Ch. 13 Genetic Disease Treatment Review

Flashcards about genetic disease treatments, covering limitations, manipulation of metabolism, molecular treatments, gene therapy, and associated risks.

What are some limitations in treating genetic diseases?

• Gene not identified/pathogenesis not understood

• pre-diagnostic fetal damage

• severe phenotypes

• mutant protein interference

Name 6 types of metabolism manipulation used in genetic disease treatment.

1. Substrate reduction - dietary or exposure restriction (PKU)

2. replacement therapy - provide essential metabolites, cofactors, hormones, etc (congenital hypothyroidism - supplement with thyroxine)

3. diversion therapy - enhanced use of alternative metabolic pathways (familial hypercholesterolemia heterozygotes)

4. Enzyme inhibition

5. Receptor Antagonism therapy (Marfan Syndrome - angiotensin II inhibotors)

6. Depletion therapy (Hemochromatosis - phlebotomy to reduce iron concentration in bloodstream)

What should be considered about long-term treatments?

Example: PKU learning and behavioral disturbances later in life

Treatment may be just to prolong life

• may lead to unforseen consequences of the disease, and cause more disease manifestations to form

  • Example: Galactosemia, Retinoblastoma, Hemophilia

How does enzyme inhibition work in treating genetic diseases?

Using drugs to inhibit specific enzymes in a metabolic pathway.

• Ex: familial hypercholesterolemia heterozygotes with statins to inhiit HMG CoA reductase - rate limiting step in cholesterol synthesis

  • lowers hepatic cholesterol and liver responds by synthesizing more LDL receptors

Name a diseases that has been addressed using receptor antagonism therapy.

Antagonize one of the critical steps in the pathway that has been inappropriately activated

Marfan syndrome (Angiotensin II inhibitors reduce TGF-β signaling by reducing transcription of receptor subunits = reduce signal reduces _____

What is depletion therapy?

Reducing the concentration of a substance in the bloodstream.

• Ex: Hemochromatosis-phlebotomy to reduce iron concentration in the bloodstream

What are some molecular treatments targeting the affected gene?

Modulation of gene expression, transplantation (stem cell or organ), gene therapy

Describe strategies small molecule therapy

Vitamins, non-peptide hormones, and most drugs to correct folding of mutant membrane proteins or increase function of enzymes

• Allows SKIPPING over nonsense codons

• can correct folding of mutant membrane proteins: pharmacological chaperones to assist in proper protein functioning

  • ex: deletion in Cystic fibrosis - small molecules can use chaperone to stabilize it

• Increase function of correctly trafficked mutant membrane proteins potentiators - enhance function of mutant CFTR proteins that are correctly positioned

• Can enhance function of mutant enzymes

Describe Protein Augmentation

• Treatment level at the protein

• common when involved with protein function in the plasma or ECF

• ECF protein replacement: extracellular administration of an intracellular enzyme

  • Ex: Adenosine Deaminase (ADA) deficiency can be replaced (put into cell?)

• *Enzyme Replacement therapy: ex: hemophilia (clotting factor infusions)

Give an example of a protein augmentation therapy.

Enzyme replacement therapy for Adenosine Deaminase (ADA) Deficiency or Gaucher disease

*Explain how increasing gene expression can be used as a treatment.

1. Increasing gene expression from the wild-type or mutant locus (if the mutant protein has residual function). Ex: hereditary angioedema

2. Increasing gene expression from a locus not affected by the disease

   1. Ex: sickle cell and B-thalassemia - has drugs that induce DNA hypomethyalation reducing gene expression of the gamma-globin gene and increasing Hb F

3. Reduce the expression of a dominant mutant gene product (small interfering RNAs (siRNA)

4. Induction of exon skipping - intervention to exclude an exon from a pre-mRNA that encodes a reading dram distrupting mutation

5. Gene editing - introducing site specific genomic sequence changes into DNA of intact orgos (Crispr-Cas9)

How do small interfering RNAs (siRNAs) work in gene therapy?

siRNAs bind to target RNA and initiate cleavage to destroy it reducing expression of a dominant mutant gene product.

What is exon skipping and how is it achieved?

Excluding an exon from pre-mRNA that encodes a reading frame-disrupting mutation using synthetic antisense oligonucleotides (ASO).

ex: Muscular dystrophy is skipping exon 51 and would restore dystrophin reading frame in 13% of DMD

T/F: Transplanted cells retain the genotype of their donor - gene transfer therapy

true

• causes issues, why

What are the indications for transplant in gene disease?

• To introduce wild-type copies of the gene

• To compensate for an organ damaged by genetic disease (more common)

What are two types of transplantations?

Stem cell transplantation and organ transplantation

What are the two defining properties of stem cells?

1. Ability to proliferate into differentiated cell types of a tissue in vivo

2. ability to self-renew (form another stem cell)

Chronic liver disease with CF and alpha1AT is treated with a transplant. What are the problems?

• morality after transplant is high

  • risk of infection during immunosuppression

  • graft vs host disease

What are some advantages of using HSC from placental cord blood?

Recipients tolerate histoincompatibilities better, widely available, reduced risk of graft-versus-host disease

What is a potential solution to organ shortages and immunological rejection in transplantations?

Induced Pluripotent Stem Cells (iPSCs) derived from the patient's own genome.

List some essentials for a gene therapy approach to occur

• Identity of the affected gene

• functional copy of the gene

• appropriate vector to deliver gene - a way to get new gene into designated cell (commonly use viruses)

• knowledge of the pathophysiological mechanism

• favorable risk-benefit ratio

• gene expression regulation

• an appropriate target cell

What is the goal of gene therapy?

Transfer theraputic gene early enough to prevent the pathogenic events that damage cells

What are the “ideal” target cells for gene therapy?

Stem cells or progenitor cells from the patient - the cells have major replication potential

why?

*Most successful is bone marrowbecause it can yield a large number of differentiated blood cells.

Which form of treatment is the most common use in treatment for loss of function mutations?

Gene therapy

Explain how viral vectors work with gene therapy

1. cells are removed from the patient

2. in the lab, the virus is altered so it can’t reproduce

3. Gene is inserted

4. Altered virus is mixed with cells from pt

5. cells from pt are genetically altered

List some risks associated with gene therapy.

Adverse response to the gene delivery vector - we don’t always know where the gene is going

• could cause interstional mutagenesis causing malignancy

  • proto-oncogene activation to become oncogene (cancer causing) and the gene will proliferate

Insertional inactivation of an essential gene - most problematice if occurs in germline - why?