Treatment of Genetic Disease

Question 1

ATD

Answer 1

Conceptually the disease is a deficiency.
Can use protein replacement therapy (recombinant).

Most effective therapy is avoidance of smoking.

Question 2

Fabry Disease

Answer 2

X-linked deficiency is alpha-galactosidase
Accumulation of glycosphingolipids causes widespread microvascular damage. Get:
-Neuron damage
-Sweat gland damage
-Renal damage
-Vascular damage: risk of heart attacks and stroke
-Cardiovascular: hypertrophy

Recombinant enzyme therapy.

Question 3

Modulation of Gene expression

Answer 3

Can be used in sickle cell patients (butyrate drug). Increases the expression of HbF.. get reduced polymerization of HbS.

Question 4

Transplants

Answer 4

Great for a genetic mutation that is causing problems in one organ system.
Hepatic and bone marrow transplant.

Question 5

What is gene therapy?

Answer 5

You are introducing DNA or RNA for treatment.

Goal is to get only somatic treatment so you are NOT altering someone’s germ-line.

Question 6

How do you do gene therapy?

Answer 6

So this can happen ex vivo (outside the body into tissues that are then given to the patient) or in vivo (DNA/RNA constructs injected).

Question 7

What needs to happen for gene therapy?

Answer 7

Good targeting: transgene delivered/targeted to the right cells. You don’t want this transgene in your normal tissues.
Expression: you need to get adequate duration and level of expression (may not need normal physiological levels)
Toxicity: duh.

Question 8

Retroviral delivery

Answer 8

Use RNA virus.
It integrates into cell genome, minimal immune problems.
But can only insert gene of certain size, and can only infect dividing cells (risk of getting into germ-line)

Pretty efficient. Pretty durable, because they are passed onto daughter cells.

Question 9

Adenoviral delivery

Answer 9

DNA virus.
You can infect many cell types, and insert a bigger gene than retroviral delivery. Stable and easy to get high titers and it DOES NOT INTEGRATE into cell genome.

Expression however can be short-lived (not passed onto daughters), can get malignancy, IMMUNE reactions.

You can infect non-dividing cells.

Question 10

Non-viral delivery

Answer 10

Could use liposomes, direct DNA.

Can insert large things (whole mini-chromosome).

Minimal immune response. Safe because it does not integrate. But it is often degraded by cellular mechanisms.

But it has low efficiency, and a short response. Not passed onto daughters.

Question 11

Gene therapy now

Answer 11

pretty much for gene replacement or deficiency. The gene is missing or non-functional.
Harder to control dominant negative or gain of fx. mutations.