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Basic Genetics > Treatment & Prevention of Genetic Disease > Flashcards

Treatment & Prevention of Genetic Disease Flashcards

1
Q

What are challenges of treating a single-gene disorder?

A
  • Gene not always known/may have multiple genes causing disorder
  • Pathophysiology may not be known (do not know what the gene specifically does, e.g., Huntington’s Disease- do not know how neuron is affected)
  • Irreversible damage may be done by the time of birth/diagnosis
  • If severe mutation, may be difficult to increase expression/function of gene product
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2
Q

What are the potential levels of intervention?

A
  1. Mutant gene (transplantation, gene therapy, expression modulation)
  2. Mutant mRNA (ribozyme gene transfer to degrade mutant)
  3. Mutant protein (protein replacement, enhancement of function)
  4. Metabolic/biochemical dysfunction (dietary/pharmacological compensation)
  5. Clinical phenotype (medical/surgical intervention)
  6. The family (genetic counseling, carrier screening, presymptomatic diagnosis)
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3
Q

What are the types of metabolic manupulations to treat genetic diseases?

A
  1. Avoidance
  2. Dietary restriction
  3. Replacement
  4. Diversion
  5. Inhibition
  6. Depletion
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4
Q

What are examples of avoidance as a metabolic intervention?

A
  • Avoid antimalarial drugs for G6PD deficiency
  • Avoid barbiturates for acute intermittent porphyria
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5
Q

What are examples of dietary restriction as a metabolic intervention?

A
  • Restrict phenylalanine for PKU
  • Restrict galatose for galactosemia
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6
Q

What are examples of replacement as a metabolic intervention?

A
  • Thyroxine supplements for congenital hypothyroidism
  • Biotin supplements for biotinidase deficiency
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7
Q

What are examples of diversion as a metabolic intervention?

A
  • Sodium benzoate for urea cycle disorders (NH3 buildup fatal; convert NH3 via glycine to hippurate, which is readily excreted)
  • Oral resins for familial hypercholesterolemia heterozygotes (cholestyramine binds bile acids in the gut and causes their excretion instead of reabsorption; cholesterol shunted to make more bile acids)
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8
Q

What are examples of inhibition as a metabolic intervention?

A
  • Statins (Lovastatin, Lipitor) to treat familial hypercholesterolemia heterozygotes (HMG-CoA inhibitors prevent cholesterol synthesis)
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9
Q

What are examples of depletion as a metabolic intervention?

A
  • LDL apheresis (direct removal of LDL from plasma) to treat familial hypercholesterolemia homozygotes
  • Phlebotomy to treat hereditary hemochromatosis (limit iron overload)
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10
Q

What are the types of treatments for mutant/misfolded/missing proteins?

A
  • Cofactor administration to increase enzyme activity
  • Protein replacement (extra/intracellular)
  • Pharmacological chaperone therapy
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11
Q

What is an example of cofactor supplementation as a treatment of mutant proteins?

A

For PKU, patient has some mutant apoenzyme activity (phenylalanine hydroxylase; PAH), but use supplementary BH4 cofactor (sapropterin) to maximize PAH action and decrease phenylalanine levels.

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12
Q

What is an example of pharmacological chaperone therapy as a treatment of misfolded proteins?

A

Use of AT2101 (Isofagomine; IFG) helps increase the production of normal glucocerebrosidase in Gaucher’s disease (lysosomal storage disorder).

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13
Q

What is an example of protein replacement as a treatment of mutant proteins?

A

Of extracellular proteins (most applicable):

  • Factor VIII in hemophilia A
  • Alpha1-antitrypsin in alpha1-AT deficiency
  • PEG-adenosine deaminase (PEG-ADA) (modified protein) in ADA deficiency

Of intracellular proteins (enzyme replacement therapy; use in treatment of lysosomal storage disorders; tag with mannose-6-phosphate):

  • Modified glucocerebrosidase in Gaucher disease
  • MPS (I, II, VI)
  • Fabry’s Disease
  • Pompe Disease

Limiting factors: host immune system, frequent infusions, cost, blood-brain barrier

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14
Q

How do geneticists modify gene expression?

A
  1. Pharmacological modulation
  2. Partial modification of somatic genotype
    1. Via transplantation
    2. Via gene transfer into somatic tissues
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15
Q

How is hereditary angiodema treated?

A
  • Modify gene expression
  • Autosomal dominant disease results from mutation in C1 esterase inhibitor
  • Danazol increases expression
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16
Q

How is sickle cell/thalassemia treated?

A
  • Modify gene expression
  • Decrease methylation of HbF by using Butyrate (a cytidine analog) so that CpG islands won’t be methylated
  • Results in an increase in fetal hemoglobin production
  • Note that response is heterogenous
17
Q

What is Spinal Muscular Atrophy (SMA), what is its genetic etiology, and how is it treated?

A
  • A group of autosomal recessive inherited diseases (SMA I, II, III) that cause muscle damage and weakness, which get worse over time and eventually lead to death.
  • Caused by Survival Motor Neuron (SMN) gene mutation on chromosome 5
    • SMN1 = telomeric copy
    • SMN2 = centromeric copy
  • Deletion of exon 7 from SMN1 leads to severely reduced SMN protein levels; SMN2 alone produces insufficient normal FL-SMN transcript/protein (10% vs. 90%; thymine base in exon 7 creates exonic splicing silencer).
  • However, SMN2 copy number modifies the SMA phenotype; more copies, milder disease (e.g., SMA III has 3-4 SMN2 copies) due to greater transcript production.
  • Thus, treated by modifying gene expression
18
Q

How can sodium phenylbutyrate treate spinal muscular atrophy?

A
  • In vitro:
    • Increases FL-SMN2 mRNA
    • Increases FL-SMN protein
  • In vivo:
    • Increased FL-SMND
    • Increased muscle strength
    • Improved motor function
19
Q

How can antisense oligonucleotides (ASOs) treate spinal muscular atrophy?

A
  • ASOs would promote the inclusion of exon 7 in SMN2.
  • Normally, thymine base in SMN2 exon 7 (cytosine in SMN1 exon 7) recruits an exonic splicing silencer (ESS), thus producing transcripts without exon 7.
  • ASOs would either block the ESS or create an exonic splicing enhancer (ESE), thus promoting FL-SMN in SMN2.
20
Q

What are examples of molecularly-based treatments for inherited conditions?

A
  • Aminoglycosides
    • Utilized in nonsense mutations that result in premature stop codons
    • Molecule binds decoding site of rRNA, induces conformational change that reduces rNA discrimination ability
    • Results in read-through of premature stop codons, leading to increased production of normal protein
    • Example: Gentamicin in cystic fibrosis
    • Other diseases with premature stop codons: Duchenne muscular dystrophy
  • Curcumin
    • Prevents CFTR delta508 mutant from getting stuck in RER
21
Q

What is an example of splicing modifications?

A
  • The reading frame rule dictates that non-functional proteins will arise from deletion of exons containing a total number of nucleotides not divisible by 3.
  • In Duchenne’s Muscular Dystrophy (DMD), a deletion of exon 50 in the dystrophin gene disrupts the reading frame, causing translation to stop prematurely, resulting in a truncated/unstable non-functional protein.
  • Use antisense oligonucleotides to mask exon 51, causing it to be spliced out with exon 50, thus restoring the reading froame and producing a functional (albeit truncated) dystrophin protein.
  • Not a cure, but still has some effect; similar to Becker’s Muscular Dystrophy (BMD).
22
Q

What are examples of transplantation as a modification of the somatic genome?

A
  • Liver transplant for inborn errors of metabolism.
  • Bone marrow transplant for hemoglobinopathies, immunodeficiencies and storage disorders.
  • Cord blood (human umbilical cord) has stem cells and is considered more sterile.
23
Q

What is congenital adrenal hyperplasia and how is it treated prenatally?

A
  • 21-hydroxylase deficiency leads to decreased cortisol and aldosterone.
  • Buildup of precursors shunts them to the testosterone/estradiol pathway.
  • Leads to virilized female fetuses (ambiguous genitalia) and shock due to hyperkalemia and hyponatremia.
  • Treatment: Give cortisol to pregnant mother: induces negative feedback and stops excess testosterone production.

Basic Genetics (14 decks)

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