Underwood 2713 PFF tail, Zhao/Dzamko/muda LRRK2 14-3-3 notes, Ambagon-Takeda aSyn R&Rs confidential, 14-3-3 isoform/YWHA table, Deal concept / R&R, Mayor (AC immune) program, Competitor list, aSyn PET, Jaewon’s Lucy Tx Q&A, Samrara Tx Triage, Individual report (T3D / Neuracle / Nuravax)
- 14-3-3 θ overexpression by AAV in SN also delayed α syn aggregation in the SN and partially rescued PFF-induced reduction in TH-positive dopaminergic cells in the SN. 14-3-3 inhibition in the SN accelerated nigral α syn aggregation and enhanced PFF-induced reduction in TH-positive dopaminergic cells
{Zhao 2015 #2265} 별 언급 없는 듯
{Dzamko 2010 #2268} 별 언급 없는 듯
{muda 2014 #2266} phosphorylated LRRK2 WT peptide (pS LRRK2-1444) bound to all three 14-3-3 isoforms (gama, theta, zeta)
20240122 Ambagon-Takeda aSyn R&Rs confidential 20240122 vFS:
- 14-3-3 is highly abundant in both healthy controls and PD patients
- The amount of 14-3-3 is not decreasing in PD and exceeds aSyn abundance by a factor of 20 - 25 (Mol Cell Proteomics. 2023 Jan;22(1):100452)
- Overexpression of human aSyn in a mouse model results in an increase of endogenous 14-3-3 expression (Neurobiol Dis. 2023 Jul;183:106166)
- Modulation of aSyn aggregation and oligomer distribution is observed at substoichiometric 14-3-3 amounts (Hum Mol Genet 2014 Nov 1;23(21):5615-29, Acta Neuropathol Commun. 2021 Jan, 7;9(1):13., Ottmann, C. et al, manuscript in preparation)
Tx strategy: selective small molecule stabilizers/molecular glue occupies 14-3-3:client binding site (phosphosite) → stabilizing the naturally occurring 14-3-3:client interaction protect α-syn from folding into a pathogenic conformation, ↑14-3-3 binding to LRRK2, ↓ LRRK2 activity (어쨌지)
- Specificity to isoforms and client protein
| Gene | |||
|---|---|---|---|
| Alpha | YWHAB | ||
| B | YWHAB | ÷ | |
| B/alpha | YWHAB | ||
| gamma | YWHAG | CSF [Karayel 2021 의 Table S4 의 gamma, epsilon (ε), zeta/delta 는 LCC cohort 에서 증가로 나온 듯 (not in HBS cohort) | |
| Epsilon (ε), | YWHAE | CSF [Karayel 2021 의 Table S4 의 gamma, epsilon (ε), zeta/delta 는 LCC cohort 에서 증가로 나온 듯 (not in HBS cohort) | |
| Delta | |||
| Zeta (ζ) |
-Brain: (Lowes, 2020), fig2a. a neurodegeration marker, although n=8, seems ↓ - CSF [Karayel 2021 의 Table S4 의 gamma, epsilon (ε), zeta/delta 는 LCC cohort 에서 증가로 나온 듯 (not in HBS cohort) | ||
| Zeta/delta | YWHAZ | - CSF: 2023 fluid & imaging BM in neuroscience, Henrik, = (vs Aβ negative CU) | |
- non-competitive stabilizers (fusicoccanes) of 14-3-3:target binding
- hit’s low potency?: EC50: 0.16 uM for LRRK2 pS910, and 3.18 uM for LRRK2 pS935 → to be reduced down to mid to low nM affinity
20240222 Ross: 14-3-3 is highly expressed in CNS. Deal: research collaboration type. aSyn is main. LRRK2 is not. Now is pre-diligence stage.
What we want to see. Aggregate inhibition X. degradation O. isoform issue.
[Deal concept]
- A-syn licensing at forefront of collaboration
- Argo to lead Target validation, Hit ID and H2L
- At H2L, Takeda will run assays which will determine whether we progress to LO (to discuss with Argo)
- LO will be done jointly by Takeda/Argo to ensure we leverage Takeda’s chemistry while keeping glue-like and 14-3-3 binding properties
- Takeda takes over after LO (lead optimization)
- Option for LRRK2
- Ability to enter two more targets into a collaboration at Takeda’s discretion
[R&R]
- 20231108 Project Argo Update.pptx : p20: Translation is on Takeda
- sharepoint
- Ambagon_QA_Feb2024_20240222_vFS.xlsx
- Takeda-Ambagon_DD Q&A_14-3-3 & aSyn conservation_20240222_vFS.pdf
- Individual report
Mayor = AC immune
(1) a β vaccine (mayor1) and (2) Alfa-syn small molecule (mayor 2).
Report out:
- Alpha-syn small molecule
- https://acimmune.firmex.com/projects/45?language=en
- AC Immune Alfa-syn Q&A Apr2023.xlsx
- https://mytakeda.sharepoint.com/sites/ProjectMAYOR
- oligomeric aSyn: field, both/either cell and animal
- Mike: current molecule has basic nitrogen, so ↑ toxicity (HERG). Back up molecule 은 nitrogen 없음 증거달라.
- Back ups: comparable in vitro pharmacology profile to ACI-15896, Herg, PK, SOLUBILITY,
- How will a quantitative relationship be built between aSyn load reduction and clinical benefit and for translatable aSyn biomarker changes? What would be assay plans for measuring phosphorylated aSyn and oligomeric aSyn in biofluids in animal model (s) and clinic?
- Mayor 1: Amyloid beta immunotherapy: PRC NBTs Oct 23, 2023
- Mayor 2: aSyn Jan 25, PRC meeting. CEI document at NDU, why PRC?
[Competitor]
- UCB0599: only at lipid, not for secondary nucleation
- Anle138b (TEV-56286): binds any beta-sheet
- https://mytakeda.sharepoint.com/:w:/s/ProjectMAYOR-A-synsubteam/EZimhGLi3lZCn-CWjhNllcgBpNFi5ZwXtksxq25Rn1MTHg?e=fNeg16
[aSyn PET]
Their small molecule will block. The aSyn will be useful only early (TE?), but not late (pharmacodynamic?)
20230426 jaewon’s answers to Jiaping,
Their program in PD is early but in my view is addressing a potentially important and interesting biological theme.
- The role of mitochondria Complex I dysfunction in PD is well supported by genetic evidence and human tissue studies.
- It is unclear presently what can be a direct target/pathway engagement biomarker in clinic that can nicely predict brain mitochondrial engagement/function. However biomarker qualification (including 31P MRS imaging) is underway in the field by various academia and we would be in a better position in a few years to have such a biomarker.
- Their compounds showed selectivity to the target and prevented rotenone-induced ATP depletion in a cell system. It would be very interesting to see compound effect on mitochondrial readouts and disease-related readouts in their planned in vivo POC model -rotenone model as they currently planned, but testing in other relevant models should build a robust story.
202210 Jaewon’s questions:
The role of mitochondria Complex I dysfunction in PD is supported by genetic evidence and human tissue studies.
It is unclear what can be a target/pathway engagement biomarker in clinic that can predict brain mitochondrial engagement.
Do Lucy Tx consider brain MC1 PET ([18F]BCPP-EF) as an imaging biomarker as such?
Selective to the target. Prevented rotenone-induced ATP depletion
Tx strategy: small molecule → F-ATPase inhibition → ↓ (undesired) ATP HYDROLYSIS ↓ ROS, improve ATP level, restore parkin recruitment
aSyn
- Q1: For PD program, are there any evidences for the target relevant to human PD, for example, gene mutation or up or down regulation in PD?
- Genetic input is one most important input. There is some date to suggest F-ATP does have impact on patients.
There is evidence of up (compensatory) or down (due to neuronal degeneration) regulation of F-ATPase in different brain regions PD patients (see Slide 15)
There are additional multiple intersecting connections linking PD to F-ATPase - all of the references listed in slides 10-11 that we sent provide connections to PINK1, PARK2, a-syn and DJ-1.
As far as we know, there are no direct genetic mutations in F-ATPase linked to PD; more compelling for us is the fact that intervention at F-ATPase reverses multiple Complex I mediated dysfunctions and that Complex I has recently been shown to be sufficient for PD progression (see attached Surmeier paper). This suggests to us that Complex I mediated PD pathology could be a causal, rate-limiting step in PD - no one has tested this hypothesis in humans, and LucyTx’s approach (small molecule F-ATPase hydrolase inhibition) offers the chance to do so. Multiple streams of human clinical data - increased risk of PD with extended metformin use (a Complex I inhibitor), MPTP exposure (obligatory Complex I involvement), link of sleep apnea (which disrupts Complex I through oxygen deprivation), all support Complex I dysfunction as a key driver of PD. Please also note as we mentioned in the presentation that some of the other Complex 1 subunit knockouts (NDUFS4) which have been generated do not actually stop Complex 1 activity in vivo and thus do not refute the findings of Surmeier. It may also be interesting to consider the article from Schooling (attached) which describes how the conflation of genetic risk factors with interventional target selection is both limiting the targets we are looking at and may also explain some of the failures of genetic targets in the clinic.
- Q2: For PD program, what is your planned in vivo studies?
Target engagement study - We have just finished an IRI (ischemia reperfusion study) to look at direct target engagement which can be measured using this technique both in heart and in brain. Stopping oxygen flow forces F-ATPase to run in hydrolysis mode and we can directly measure the ability of our compounds to stop the ongoing ATP hydrolysis via ATP measurements and / preservation of tissue (histopathology).
Acute and chronic rotenone studies - Please see the Greenamyre paper (attached) for evidence of how chronic low-dose rotenone mimics both the progression of PD deficits seen in humans as well as the specificity of those effects even from systemic exposure. We will be looking to reverse multiple pathologies in our low-dose rotenone model study (DA levels, a-syn levels / aggregation, midbrain neuronal degeneration and others.)
Further info on our in vivo study plans can be found on Slides 33-39 of the confidential deck as well.
- Q3: For Rett program, just if it can be disclosed, is that target mGluR5 that is already known as a potential therapeutic target for Rett syndrome?
- No - we are not looking at mGluR5 for Rett.
20240222 Ross: Philip ? wants to take mayor 2 at PE stage, but they want to keep until CS. aSyn PET is included in deal conversation. But, It would be possible we can use QST PET for AC immune’s compound PD clinical trial.
Samrara
Based on the recent meeting could folks for your area of coverage update the feedback previously provide for potential of their NeuroD and NeuroM programs:
- TRPML1
- Beclin modulator, CNS active
- Beclin modulator, peripheral
- Rab1a activator
Samrara Tx Triage Response NeuroD 2022.xlsx
Individual report (start)
| Company | Note |
|---|---|
| T3D | Alzheimer’s is a metabolic disease of the brain related to … |
| Neuracle | NS101 and the abstract of mechanisms of action report for FAM19A5-directed treatment of neurological disease. The therapeutic antibody program holds a mechanism of action for multiple diseases relating to the dysfunction of synapses, not only AD but also other neurological diseases such as ALS |
| Nuravax | company is starting a phase 1 for a first product and getting 2 more INDs next year (Tau vaccine and DUAL (Aβ + Tau) vaccine). The company stated … |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| 14-3-3 isoform table / Delta row | empty Gene cell | Delta row is shown without a YWHAH/YWHAQ gene token; preserved as empty (no inferred gene). |
| Individual report tail | T3D / Nuravax rows | rows are clipped at the right edge; the visible cells continue in 20240722_182735. |