Targeted Drug Delivery - CNS Flashcards
Name 5 RMT research targets
Transferrin receptor
Insulin receptor
Members of the LDL family
Melanotransferrin
CD98 heavy chain
Give 4 examples of fusion proteins used in RMT
Lysosomal enzymes
Neurotrophins
Decoy receptors
Therapeutic antibodies
If these are bound to targeting proteins, then they are fusion proteins
Why is insulin unsuitable as a substrate for IR in RMT?
Risk of hypoglycaemia if it binds to receptors on peripheral cells
Why is transferrin unsuitable as a substrate for TfR in RMT?
Because of competition for uptake from endogenous transferrin
Name 2 anti-insulin mAbs for the IR
mAb 83-7
mAb 83-14
Name an anti-transferrin mAb for RMT
Ox26
Explain how TfR-Based RMT is used to treat Hunter’s syndrome
Hunter’s syndrome is a lysosomal storage issue
Make a fusion protein consisting of the missing lysosomal enzyme (iduronate-2-sulfatase (IDS)) and an anti-human TfR antibody (JR-141)
Explain how TfR-Based RMT is used to treat Alzheimer’s disease
Bispecific antibody technology is used
An anti-amyloid-B antibody (gantenerumab) is coupled to a single Fab specific for TfR
This is Brain Shuttle Technology
Why would you use lower affinity anti-TfR antibodies?
Because the higher affinity ones stick to the BBB and often have poorer delivery. Lower affinity ones have a higher distribution
Give 3 examples of BBB penetrating biologics which for AD
- IgG- TNFR fusion protein
- IgG - AAA fusion protein (bispecific antibody)
- IgG - EPO fusion protein
What does IgG- TNFR do?
Sequesters TNF-a to suppress neuro-inflammation
What does IgG-AAA fusion protein do?
Disaggregates the amyloid beta plaques
What does IgG-EPO fusion protein do?
Activates neuronal EPOR to induce repair of dystrophic neurites, which leads to resolution of the dementia in AD
what are VH434 and VH4127?
They are small peptides shown to bind LDLR and promote transcytosis
How do adeno-associated viruses enter the brain?
Adeno-associated viruses enter the brain by binding to a surface protein on neurovascular endothelial cells, triggering receptor-mediated transcytosis.
How does HIV cross the blood-brain barrier?
HIV infects monocytes, which serve as Trojan horses to cross the BBB.
Infected monocytes can either pass through during normal turnover of perivascular macrophages or compromise the BBB by producing proinflammatory cytokines like CCL2.
How do sensory and motor neurons act as an entry point for viruses?
Sensory and motor neurons that extend beyond the BBB can serve as entry points for viruses, such as rabies. These viruses bind to neurons at the neuromuscular junction and use the axonal transport system for retrograde transport.
Which AAV vector is used in Zolgensma?
Zolgensma uses the AAV9 vector.
What is Zolgensma
Zolgensma is a gene therapy for treating Spinal Muscular Atrophy (SMA) type 1.
How does Zolgensma work?
Zolgensma delivers a functional SMN gene to motor neurons, allowing them to produce the SMN protein necessary for neuron survival and muscle function.
Why is the SMN protein important?
The SMN protein is essential for motor neuron survival and supporting muscle functions. Without enough SMN protein, motor neurons die, causing weakness. it is the gene missing in people with SMA
How is Zolgensma administered?
Zolgensma is given as a one-time IV infusion (intravenous infusion).
What is a bi-functional PEG linker in liposomes?
A bi-functional PEG linker binds an anti-transferrin antibody to the liposome, enabling targeted delivery to specific cells using transferrin receptors.
What are immunoliposomes and RMT?
Immunoliposomes are liposomes with antibodies on their surface for targeted delivery, and RMT (Receptor-Mediated Transport) helps them cross barriers like the BBB.
