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1st generation complement inhibitors
intravenous
high dose
frequent dosing
total blokade
recombinant proteins
2nd generation complement inhibitors
subcutaneous
complement modulation
target neoepitopes/ activation products
longer duration of action
oral
3rd generation complement inhibitors
delivery across barriers (BBB)
specific organ delivery
gene therapy
Crosstalk?
adaptive immunity?
intracellular complement?
coagulation?
siRNA approaches
small interfering RNA
siRNA are delivered to targeted cells
silences a specific Gene by inactivating mRNA available for translation into protein
targeting the specific mRNA for degradation in the cytoplasm
inactivates but cutting mRNA or prevent ribosome from binding
can target specific organ
Targeting the Liver
The liver is the main site of complement protein synthesis.
ALN-CC5: siRNA approaches can be used to target C5 RNA in the liver
Delivery methods include subcutaneous administration in mice, rats, and non-human primates (NHP)
NHP ablate for 2 months before C5 begins to increase: better than Eculizumab
ALN-CC5: Myasthenia Gravis Model
Alnylam Pharmaceuticals
ALN-CC5 is used in pre-clinical testing for this model.
Mice are immunized with 40µg of torpedo AChR in Complete Freund's Adjuvant (CFA).
Two subcutaneous injections are administered at the base of the tail.
Better with siRNA-C5 pre and post disease
Clinical Trial Data in PNH
5x doses of 400mg effective out to 10 months.
Eculizumab had to be weaned off patients before adminisering ALN-CC5
99% inhibition predicted using 600mg ALN-CC5.
5x doses of 400mg effective out to 10 months.
Antisense Technology
Antisense strand binds to mRNA, leading to mRNA degradation via RNase H.
Targeting Factor B (FB) using ASO
Targets alternative pathway
ASO knocks down Fb expression
FB ASO #1 and FB ASO #2 were tested
Significant reduction in FB mRNA levels with both ASOs
Lupus Nephritis: FB ASO #2 reduces C3 deposits in the kidney
mouse models show:
improved renal pathology scores with FB ASO #2
Improved survival rates with FB ASO #1 and #2
Knocking down C3 in kidney disease
effect on transplantation and fibrosis
Personalized Medicine - Batten's Disease Treatment
Treatment of one patient with Batten's Disease (a rare and fatal neurodegenerative disease) with milasen
Age-Related Macular Degeneration (AMD)
AMD causes irreversible sight loss and is the leading cause of blindness in the western world.
Complement in AMD
Complement components identified in Drusen (lipid depositions of acellular debris in eye)
reliant on one regulator to work
complement factors H, I and B
30% of Europeans have polymorphism for FH on one allele, increasing AMD risk.
Challenges in Pre clinical modelling in AMD
Wet AMD – CNV (choroidal neovascularization) – fairly easy to model.
Dry AMD with Geographic atrophy – challenging
Limitations: Mice do not have a macula.
Smoking Mice - Model of AMD
Smoking chamber setup for mice to model AMD.
can replicate damage of AMD in humans
Adeno-Associated Virus as a gene delivery tool in an AMD
TT30 targets C3d and factor H
transport from apical to basal side.
prevents further activation of the complement
better with gene therapy than intra venous drugs
Subretinal injections are optimal for expression in the RPE/choroid
Increasing Complement Factor I in the Eye
to increase regulatory function
monthly injection in eye
phase ½ saftey trials
localised regulation
no big adverse effects with inflammation
there was increased expresssion of factor I and a reduction of complement activation
failed to meet primary efficacy, did not have less geographic atropy in dry AMD patients
Immune Response to AAV
not immuno silent
complemnt system can trigger immunity response to gene terapies
may needto target complement against virus before gene therapy
using Compstatin (C3) inhibitor to protect AAV therapy
Targeting Complement in the Brain & BBB
Parkinson's Disease: CR3 knockout mice were protected from dopaminergic neuron loss and motor dysfunction.
complement opsonization + CR3 contribute to disease
Huntington's Disease: Oral administration of C5aR antagonist reduced weight loss and motor deficits in an animal model.
peptide cross BBB
evidence MAC is associated with disease
Amyotrophic Lateral Sclerosis: Oral administration of PMX205 reduced weight loss and motor deficit scores and slowed disease progression + better survival in mice and rats
Alzheimer's Disease: PMX205 decreased amyloid and tau deposits, reduced activated glia, and improved cognition
evidence MAC is associated with disease
Anti-C7 Monoclonal Therapy
difficut for mAb to cross the blood-brain barrier (BBB)
Anti-C7 is highly effective in experimental autoimmune myasthenia gravis (EAMG) model
Blocking C7 prevents MAC-mediated damage
both pre and post disease
Getting Drugs/Anti-C7 mAb Across the BBB
smaller to diffuce - may lose functionality
Receptor-Mediated Transcytosis (RMT): attach to something that can be detected by a receptor (insulin, IL)
Which complement protein is most associated with AMD?
Complement Factor H (CFH)
CFH regulates the alternative pathway, preventing overactivation on host tissues like the retina
What is the big advantage of gene therapy over other drugs?
Long-term, sustained expression from a single treatment
Gene therapy delivers genetic material (e.g., via AAV vectors) to continuously produce the therapeutic protein, reducing the need for repeated dosing.
Especially useful in chronic diseases like AMD or inherited disorders.
What is the main drawback of gene therapy for treating complement-mediated diseases?
Immune response activated to AVV virus vector
What is the main challenge of targeting complement activation in the brain?
Most complement inhibitors (especially large biologics like mAbs) cannot easily cross the BBB