JS PD KB

20240722_183342

5 min read

Background

  • C5a
    • Activation of the complement system leads, amongst others, to the generation of the potent anaphylatoxin C5a.
    • C5a is a strong chemoattractant and an effective inflammatory mediator, which, upon binding to its G protein-coupled membrane-bound receptor C5aR1 (C5R1, C5aR, CD88) provokes and amplifies inflammatory reactions by inducing degranulation, cytokine release and oxidative burst of immune cells4.
  • C5aR1
    • a receptor for the complement activation proinflammatory fragment, C5a,
    • = complement component 5a receptor 1 (C5AR1) or CD88 (Cluster of Differentiation 88)
    • a G protein-coupled receptor for C5a.
    • expression
      • tissue
        • in brain: both RNA and protein expression of C5aR1
      • i. CELL type
        • Immune cells, Granulocytes, Monocytes, Dendritic cells Hepatoma-derived cell line HepG2 Astrocytes Microglia
    • C5aR1 is required for full activation of microglial inflammasome as an essential co-factor.
  • TLR stimulation synergize with C5aR1 signaling in the periphery in mice, → increasing the pro-inflammatory cytokine production over TLR signaling alone
    • C5근거: -
      • ↑ C5a in postmortem, blood, CSF
      • C5aR1 inhibition by pharmacologic inhibitor or KO → ↓ activation of microglial inflammasome
  • 아래 그림과 달리 Dr. Woodruff thinks C5aR1 is involved in NLRP3 assembly step only (not priming step).

Pipeline C5aR1

xxxvii) Avacopan

(2020) 114156

Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function

Eddie X. Li, Jhes D. Lee, Nicholas L. Massey, Carolyn Genn, Avril A.B. Robertson and J. Clark, Trent M. Woodruff

Limitation: Rank-order of efficacy is variable based on assay/cell

Innomedica (Haven)

Talineuren (GM1 ganglioside) development program for PD, ALS and AD. Confidential meeting to be scheduled delivery GM1 ganglioside across the BBB, using Innomedica’s proprietary NeuroRegenosome delivery system.

https://web.drooms.com/home Annafreud52ohe4102!

[Diligence Questions_Innomedica.xlsx](Diligence Questions_Innomedica.xlsx)

Project Haven internal TEAMS site: General

Diligence Q&A: [Diligence Questions_Innomedica.xlsx](Diligence Questions_Innomedica.xlsx)

Project Haven Team list: [Project Haven Team Deliverables and Dates.xlsx](Project Haven Team Deliverables and Dates.xlsx)

Updated timeline

  • For this initial diligence stage, please complete the 1-page diligence summary (links below) by Wed 6/29
  • David and I are planning a joint meeting with Innomedica for next week - stay tuned
  • Current Ph1 data coming end of July so we plan to submit initial terms after data review
  • We will need to align with Senior Leadership (including Neuro DDU, TAU and commercial) and PRC on terms before we submit non-binding terms to Innomedica – timing still TBD: the presentation with PRC be scheduled after the Phase 1 data review

In Vivo Clibration

targetDrug effect BraincaudateCSFplasma
cortexcaudate
SchizophreniaD2 agonist
tominersen In vivo preclinical data were used to define target — CSF mHTT reduction

Tissue lowering to efficacy1,2: Transgenic mouse models — Cortex ~30-80% / Caudate ~30% ✓

Cyno tissue/CSF-HTT relationship: % CSF HTT KD 20-30 → % HTT KD in cortex 30-55, % HTT KD in caudate 5-20; 30-40 → 40-70, 15-35; 40-50 → 55-80, 25-45.

Target trough human CSF mHTT reduction range: ~30-50%

CSF mHTT lowering of ~20-30% at trough meets observed cortical threshold of efficacy in preclinical models of HD; caudate lowering is only covered at higher levels of CSF reduction (e.g. >30%).
Based on preclinical evidence, a CSF mHTT lowering of 30-50% is expected to be associated with broad therapeutic benefits.

level order of drug effect: cortex > CSF > caudate, SO 다음의 예상 가능? for small molecule: (cortex=caudate) > CSF
Target ↑ > 30% in clinic
lustat 1 (Prevail)

xviii) Resource

a. (Tran, 2020 #1931): metaanalysis, stressor, protocol, culture trajectory (The intermediate stages may include embryoid bodies (EB, stem cells in suspension), EZ sphere (aggregates of early neural stem cells in suspension), neural rosettes (early neural stem cells with radial arrangements), neurosphere (neural progenitors in suspension), and neuralprogenitor cells (NPC, neural precursors with bipolar morphology

xix) Multigenic Heterogeneity

a. How to reduce it → the patients from which the biopsies are taken may be selected based on gender, age, ethnicity, social context (i.e., farmers professional athletes exposed to repetitive injuries… symptoms… Ultimately, the

Uncertain Spans

locationtranscriptionuncertainty
Avacopan paper authorsauthor listAuthor surnames are partly obscured by the citation watermark; reading is best-effort.
Innomedica passwordAnnafreud52ohe4102!Password string is rendered in small font; reading is best-effort.
In Vivo Clibration tablecolumn-header alignmentThe Drug effect column is split into Brain (cortex / caudate) sub-columns and additional CSF / plasma columns; the visible header row is partially merged in the source and the reconstruction here preserves what is visible.

그래프 뷰

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