Pgx Drug Discovery III

Question 1

Antisense Oligonucleotides (ASO)

Answer 1

• blocking the mRNA directly to REDUCE the protein being made from that particular DNA
• ASO binds to the matured mRNA to form a double strand stopping protein from being produced
• we desire allele specificity to allow for drug to bind to only mutant allele and not the normal allele –> most are heterozygous

Question 2

Innovator in RNA Therapeutics

Answer 2

Ionis

Question 3

mRNA Medicine

Answer 3

1. Scientists generated an mRNA sequence that codes for the virus spike protein
   - mRNA sequence does not contain the whole genome, only the spike protein
2. The RNA sequence, a blueprint for making the spike, is swathed in a lipid coating for delivery
   - evidence has shown this can cause the responses following injection (fever, chills, rash)
3. Once it arrives, cells read the information in the mRNA sequence to produce millions of copies of the spike protein on cell surface
4. The protein fragments spur the immune response to produce antibodies that can protect when a real virus enters the body

Question 4

Critical Aspects of mRNA medicine

Answer 4

Making the exogenous mRNA stable is key

Finding the right “coating” to deliver them into the cell is critical

Question 5

Monoclonal Antibodies & ADC

Answer 5

???

Question 6

Gene Therapy with Adeno-associated virus (AAV)

Answer 6

Two component:
- content or gene
- delivery

Transgene is packaged into the AAV vectors and injected into the body by a one time IV infusion

AAV carry transgene to the target within the liver

Question 7

SMA

Answer 7

• neuromuscular disorder by a mutation in the SMN1 gene which leads to a decrease in SMN protein

Zolgensma is a biologic drug consisting of AAV9 capsids that contain the SMN1 transgene along with other synthetic promoters

Question 8

How long does AAV drug last?

Answer 8

• we do not know exactly but have saw drugs wearing off in 3-5 years

Question 9

Issue Associated with Multiple AAV Injections

Answer 9

Injected once: AAV has its effects but antibodies will be produced for it

Injected the 2nd time: AAV is destroyed by the immune response before eliciting its response

Question 10

AAV DRUGS ACCUMULATE WITHIN THE LIVER

Answer 10

AAV DRUGS ACCUMULATE WITHIN THE LIVER

Question 11

CRISPR/Cas9 –> MAGIC SCISSORS

Answer 11

Mechanism: DNA editing

Process:
- a cell is infected with an enzyme complex containing guide molecule, healthy DNA copy, and DNA cutting enzyme
- the guide molecule finds the target DNA strand
- DNA cutting enzyme cuts off the target DNA strand
- the defective DNA strand is replaced with health DNA copy

ONLY DONE IN VITRO

Question 12

Stem Cell Therapy

Answer 12

NO FDA APPROVED THERAPY

most promising is induced pluripotent stem cells (iPSC) –> must use autologous stem cell within your own body