CRISPR/Cas9 editing

Answer 16

-Clustered Regularly Interspaced Short Palindromic Seq
-cell transfected w enzyme complex (guide molecule + healthy DNA copy + DNA-cutting enzyme)
-specially designed guide molecule finds target DNA strand
-enzyme cuts off strand
-replace w healthy copy of DNA

Question 17

Stem Cell Therapy options

Answer 17

-induced Pluripotent Stem Cells (iPSCs) = most promising
-Embryonic stem cells (ESC)
-Neural stem cells (NSC)
-Progenitor cells

Question 18

iPSC mech