Autophagy Process
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Questions and Answers

What is the typical size range of antisense oligonucleotides (ASOs)?

  • 10 to 20 nucleotides
  • 8 to 50 nucleotides (correct)
  • 5 to 10 nucleotides
  • 20 to 100 nucleotides
  • What is the main mechanism of RNAse H-dependent ASOs?

  • mRNA degradation (correct)
  • Modulation of the splicing process
  • Inhibition of translation
  • Blocking of microRNAs
  • What was modified in the first generation of ASOs?

  • The ribose sugar
  • The furanose ring
  • The oxygen atom in the backbone (correct)
  • The phosphate linkages
  • What is the result of the mutations in the DMD gene?

    <p>A prematurely truncated, unstable dystrophin protein</p> Signup and view all the answers

    What is the goal of antisense oligonucleotides-based therapy for DMD?

    <p>To treat DMD</p> Signup and view all the answers

    What type of disease is Duchenne muscular dystrophy?

    <p>X-linked recessive disease</p> Signup and view all the answers

    What is the main characteristic of Duchenne muscular dystrophy?

    <p>Progressive muscular degeneration and weakness</p> Signup and view all the answers

    What is the function of RNAse H?

    <p>To degrade mRNA</p> Signup and view all the answers

    What is the main difference between the first and second generation of ASOs?

    <p>The type of modifications in the ribose sugar</p> Signup and view all the answers

    What is the outcome of the modifications made in the third generation of ASOs?

    <p>Enhanced stability and better pharmacokinetic profiles</p> Signup and view all the answers

    Study Notes

    Gene Therapy Strategies

    • Gene augmentation: adding a new normal protein-coding gene to cells with non-functional gene
      • Can be classified into two categories: gene replacement therapy and gene addition therapy
    • Gene silencing: the use of DNA or gene editing technologies to enhance the function of a healthy person
      • Examples: increased muscle mass, improved oxygen delivery, and accelerated recovery

    Gene Doping

    • The use of DNA or gene editing technologies to enhance the function of a healthy person
      • Banned by the World Anti-Doping Agency (WADA) for non-therapeutic forms of genetic manipulation
    • Examples: introducing genes that promote muscle growth, genes that encode for erythropoietin (EPO), and genes that promote tissue repair and regeneration

    Gene Augmentation

    • Gene replacement therapy: the delivery of a correct copy of the gene to restore the production of a defective or missing protein
      • Example: Spinal Muscular Atrophy (SMA) gene replacement therapy
    • Gene addition therapy: the delivery of a protein-coding gene to improve cellular function and homeostasis
      • Example: autophagy gene addition therapy for neurodegenerative diseases

    Gene Replacement Therapy

    • Spinal Muscular Atrophy (SMA) is a group of genetic disorders characterized by the degeneration of anterior horn cells and subsequent muscle atrophy and weakness
      • Caused by mutations in the SMN1 gene, which produces a functional protein essential for motor neuron development
    • SMA patients have a non-functional SMN1 protein, and the only functional protein is produced by the SMN2 gene
      • The number of copies of the SMN2 gene modifies the severity of the condition
    • Example: Zolgensma, a gene replacement therapy for SMA, delivers a functional copy of the SMN1 gene to motor neuron cells
      • FDA approved therapy with a marketing price of $2.125 million

    Gene Addition Therapy

    • Autophagy is a highly regulated cellular process that facilitates nutrient recycling and degrades damaged organelles and proteins
      • Important in neurodegenerative diseases, where abnormal protein accumulation occurs
    • Mechanisms of autophagy:
      • Microautophagy: direct engulfment of cytosolic material through lysosomal invagination
      • Chaperone-mediated autophagy: selective degradation pathway targeting proteins with recognition motifs
      • Macroautophagy: formation of phagophore, autophagosome, and autolysosome to degrade cellular material
    • Example: Machado-Joseph disease (MJD) or Spinocerebellar Ataxia Type 3 (SCA3), a polyglutamine disease caused by an unstable expansion of a CAG repeat sequence in the ATXN3 gene
      • Upregulation of the autophagy pathway as a therapeutic strategy to clear mutant ataxin-3 and improve neuronal homeostasis

    Gene Silencing

    • Methods of gene silencing:
      • Antisense oligonucleotides (ASOs)
      • RNA interference (RNAi)
    • Antisense oligonucleotides (ASOs):
      • Synthetic, unmodified or chemically modified, single-stranded nucleic acid molecules that hybridize to their target mRNA
      • Exert action through RNAse H-dependent or RNAse H-independent mechanisms
    • Example: Duchenne muscular dystrophy (DMD), an X-linked recessive disease caused by mutations in the DMD gene, resulting in a prematurely truncated dystrophin protein
      • Antisense oligonucleotides-based therapy for DMD

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    Description

    This quiz covers the mechanism of autophagy, including the formation of autolysosomes and the role of phagophore and autophagosome in degrading cytoplasmic material.

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