Lecture 9 - Complement Therapeutics, next generation Gene therapy

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26 Terms

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1st generation complement inhibitors

  • intravenous

  • high dose

  • frequent dosing

  • total blokade

  • recombinant proteins

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2nd generation complement inhibitors

  • subcutaneous

  • complement modulation

  • target neoepitopes/ activation products

  • longer duration of action

  • oral

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3rd generation complement inhibitors

  • delivery across barriers (BBB)

  • specific organ delivery

  • gene therapy

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Crosstalk?

adaptive immunity?

intracellular complement?

coagulation?

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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

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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

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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

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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.

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Antisense Technology

  • Antisense strand binds to mRNA, leading to mRNA degradation via RNase H.

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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

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Knocking down C3 in kidney disease

effect on transplantation and fibrosis

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Personalized Medicine - Batten's Disease Treatment

  • Treatment of one patient with Batten's Disease (a rare and fatal neurodegenerative disease) with milasen

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Age-Related Macular Degeneration (AMD)

  • AMD causes irreversible sight loss and is the leading cause of blindness in the western world.

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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.

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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.

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Smoking Mice - Model of AMD

  • Smoking chamber setup for mice to model AMD.

  • can replicate damage of AMD in humans

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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

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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

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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

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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

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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

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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)

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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

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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.

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What is the main drawback of gene therapy for treating complement-mediated diseases?

Immune response activated to AVV virus vector

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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