L6 Gene Therapy for Neurological Disorders Flashcards
(42 cards)
What does gene replacement allow for?
Correction of loss-of-function (e.g. SMN in SMA) and gain-of-function mutations (e.g. silencing SOD1 in ALS)
What will most CNS gene-based therapies require?
A sustained delivery of the exogenous transgene throughout life, which can be achieved with AAV
AAV expression can endure for decades in __ cells, like __
post-mitotic cells like neurons
What do gene-based therapies offer?
- Ability to directly target disease pathogenesis
- Capacity to achieve a ‘permanent correction’
- A single long-lasting intervention that provides sustainable pharmacology and efficacy
Why are AAV vectors the current major players in gene-based therapies?
- demonstrate strong neuronal tropism
- widespread distribution
- have mostly shown positive safety profiles in early stage clinical trials
Essential components of gene therapy
- vector
- promoter
- transgene
AAV genome contains genes for __ and __ , which are flanked by __
Rep and Cap
inverted terminal repeats (ITRs)
How many proteins does Rep gene encode?
4, which are required for viral genome replication & packaging
Cap gene encodes…
3 overlapping structural viral capsid proteins - form the outer capsid shell that protects viral genome (also involved in cell binding & internalisation)
Importance of AAV capsid
Important in determining several key features of effective AAV gene therapy:
- Tissue tropism
- Distribution
- Susceptibility to targeting by nAbs
Administration of AAV vectors to CNS via __ route demonstrates sustained transduction of neurons
intraparenchymal
Which viral vector is most frequently used in clinical trials?
AAV2
Greatest challenges with AAV delivery for NDDs
Biodistribution and homogeneity of cellular transduction
Primary cell surface receptor used by AAVs
heparin sulfate proteoglycans
Secondary receptors for AAVs
FGF receptor, laminin receptor, αVβ5 integrin (for AAV2)
Advantages of IPa delivery
- bypasses BBB and delivery genes directly
- one and done feature
- well-tolerated
- minimal biodistribution to peripheral organs
- reduced immunogenicity
- significantly lower vector doses required
Additional routes of administration
- Intrathecal
- Intracerebroventricular
- Intracisternal
- Intravenous
Disadvantages of IV administration
- 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
What is spinal muscular atrophy?
A progressive monogenic lower motor neuron disease
SMA is primarily caused by…
the homozygous deletion of the SMN1 gene that encodes the survival motor neuron protein
As patients with SMA lack a functional SMN1 gene, severity of symptoms and age of disease onset is determined by…
copy numbers of the SMN2 gene
Most common form of SMA
SMA type 1: patients tend to have 2 copies of SMN2 gene
What happened in the landmark gene therapy clinical trial in 15 infants with SMA type 1?
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%.
When was AVXS-101 FDA approved?
2019
