Hunter Syndrome and Gene Therapy
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Questions and Answers

What is the purpose of Zinc Finger proteins 1 and 2 in gene therapy for Hunter Syndrome?

Transcribed and translated in the liver cell to introduce a double-stranded break in the albumin gene

What is the role of homology direct repair (HDR) in gene therapy for Hunter Syndrome?

  • Making the I2S enzyme in liver cells
  • Repairing double-stranded breaks using complementary regions (correct)
  • Inserting the IDS gene into the liver cell
  • Increasing albumin production in hepatocytes

    • What is the enzyme that is made in liver cells from the IDS gene added during gene therapy for Hunter Syndrome that facilitates the breakdown of GAGs?

    I2S

    Drug metabolism primarily makes water-soluble drugs more lipid-soluble for excretion.

    <p>False</p> Signup and view all the answers

    Match the drug excretion route with its description:

    <p>Lungs = Can remove gases and volatile liquids Sweat, saliva, mucous, tears &amp; milk = Excretes small amounts of drugs, some of which may be dangerous to infants Kidneys = Filtration, secretion, &amp; reabsorption for drug elimination</p> Signup and view all the answers

    What genetic predisposition is associated with Toll-like receptor (TLR) gene variants in systemic lupus erythematosus (SLE)?

    <p>TLR7 gain-of-function mutation variant</p> Signup and view all the answers

    Which protein is an adaptor downstream of TLR7, dependent on MyD88 signaling in SLE?

    <p>MyD88</p> Signup and view all the answers

    B cell activation and inflammation are linked to TLR7 gain-of-function mutation in SLE.

    <p>True</p> Signup and view all the answers

    TLR7 is a sensor of viral RNA and binds to __________ in systemic lupus erythematosus.

    <p>guanosine</p> Signup and view all the answers

    Match the following autoimmune disease treatments with their respective targets:

    <p>Rituximab, Ocrelizumab, Ofatumumab = B cell surface markers (CD20) Belimumab = B cell survival factor (BAFF)</p> Signup and view all the answers

    What is the pathophysiology of Hunter Syndrome?

    <p>Accumulation of partially degraded GAGs, resulting in thickening of tissue and compromising cell and organ function over time.</p> Signup and view all the answers

    How can adeno-associated virus (AAV) vectors be used to deliver gene therapy treatments?

    <p>AAV vectors can deliver genetic material in the form of episomes to target cells, providing stable transgene expression for years.</p> Signup and view all the answers

    What is the primary purpose of gene therapy using AAV vectors?

    <p>Introducing corrective genes into target cells</p> Signup and view all the answers

    Enzyme replacement therapy (ERT) for Hunter syndrome can effectively treat neurological symptoms.

    <p>False</p> Signup and view all the answers

    What is the enzyme used in enzyme replacement therapy for Hunter syndrome? Elaprase contains __________.

    <p>idursulfase</p> Signup and view all the answers

    Match the following gene editing techniques with their descriptions:

    <p>Zinc finger nucleases (ZFNs) = Protein modules binding 3 nucleotides and activating Fok1 nuclease Transcription activator-like effector nucleases (TALENs) = Protein modules binding individual nucleotides, activating Fok1 nuclease RNA-guided engineered nucleases (CRISPR/Cas9) = RNA molecule designed to target Cas9 nuclease to specific sites</p> Signup and view all the answers

    What are some examples of abnormal metabolic pathways and their targeting strategies for potential treatment?

    <p>OXPHOS - Metformin, GAPDH - Dimethylfumarate, mTOR - Rapamycin/sirolimus, Glucose transporter - CG-5, Hexokinase/Glycolysis - 2-deoxyglucose (2-DG), Glucose-6-phosphate dehydrogenase - 6-aminonicotinamide (6-AN), ROS - Vitamin K3 or buthionine sulfoximine (BOS)</p> Signup and view all the answers

    Which of the following treatments have been tested in clinical trials for Systemic Lupus Erythematosus (SLE)?

    <p>Atacicept</p> Signup and view all the answers

    Plasma cells derived from autoreactive B cells play a key role in autoimmune diseases.

    <p>True</p> Signup and view all the answers

    Epigenetic and genetic changes in cancer cells can lead to the loss of tumor suppressor genes expression such as ____ and the expression of oncogenes such as mutant EGFR.

    <p>p53</p> Signup and view all the answers

    Match the stages of melanoma classification (0-4) with their relation to the multi-step process of cancer:

    <p>Stage 0 = Initiation Stage 1 = Promotion Stage 2 = Promotion Stage 3 = Progression Stage 4 = Progression</p> Signup and view all the answers

    What is the process by which metabolism of warfarin occurs?

    <p>Metabolism of warfarin occurs through CYP2C9.</p> Signup and view all the answers

    What is pharmacogenomics?

    <p>Pharmacogenomics is the use of genetic information to guide drug therapy.</p> Signup and view all the answers

    What is clearance in drug metabolism?

    <p>Clearance is the volume of plasma cleared of drug per unit time.</p> Signup and view all the answers

    What does plasma half-life represent?

    <p>Plasma half-life (t½) is the time taken for the amount of drug in the plasma to fall by half.</p> Signup and view all the answers

    What is the major determinant of dosing frequency in drugs?

    <p>Plasma half-life (t½) is a major determinant of dosing frequency in drugs.</p> Signup and view all the answers

    Which autoimmune disease is characterized by Lupus malar 'butterfly' rash, arthritis, and CNS inflammation?

    <p>Systemic Lupus Erythematosus (SLE)</p> Signup and view all the answers

    What is the role of immune complexes in causing nephritis in Lupus nephritis?

    <p>Immune complexes can deposit in the kidneys' glomeruli, recruit inflammatory cells, and cause injury to the glomerulus in Lupus nephritis.</p> Signup and view all the answers

    What is the main aetiological factor for skin cancer?

    <p>UV radiation</p> Signup and view all the answers

    What is the role of melanin in protecting against skin cancer?

    <p>Absorb UV light</p> Signup and view all the answers

    A single amino acid change in DNA can significantly impact protein function.

    <p>True</p> Signup and view all the answers

    Telomeres protect the chromosome end from deterioration or fusion with neighboring chromosomes. As cells divide, the telomeres shorten. When telomeres shorten to a critical length, the cell undergoes 'replicative _________.'

    <p>senescence</p> Signup and view all the answers

    Match the following skin cancer types with their corresponding cell types:

    <p>Basal Cell Carcinoma = Basal cells Squamous Cell Carcinoma = Squamous cells Malignant Melanoma = Melanocytes</p> Signup and view all the answers

    What is the mechanism of action of Pertuzumab (Perjeta)?

    <p>Blocks interaction with HER2</p> Signup and view all the answers

    Dendritic cells are found in ______ tissues.

    <p>peripheral</p> Signup and view all the answers

    Infection or Toll-like receptor activation leads to dendritic cell maturation.

    <p>True</p> Signup and view all the answers

    What is required for B cell activation?

    <p>Cross linking of antigen receptors (BCR) and second signals (co-stimulation/cytokines)</p> Signup and view all the answers

    Match the antibody isotype with its corresponding class switching: IgM, IgG, IgA, IgE

    <p>IgM = 10-14 days IgG = Low affinity concentration IgA = Years after vaccination IgE = High affinity concentration</p> Signup and view all the answers

    What is the role of Sildenafil?

    <p>Relaxing blood vessels</p> Signup and view all the answers

    What was done in the mid-1990s to improve the potential of therapeutic monoclonal antibodies?

    <p>Humanisation of the mAb</p> Signup and view all the answers

    Which mechanism of action of therapeutic monoclonal antibodies is not dependent on the specific antigen recognized by the antibody?

    <p>ADCP</p> Signup and view all the answers

    Therapeutic antibodies can only be used as single agents and not as delivery mechanisms for other modes of therapies.

    <p>False</p> Signup and view all the answers

    Discovery of HER2 amplified in breast cancer occurred in ______.

    <p>1987</p> Signup and view all the answers

    Match the HER2 receptor components with their functions:

    <p>Extracellular domain = Binds ligand Transmembrane domain = Anchors receptor in cell membrane Intracellular/kinase domain = Contains tyrosine kinase domain</p> Signup and view all the answers

    What is another name for Trastuzumab?

    <p>Herceptin</p> Signup and view all the answers

    What is a mechanism of Herceptin in inhibiting cell effects?

    <p>All of the above</p> Signup and view all the answers

    Resistance to Herceptin can be overcome only through combination treatments.

    <p>False</p> Signup and view all the answers

    What are the potential mechanisms underlying the development of Vemurafenib resistance?

    <p>Resistance to Vemurafenib in Melanoma is mediated by further genetic events and aberrant splicing of the B-RAF(V600E) mutant leading to constitutively active Ras-independent homodimers.</p> Signup and view all the answers

    What is the significance of elevated telomerase activity in the melanomas? How does it impact proliferative potential?

    <p>Elevated telomerase activity in melanomas allows for the maintenance of telomere length, which aids in cellular proliferation by preventing cell senescence and enabling indefinite cell division.</p> Signup and view all the answers

    Is the melanoma more likely to be benign or metastatic? Why?

    <p>The melanoma is more likely to be metastatic due to the involvement of B-RAF mutations which are associated with aggressive and malignant characteristics in tumors.</p> Signup and view all the answers

    What effect if any do you predict the T266K mutation has on Sos activity and function?

    <p>The T266K mutation in Sos is predicted to enhance the catalytic activity and function of Sos, leading to increased activation of Ras and downstream signaling pathways.</p> Signup and view all the answers

    Five patients in the trial that did NOT respond to the initial Vemurafenib treatment, but did respond to the subsequent MEK inhibitor, did not have a B-RAF or Sos mutation. Therefore, the causative mutation may be located _____ the signaling pathways.

    <p>downstream</p> Signup and view all the answers

    What is the likely mechanism of Vemurafenib-resistance in the patients with the BRAF(V600E) mutation? Illustrate how the mechanism of action of the resistance mutant differs to BRAF(V600E) in the context of MAPK signaling.

    <p>The likely mechanism of Vemurafenib resistance in patients with the BRAF(V600E) mutation involves mutations resulting in homodimer formation and constitutive activation, bypassing the need for Ras-GTP binding. This leads to unresponsiveness to Vemurafenib that inhibits kinase activity and downstream signaling cascades.</p> Signup and view all the answers

    Study Notes

    Hunter Syndrome Pathophysiology

    • Hunter syndrome is a chronic progressive disease caused by the accumulation of partially degraded GAGs, leading to thickening of tissue and compromising of cell and organ function over time.
    • The IDS gene produces the I2S protein, which is necessary for the breakdown of GAGs in lysosomes.
    • Mutations in the IDS gene cause Hunter syndrome.
    • Incorrect glycosylation of the I2S protein may interfere with lysosomal targeting through impaired binding to the mannose-6-phosphate receptor.

    Enzyme Replacement Therapy (ERT)

    • ERT with idursulfase (Elaprase) improves somatic signs and symptoms of Hunter syndrome.
    • However, the drug does not cross the blood-brain barrier, making treatment of neurological aspects of the disease challenging.
    • Intracerebroventricular injection is an option, but it poses difficulties for widespread use.
    • Elaprase works by reducing the amount of creatinine in urine, indicating improved kidney health.

    Gene Replacement Therapy

    • Gene therapy involves delivering a functional IDS gene to the liver using AAVs.
    • The IDS gene is inserted into the albumin gene, allowing for the production of the I2S protein in hepatocytes.
    • The I2S protein facilitates the breakdown of GAGs in lysosomes, potentially reducing the burden of Hunter syndrome on hepatocyte cells.

    AAV Vectors

    • AAVs are single-stranded DNA viruses with a simple genome packaged in an icosahedral capsid.
    • The genome is typically "gutted" to make room for the gene of interest, ensuring safety and efficiency.
    • The size of the insertion is a limiting factor, and AAV vectors lack the integration-promoting gene, making them safe for gene therapy.

    Gene Editing

    • Gene editing involves modifying genes using site-directed nucleases such as ZFNs, TALENs, and CRISPR/Cas9.
    • These nucleases introduce double-strand breaks, which can be repaired using homology-directed repair (HDR) or non-homologous end joining (NHEJ).
    • HDR is a precise method, but NHEJ can result in insertions or deletions of nucleotides, disrupting the reading frame of genes.

    Volume of Distribution

    • Volume of distribution (Vd) is a theoretical concept that relates the plasma concentration to the total amount of drug in the body.
    • Vd is affected by the drug's ability to move out of the plasma compartment, with lipophilic molecules having a larger Vd.

    Metabolism and Excretion

    • Metabolic degradation and renal excretion of unchanged active drugs are important factors in drug elimination.
    • Renal clearance is the sum of glomerular filtration, tubular secretion, and reabsorption.
    • Drug metabolism makes lipid-soluble drugs more water-soluble, allowing for excretion via the kidneys.
    • Phase I reactions involve functionalization, making the drug more polar, while Phase II reactions involve conjugation with endogenous molecules.### Phase I Drug Metabolizing Enzymes
    • Broad substrate specificity, meaning one enzyme can catalyze the metabolism of many different drugs
    • One drug can be metabolized by multiple enzymes/isozymes
    • Liver drug metabolizing enzymes are usually embedded in endoplasmic reticulum (microsomal)
    • Important family of enzymes is cytochrome P450 "super" family, which catalyzes oxidative metabolism of a range of xenobiotics

    Cytochrome P450s

    • Differ in amino acid sequence, sensitivity to inhibitors and inducing agents, and substrate specificity
    • Enzyme reaction requires molecular oxygen, NADPH, and NADPH-P450 reductase (a flavoprotein)
    • Forms a hydroxylated product
    • There are approximately 74 CYP450 gene families, with three major families involved in drug metabolism in the liver (CYP1, CYP2, CYP3)

    Metabolising Enzymes

    • Are potentially saturable, and activity can be influenced by many factors, including genetics, other drugs, and environmental factors
    • Caution is needed when elimination involves enzymic metabolism, as drug interactions can occur via metabolizing enzymes

    Drug Interaction via Metabolizing Enzymes

    • Enzyme inhibition: drugs metabolized by the same enzyme, if administered together, will compete for the metabolizing enzyme
    • Enzyme induction: some drugs can increase the activity/levels of the enzymes that metabolize them (e.g. alcohol, barbiturates)
    • Interaction can also occur between drugs and "herbal" medicines or food components (e.g. St John's Wort, grapefruit juice)

    Biliary Clearance of Drugs

    • Enterohepatic recycling can occur, where drugs are excreted into the bile and then reabsorbed into the bloodstream

    Other Routes for Excretion of Drugs

    • Lungs can remove gases and volatile liquids (e.g. many general anaesthetics)
    • Sweat, saliva, mucous, tears, and milk can excrete small amounts of drugs (some drugs in milk can be dangerous to infants)

    Polymorphisms in Cytochrome P-450

    • All genes encoding CYP1/2/3 family of P-450 enzymes are polymorphic
    • Clinically important polymorphisms are seen in CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (account for 60-70% of phase 1 dependent metabolism of clinically important drugs)
    • Variations in CYP alleles can affect drug metabolism, e.g. CYP2D6 metabolizes 25% of drugs

    Consequences of Polymorphisms in CYP2D6

    • Poor metabolizers (no CYP2D6 enzymes) have drug metabolism that is too slow, leading to high drug levels and increased risk of adverse effects
    • Ultrafast metabolizers (CYP2D6 gene duplications) have drug metabolism that is too fast, leading to no drug response at ordinary dosage

    Warfarin

    • Has a high rate of adverse events
    • Warfarin maintenance doses are characterized by large inter-individual variability
    • Warfarin pharmacogenetics: metabolism of warfarin occurs through CYP2C9, and clinically relevant SNPs have been identified in CYP2C9, resulting in reduced enzymatic activity

    Pharmacogenomics

    • The use of genetic information to guide drug therapy
    • Differences in the response of individuals to drugs can be predicted from knowledge of genetic makeup

    Pharmacokinetics

    • The rate of elimination is driven by Cp (concentration of the drug in the plasma)
    • Constant/repeated dosing will achieve a steady state Cp
    • Time to reach steady state is determined by t½ (plasma half-life)
    • Time for "removal" is determined by t½

    Systemic Lupus Erythematosus (SLE)

    • A systemic disease, mostly in women, with high morbidity
    • Different epidemiologic subgroups (e.g. race/ethnicity, gender, and age of onset) tend to have varying degrees of disease activity and may thus affect disease outcome
    • Disease manifestations include lupus malar "butterfly" rash, arthritis, CNS inflammation, and lupus nephritis
    • Lupus nephritis is caused by deposition of immune complexes in kidneys, leading to injury to the glomerulus

    Mortality in SLE

    • Linked to early organ damage
    • Survival probability in patients with and without early damage is affected by the presence of early damage

    Autoantibodies in SLE

    • Against molecules in nuclei, such as dsDNA, ribonucleoproteins, and other nuclear proteins complexed with nucleic acids
    • These autoantigens are ligands for "danger sensors" on antigen-presenting cells and B cells

    Genetic Predisposition

    • Clearance of apoptotic particles and immune complexes
    • The role of SLE risk alleles in the pathogenesis of SLE
    • Polymorphisms in genes involved in the immune clearance of apoptotic particles and nucleic-acid-containing immune complexes
    • Polymorphisms in genes involved in innate immunity and adaptive immunity

    Environmental Triggers

    • UV light, smoking, air pollution, trace elements, diet, oestrogens, hormone replacement, and medications

    • Localized tissue damage, leading to release of autoantigens and localized inflammation, causing up-regulation of co-stimulatory proteins on antigen-presenting cells### Systemic Lupus Erythematosus (SLE)

    • All components of the innate immune system are involved in the inflammatory response in SLE.

    • Decreased clearance of apoptotic cells leads to prolonged exposure of potential auto-antigens, promoting tissue damage and pro-inflammatory cytokine production.

    • Decreased anti-inflammatory heme oxygenase-1 (HO-1) and increased pro-inflammatory cytokine production contribute to the inflammatory response.

    • Infiltrating tissue lesions and reduced number of ILC2 cells lead to increased pro-inflammatory cytokine production.

    Innate Immune System Activation in SLE

    • Activation of the innate immune system leads to increased tissue damage and pro-inflammatory cytokine production.
    • Decreased clearance of apoptotic cells and decreased anti-inflammatory HO-1 contribute to the inflammatory response.

    Lupus Nephritis

    • Deposition of immune complexes in kidneys leads to glomerulonephritis.
    • Immune complexes activate complement and lead to inflammation and tissue damage.

    Cyclic Exacerbation of Disease

    • Cyclic exacerbation of disease leads to irreversible tissue damage.
    • Clinical disease onset is characterized by rash, nephritis, arthritis, leukopenia, and CNS inflammation.
    • Irreversible tissue damage can lead to organ failure, such as renal failure, atherosclerosis, pulmonary fibrosis, and stroke.

    Current Treatment for Autoimmune Diseases

    • B cell-targeting therapies, such as anti-CD20 and anti-CD19 monoclonal antibodies, are used to deplete B cells.
    • Monoclonal antibodies targeting B cell surface markers, such as rituximab and ocrelizumab, are approved for autoimmune diseases.
    • Belimumab, a human IgG1 recombinant monoclonal antibody anti-BAFF, is approved for SLE.

    Treatment Under Investigation for Autoimmune Diseases

    • Cytokine-targeting therapies, such as mirikizumab, are being investigated for autoimmune diseases.
    • B cell-targeting therapies, such as ianalumab, are being investigated for autoimmune diseases.
    • Kinase-targeting therapies, such as evobrutinib and tolebrutinib, are being investigated for autoimmune diseases.

    Potential Treatment for Autoimmune Diseases

    • Cell therapies, such as CAR-T cells, CAR-Treg cells, and CAAR-T cells, are being investigated for autoimmune diseases.
    • Targeting metabolic pathways, such as oxidative phosphorylation, mTOR, and glucose metabolism, is being investigated for autoimmune diseases.

    Current and Potential Treatment for Systemic Lupus Erythematosus

    • Rituximab, bortezomib, and atacicept are being investigated for SLE.
    • CD19-targeting CAR-T cells are being investigated for refractory SLE.

    Potential Target for Autoimmune Diseases

    • Autoantibody-secreting plasma cells are a potential target for autoimmune diseases.
    • Depleting plasma cells while redirecting the immune response towards non-autoreactive antigens is a potential strategy.

    Future Perspectives for Treating Autoimmune Diseases

    • New diagnostics, such as genome-wide screening for genes related to autoimmune diseases, are being developed.
    • Personalized medicine, using high-throughput analysis of integrated datasets, is being developed.
    • Preventive medicine, using polygenic risk scores and lifestyle modifications, is being developed.

    Hallmarks of Cancer

    • The hallmarks of cancer include sustained proliferative signaling, evading growth suppressors, and activating invasion and metastasis.
    • Cancer cells acquire hallmark capabilities through genetic and epigenetic changes.

    Cancer Development

    • Cancer development is a multi-step process involving initiation, promotion, and progression.
    • Genetic changes, such as mutations in oncogenes and tumor suppressor genes, drive cell transformation.

    Invasive and Metastatic Cancer

    • Cancer cells require critical traits to undergo invasion and metastasis.
    • VEGF expression is increased in invasive and metastatic cancer.

    Hallmarks of Cancer Cells

    • Hallmarks of cancer cells include sustained proliferative signaling, evading growth suppressors, and activating invasion and metastasis.
    • Cancer cells acquire hallmark capabilities through genetic and epigenetic changes.

    Positive and Negative Regulators of Proliferation

    • Positive regulators of proliferation, such as growth factors and integrin signaling, promote proliferation.
    • Negative regulators of proliferation, such as E-cadherin, inhibit proliferation.

    Hallmark 1: Sustained Proliferative Signaling

    • Cancer cells acquire pro-proliferative signaling through genetic and epigenetic changes.
    • Overexpression of growth factor receptors, such as HER2, renders cancer cells hyper-responsive to pro-proliferation signals.

    Hallmark 2: Evading Growth Suppressors

    • Cancer cells are resistant to anti-proliferative signals via E-cadherin loss.
    • E-cadherin is a tumor suppressor gene that suppresses proliferation via cell-to-cell contact inhibition.

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    Description

    This quiz assesses understanding of Hunter Syndrome, its pathophysiology, and treatment options, including enzyme replacement therapy and gene therapy using adeno-associated virus vectors.

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