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PMCOL 412 > HD II > Flashcards

HD II Flashcards

1
Q

the goal of HD treatment

A

to increase the firing of the GABAergic Enk+ neurons (D2R-expressing) in the striatum to reduce dyskinesia

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2
Q

Pharmacological approaches to treat HD motor symptoms

A
  • relief of dopamine inhibition by dopamine antagonists (classic antipsychotics such as haloperidol and chlorpromazine)
  • Atypical antipsychotic (clozapine and olanzapine) are also used with less side effects
  • TETRABENAZINE (presynaptic monoamine-depleting agent)
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3
Q

Gold standard treatment of motor symptoms in HD

A

TETRABENAZINE (presynaptic monoamine-depleting agent)

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4
Q

Tetrabenazine (TBZ): mechanism

A

Reversible inhibitor of vesicular monoamine transporter 2 (VMAT-2) –> depletes DA stores –> no DA release in striatum –> prevents too much movement
Also a weak inhibitor of D2 receptors

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5
Q

VMAT 2 role

A

Transports DA back into vessicles

inhibited by TBZ so that no DA is stored in vesicles and therefore no DA will be released in striatum

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6
Q

Tetrabenazine (TBZ): drug type/use

A

benzoquinolizine derivative used for the treatment of various diskinetic disorders

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7
Q

Tetrabenazine (TBZ): Side effects

A

Side effects are similar to those caused by anti-psychotics:

  • depression (15% of patients)
  • suicidal thoughts
  • akathisia (restlessness)
  • dizziness, sedation
  • parkinsonism
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8
Q

TBZ vs classic antipsychotics (side effects)

A

Reduced incidence of complications such as parkinsonism and dyskinesia with respect to classic antipsychotics (due to much weaker D2R affinity)

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9
Q

______ is a major concern with TBZ treatment and patients need to be carefully monitored

A

Increased depression and suicidal thoughts are a major concern and patients must be carefully monitored for such complications.
This concern decreases the number of “treatable” patients.
patient with existing psychiatric issues should avoid TBZ

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10
Q

What limits the number of patients on TBZ

A

concerns regarding increased depression and suicidal thoughts

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11
Q

Deuterated tetrabenazine (Deutetrabenazine): what is it

A

Analogue of tetrabenazine with the hydrogen atoms in the two methoxy groups replaces with the isotope deuterium

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12
Q

Deutetrabenazine vs. TBZ

A

Deuterium substitution slows down the oxidative
metabolism of the methoxy groups –> decreased metabolism (longer half-life) –> Decreased dosage, greater tolerability and improved dosing regimen

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13
Q

Antisense oligonucleotide (ASO): what are they

A

short synthetic modified nucleic acids that:

  • are delivered as a single strand
  • Target RNA in cytoplasm and nucleus
  • Can be taken up by cells in a naked form (+ enter nucleus)
  • have poor passage through the BBB
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14
Q

ASOs goal

A

to silence mutant huntingtin

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15
Q

ASO mechanism simple

A

ASOs are able to recognize and bind to complementary mRNA through Waston and Crick Base Pairing then modulate the fate of that RNA

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16
Q

ASO mechanism: target mutations

A

Once bound, form duplex RNA-DNA recognized by RNAse H1 (enzyme) that degrades the RNA, leaving the DNA intact –> allows further degradation = decreased intracellular levels of mutant HTT

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17
Q

ASO mechanism: target splice sites

A

antisense nucleotide binding to intron/exon regions of preRNAs –> blocks RNA splicing –> decreased production of target protein

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18
Q

ASO mechanism: target translation start sites

A

target translation start sites –> prevent protein translation –> decreased production of target protein

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19
Q

ASO mechanisms

A
  • target mutations
  • target splice sites
  • target translation start sites
    = all end up decreasing pathological protein production
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20
Q

Small interfering RNA (siRNA): characteristics

A
  • Delivered as a duplex
  • Target mRNA in cytoplasm only
  • Must be delivered with viral vectors (can’t get into cells themselves)
  • Poor passage through the BBB
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21
Q

Goal of siRNA

A

to silence mutant huntingtin

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22
Q

siRNA: mechanism

A

Delivered as a duplex –> associates with AGO part of RISC –> passenger strand is removed –> guides AGO in search of of complementary sequence –> once complementary sequence is found RISC complex degrades the complement mRNA (if perfect match) OR represses/blocks it (if partially mismatched)

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23
Q

RISC

A

RNA-inducing silencing complex

24
Q

Guide strand in siRNAs

A

Complementary to RNA targetted and is retained attached to AGO to help guide AGO to find complementary sequence –> once complementary sequence is found it is degraded (if perfect match) or blocked but not cleaved (if imperfect match)

25
Q

T/F: ASOs are rapidly degraded by nucleases if their structure is not chemically modified

A

TRUE

need to modify their phosphate backbone increases ASOs stability

26
Q

Phosphorothioate DNA (PS)–what is it used for and how does it work

A

Used to increased ASO stability

Substitution of a non-bridging oxygen in the phosphate backbone with a sulfur atom –> Resistance to exo- and
endonucleases, BUT Recognition and cleavage
of target sequence by RNase H preserved.

27
Q

Modifications to ASO

A
  • Phosphorothioate DNA (modify their phosphate backbone)

- Modifications of the 2’ position of the sugar

28
Q

Modifying sugar of ASO

A

Modifications of the 2’ position of the sugar:
- enhance ASO potency by stabilizing target binding
- increase resistance to nucleases
- reduce nonspecific protein binding
Results in MOE (2’-O-Methoxyethyl)

29
Q

Which is the more common modification to ASO

A

Phosphorothioate DNA more common that modifications to 2’

30
Q

How ASO and siRNAs are delivered

A
  • NOT suitable for oral delivery (poor intestinal absorption and poor BBB permeability)
  • ADMIN: Intraparenchimal, intracerebroventricular or intratechal (not ideal–hard to do)
  • Continuous or repeated administration over the course of the disease
31
Q

siRNA and ASO in multiple Phase I/II trials:

A
  • silencing of apoB in familial hypercholesterolemia (approved by FDA)
  • silencing of XIAP in acute myeloid leukemia
  • silencing of mutant SOD1 in familial ALS (ISIS-SOD1-Rx)
  • Also in clinical trial for the silencing of LRRK2 in PD, tau in AD.
32
Q

What should you silence for effect

A

Silencing of huntingtin should be specific for the mutant allele product to avoid loss of normal huntingtin

33
Q

___% of HD patients have a Single Nucleotide Polymorphism (SNP) in the mutant HD allele (but not in the normal allele) allows…

A

65%; allows for specific targeting of the mutant allele with specific ASOs

34
Q

ASOs efficacy

A
  • Only 10-50% of ASOs effectively reduce expression of the target
  • Potential off-target effects must be carefully evaluated
35
Q

IONIS-HTTRx Phase I trial in HD patients: what is it

A

48 patients given a bolus of AOS intrathecally once monthly for 4 months –> then monitored for 4 more months

36
Q

IONIS-HTTRx Phase I trial in HD patients: Results

A

~40% reduction in mutant HTT levels in patients receiving the drug.

37
Q

GM1 works by

A

modulating HTT post-translational modifications

38
Q

GM1 props

A
  • Constitutes ~25% of the total brain ganglioside pool
  • Enriched in membrane microdomains involved in cell
    signaling
  • Modulates the activity of various membrane receptors and ion channels
  • belongs to class of glycolipid called gangliosides
39
Q

Components of GM1

A
  • Gycan Headgroup – Protrudes towards the extracellular
    space and makes connections with proteins and other molecules
  • Lipid tail – anchors the molecule to membranes (made of ceramide)
40
Q

Gangliosides act as ________

A

“lipid chaperones”

41
Q

How Gangliosides work

A

Inserted into bio-membrane can interact with membrane protein receptors with high specificity –> interact and help deliver them to signalling microdomains where they facilitate the interaction of the ligands with receptors and recruitment of downstream signalling complexes

42
Q

Gangliosides have roles in:

A
  • Modulation of receptor activity (PDGFR, FGFR, EGFR, IR, Trk)
  • Neuritogenesis and axon sprouting
  • Cell adhesion
  • Myelin-axon interactions
  • Cell-cell communication
43
Q

Disruption of ganglioside biosynthesis leads to

__________

A

Neurodegeneration

Loss of function mutations in genes of the ganglioside biosynthetic pathway cause severe neurodegenerative disorders

44
Q

Loss of function mutations in genes of the ganglioside biosynthetic pathway cause these disorders

A
  • Infantile-onset symptomatic epilepsy syndrome (progressive brain atrophy, epilepsy and motor symptoms)
  • Complex hereditary spastic paraplegia (epilepsy, cognitive impairment, motor symptoms and deafness)
  • loss of GM1 observed in DA neurons in human PD in substantial nigra
45
Q

Admin of ___ protects HD cells from apoptosis

A

GM1 (it’s neuroprotective!)

Addition of GM1 protective in both WT and HD

46
Q

in HD cells levels of ____ are decreased if we provide ___ it ____ cells

A

gangliosides; GM1: protects

GM1 protects cells from stress and apoptotic stimuli (return to WT levels of apoptosis)

47
Q

Administration of GM1 induces ____ of mutant HTT which suggests that GM1 can ____ and ameliorate ___ symptoms

A

phosphorylation; slow disease progression; motor

admin of GM1 induces phosphorylation of mutant HTT at serine 13 and 16

48
Q

Why is it important that GM1 phosphorylates serine 13 and 16

A

phosphorylation of these residues is crucial to modulate mutant huntingtin toxicity (decrease toxicity)

49
Q

Motor tests of HD models

A

cross a ladder
WT have no problem
HD mice have trouble
HD + GM1 look more like WT

50
Q

Effects of GM1 on crossing narrow beam

A

W/in 14 days of GM1 treatment HD + GM1 mice retun to normal (WT-like) performance

51
Q

GM1 on non-motor symptoms

A
  • Administration of GM1 corrects non-motor symptoms of HD (depression, anxiety, cognitive problems)
  • GM1 slows down neurodegeneration in HD mice (less degen of striatal neurons)
52
Q

Depression in HD

A

HD animals have higher depression + anxiety than WT but GM-1 returns these behaviours to WT-levels

53
Q

Administration of GM1 decreases ____ and ____

A

soluble mutant HTT (act on misfolded mutant HTT); insoluble aggregates (act on fibrils/aggregates)

54
Q

Domino effect and GM1

A
  • Restoring GM1 in the brain restores cellular functions
  • BUT GM1 also has direct effects on mutant HTT (promotes phosphorylation, helps degradation of muHTT, prevents aggregation)
  • leads to increased neuronal survival and therefore fewer symptoms
55
Q

Challenges to move GM1 to clinical trials

A
  • Modality of administration is challenging due to poor/unclear permeability of the BBB to GM1 (routes are not ideal–ex. intraventricularly)
  • Mechanism of action still not completely clear and likely to be pleiotropic (makes it harder to translate into clinical use)

PMCOL 412 (35 decks)

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