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PT4024 > L6 Gene Therapy for Neurological Disorders > Flashcards

L6 Gene Therapy for Neurological Disorders Flashcards

1
Q

What does gene replacement allow for?

A

Correction of loss-of-function (e.g. SMN in SMA) and gain-of-function mutations (e.g. silencing SOD1 in ALS)

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2
Q

What will most CNS gene-based therapies require?

A

A sustained delivery of the exogenous transgene throughout life, which can be achieved with AAV

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3
Q

AAV expression can endure for decades in __ cells, like __

A

post-mitotic cells like neurons

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4
Q

What do gene-based therapies offer?

A
  • Ability to directly target disease pathogenesis
  • Capacity to achieve a ‘permanent correction’
  • A single long-lasting intervention that provides sustainable pharmacology and efficacy
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5
Q

Why are AAV vectors the current major players in gene-based therapies?

A
  • demonstrate strong neuronal tropism
  • widespread distribution
  • have mostly shown positive safety profiles in early stage clinical trials
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6
Q

Essential components of gene therapy

A
  • vector
  • promoter
  • transgene
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7
Q

AAV genome contains genes for __ and __ , which are flanked by __

A

Rep and Cap
inverted terminal repeats (ITRs)

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8
Q

How many proteins does Rep gene encode?

A

4, which are required for viral genome replication & packaging

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9
Q

Cap gene encodes…

A

3 overlapping structural viral capsid proteins - form the outer capsid shell that protects viral genome (also involved in cell binding & internalisation)

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10
Q

Importance of AAV capsid

A

Important in determining several key features of effective AAV gene therapy:
- Tissue tropism
- Distribution
- Susceptibility to targeting by nAbs

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11
Q

Administration of AAV vectors to CNS via __ route demonstrates sustained transduction of neurons

A

intraparenchymal

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12
Q

Which viral vector is most frequently used in clinical trials?

A

AAV2

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13
Q

Greatest challenges with AAV delivery for NDDs

A

Biodistribution and homogeneity of cellular transduction

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14
Q

Primary cell surface receptor used by AAVs

A

heparin sulfate proteoglycans

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15
Q

Secondary receptors for AAVs

A

FGF receptor, laminin receptor, αVβ5 integrin (for AAV2)

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16
Q

Advantages of IPa delivery

A
  • bypasses BBB and delivery genes directly
  • one and done feature
  • well-tolerated
  • minimal biodistribution to peripheral organs
  • reduced immunogenicity
  • significantly lower vector doses required
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17
Q

Additional routes of administration

A
  • Intrathecal
  • Intracerebroventricular
  • Intracisternal
  • Intravenous
18
Q

Disadvantages of IV administration

A
  • Exposes the virus to potential Ab neutralisation in subjects who have been pre-exposed to natural AAV infections
  • Typically requires higher total doses to achieve efficient transduction
  • Broad distribution to multiple peripheral tissues
19
Q

What is spinal muscular atrophy?

A

A progressive monogenic lower motor neuron disease

20
Q

SMA is primarily caused by…

A

the homozygous deletion of the SMN1 gene that encodes the survival motor neuron protein

21
Q

As patients with SMA lack a functional SMN1 gene, severity of symptoms and age of disease onset is determined by…

A

copy numbers of the SMN2 gene

22
Q

Most common form of SMA

A

SMA type 1: patients tend to have 2 copies of SMN2 gene

23
Q

What happened in the landmark gene therapy clinical trial in 15 infants with SMA type 1?

A

They received a single IV injection (high or low dose) of AAV9 vector carrying SMN1 gene (AVXS-101). All patients were alive & event-free at 20 months with a historic survival rate of 8%.

24
Q

When was AVXS-101 FDA approved?

A

2019

25
Q

AAV-based gene therapies have been used to … in PD

A

upregulate DA signalling

26
Q

3 rate-limiting enzymes that regulate DA synthesis pathway

A

GCH1, TH, AADC

27
Q

Clinical trials with IPa administration of AAV2 encoding __ in PD patients

A

AADC (aromatic L-amino acid DOPA decarboxylase)

28
Q

What is the benefit of administering AAVs encoding rate-limiting enzymes involved in DA synthesis pathway to PD patients?

A
  • Patients can regulate the amount of L-DOPA they take to control the amount of dopamine produced by this new depot
  • Bypasses degenerating dopaminergic neuronal projections from SN
29
Q

Lentivirus-based gene therapy that delivers all 3 rate-limiting enzymes

A

ProSavin - well tolerated in Phase I/II

30
Q

2 promising candidates involved in promoting survival of DA midbrain neurons

A

GDNF and Neurturin

31
Q

Phase I trials to determine the safety of bilateral … injections into the putamen are ongoing

A

AAV2-GDNF IPa injections

32
Q

A possible reason for the limited success of GDNF and NTRN in PD

A

Some patients show reduced expression of Ret, the receptor of both NTRN and GDNF, so these trophic factors cannot confer protection through Ret

33
Q

Strategies to target genes in PD

A
  • Attenuate LRRK2 expression
  • Augment GCase activity
34
Q

Where does the most common PD risk variant, G2019S, lie?

A

in the catalytic site of LRRK2, enhancing its kinase activity

35
Q

Why is gene therapy useful for targeting LRRK2?

A

Because LRRK2 is also expressed in lungs, kidneys and spleen. Gene therapy can specifically inhibit LRRK2 in the brain, while avoiding pathological changes in other tissues.

36
Q

LRRK2 ASO in Phase I trial

A

BIIB094

37
Q

Why is increasing GCase activity a promising therapeutic approach in PD?

A

Because decreased GCase levels are seen in cases of PD with GBA1 mutations (cause GCase deficiency), as well as sporadic PD (without GBA1 mutations)

38
Q

What did direct IPa injections of AAV-GBA1 in the brain of preclinical models lead to?

A

Decreased α-synuclein levels and pathology

39
Q

Phase I/II clinical trial was recently launched to treat patients with PD by intracisternal injection of…

A

AAV9-GBA1 into the CSF

40
Q

Preclinical models showed that injection of AAV-HTT miRNA into striatum…

A

significantly reduced HTT expression, which led to improved motor and behavioural deficits without over neurotoxicity

41
Q

What is AMT-130?

A

Consists of an AAV5 vector carrying an artificial miRNA specifically tailored to silence the HTT gene (currently in Phase I/II trial)

42
Q

Result of gene-based therapy for ALS in transgenic SOD1 mouse model

A

IV delivery of AAV9-SOD1 shRNA reduced SOD1 levels, slowed disease progression and prolonged lifespan

PT4024 (12 decks)

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