SNCA BTV (HDO) (PFR-4067-100)

Single-program entity page for the SNCA BTV (HDO) (PFR-4067-100) α-synuclein knockdown program led by Ryouta Maeda. Promoted from the therapeutic-programs Entity Backlog. Per-axis α-synuclein narrative continues to live on alpha-synuclein § Antibody and Immunotherapy Programs / SNCA-Knockdown Programs; this page collects the program-level evidence package across the single primary source page indexed under the program nav-root. Every substantive statement links back to a source note or the canonical by-photo Markdown. Where the source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Program Overview

SNCA BTV (HDO) (PFR-4067-100) is an α-synuclein knockdown program led by Ryouta Maeda. The corpus material captures the program at the LGE / Pre-Exploratory phase: the source frames it as a heteroduplex oligonucleotide (HDO) effort with a parallel intrathecal (IT) ASO/HDO track and a transferrin-receptor-conjugated brain-transport-vehicle (BTV) track, with team prioritisation favouring HDO based on tool- molecule plasma duration and biodistribution data (20240722_181831).

The single source page (20240722_181831) documents the program plan table (LGE / PE: IT / PE: BTV / CN / CS / IND phase columns with 2018 (?) LGE marker, PE: within FY2022 for IT and the deferred BTV PE, Selected 18개 18mer ASO in vitro screen, Pilot in vivo -> Select one or two ASO, 50% KD (m RNA, at low dose to secure safety margin). Animal model TBD, But SNCA BAC TG (human WT aSyn) is unlikely b/c it does not show pathologic aSn, Focal necrosis is important, Maiko wants to clear this in mice (it is not clear whether this is PE criteria), and NHP biodistribution before CN); the DMPK MTV ASO-vs-HDO selection rationale (HDO prioritised because of long plasma duration, better biodistribution, and TfR-conjugated HDO showing better distribution than TfR-conjugated ASO by tool molecules; ASO not excluded; HDO timeline not significantly different from ASO although some additional work is needed); the Ryouta Maeda program notes (202104 rationale for moving from systemic to IT due to low CNS exposure, no cholesterol ligand, Still system option by transferrin (peptidream, Denali), Expected dosing frequency: Every 1-3 m; 20200702 PD and disease progression marker proposal of total / oligomer α-syn in CSF and SNCA mRNA in plasma NDE as TE marker similar to MAPT HDO PJ; 20220713 differentiation against IONIS IT SNCA ASO BIIB101 by potency, the program’s parallel evaluation of HDOs and IONIS ASOs by ICV in model mice, and the firewall-bound non-disclosure of the Wave-collaboration discontinuation reason and the MAPT HDO IT failure narrative); the 20230630 differentiation question list anchored on the BIIB101 / ION464 Cole 2021 reference; the SharePoint folder URL preserved verbatim because of SCNA vs SNCA, percent-encoding, and long-View token visual ambiguity; the Translation table mapping program readouts (PK, TE / exposure aSyn mRNA across monomeric / phosphorylated / oligomeric forms / regional, ↓ aSyn protein and neuroprotection, TfR1 PET / ASO NDE mRNA / aSyn spreading NHP / P aSyn / RT-QuIC / total aSyn CSF / ASYN PET (QST) / Retinal BM / MIBG / DATscan / Vmri for LBD); the HDO PET Needs And Questions block explaining that ASOs have notoriously poor penetration in deep brain and subcortical structures and that the purpose of HDO PET is to visualise drug distribution (not TE / TO) with quantification as the caveat, with parallel ASO PET work led by Paul McQuade; the four Paul McQuade 20200923 technical questions for HDO PET feasibility (plasma/brain ratio change over time, chemical-modification impact on HDO PK, imaging duration vs label half-life with Up to 6 h (F), up to 10 days (I, Zr), >10 days (Pre-targeting) options, and clinical translatability with Correct preclinical model and Dosimetry sub-points); and the HDO PET Development Workflow flowchart (Figure 20200521, Steps 1–4 with go/no-go gating — Step 1 PK study to compare plasma-to-brain ratios over time → Step 2 chemical-modification PK impact → Step 3 rodent PET imaging protocol → Step 4 preclinical-species translatability).

Source Scope And Boundary Notes

This entity is a single-source program: only 20240722_181831 carries the program nav root SNCA BTV (HDO) (PFR-4067-100) as its first nav_path entry, and it is the only page indexed under snca-btv-hdo-pfr-4067-100. The page is fully included for evidence; the program nav root is the first nav_path entry, so the strict “first nav_path entry == program nav root” rule applies without exception.

Adjacent material that is excluded from this entity:

• The α-synuclein Tier 1 page aSyn programs > aSyn Propagation Suppressor (20240722_181827) carries a portfolio-grid row labelled SNCA BTV (Brain Transport Vehicle: ASO/HDO + transferrin receptor (TfR) ligand): Maeda Ryota (SNCA HDO의 후예). The page also contains the SNCA BTV TfR construct cell flagged as a PaddleOCR TfR vs Apple TTR reading ambiguity per alpha-synuclein § Uncertainties Carried Forward. That umbrella page is the canonical owner of the aSyn programs umbrella and is delegated to the upcoming entities/programs/asyn-propagation-suppressor backlog candidate per therapeutic-programs; the BTV / HDO row there is referenced via Related Pages rather than re-narrated here.
• The α-synuclein Tier 1 page SNCA ASO (WAVE) > Clinical plan of SNCA ASO (20240722_181835) is the sibling SNCA-knockdown program entry covered by alpha-synuclein § Antibody and Immunotherapy Programs (SNCA ASO (WAVE) sub-axis); the SNCA BTV (HDO) program references it indirectly through the IT ASO/HDO comparison narrative (the team is “currently prioritizing HDO” but “not excluded ASO” — see the DMPK MTV row of the Evidence Package below). The SNCA ASO source is referenced via Related Pages rather than re-narrated here.
• The α-synuclein Tier 1 page TAK-341 (MEDI1341) > Clinical studies (20240722_181822) is the sibling antibody-modality program; it does not reference SNCA BTV (HDO). The TAK-341 page is referenced via Related Pages for cross-modality navigation only.
• The cross-pipeline Pipeline-of-PD aSyn - Antibody / aSyn - Small molecules / aSyn - Vaccine competitor-inventory pages (20240722_184324, 20240722_184327, 20240722_184330) do not list SNCA BTV / HDO modality rows. They are excluded from this entity and remain owned by alpha-synuclein § Antibody and Immunotherapy Programs and by tak-341 for the TAK-341 / MEDI1341 cross-pipeline rows.

The page does not appear under the Pipeline of GD & GBA-PD inherited-thread band in the nav_path (its first entry is SNCA BTV (HDO) (PFR-4067-100) — a free-standing program nav root, not a Pipeline of GD & GBA-PD > … > SNCA BTV … sub-path), so the entity scope is unambiguously the single nav-rooted page.

Evidence Package

evidence area	source-captured detail	source
SNCA BTV (HDO) Plan Table — phase columns	Six-column matrix LGE / PE: IT / PE: BTV / CN / CS / IND with 2018 (?) LGE marker; PE:IT row notes possibility to develop for MSA. PE: within FY2022. However, we have to confirm the thought of TAU for IT asset generation, because Wave collaboration was discontinued and MAPT HDO IT failed; PE:BTV row notes PE within FY2022 would be difficult because of lack of preparation for peptide ligand selection and animal model.; CN / CS / IND cells are blank in the visible photo.	20240722_181831
SNCA BTV (HDO) Plan Table — in vitro / in vivo / safety / note	PE:IT in vitro Selected 18개 18mer ASO; PE:IT in vivo Pilot in vivo -> Select one or two ASO; CN in vivo 50% KD (m RNA, at low dose to secure safety margin). Animal model TBD, But SNCA BAC TG (human WT aSyn) is unlikely b/c it does not show pathologic aSn; PE:IT safety Focal necrosis is important, Maiko wants to clear this in mice (it is not clear whether this is PE criteria); PE:IT note NHP biodistribution before CN.	20240722_181831
DMPK MTV — ASO vs HDO selection rationale	About ASO vs HDO in TfR construct, team is not excluded ASO and will select ASO or HDO by direct comparison. Team is currently prioritizing HDO because it generally has long duration in plasma and better biodistribution, and TfR conjugated HDO showed better distribution than TfR conjugated ASO by tool molecules. Timeline for HDO is not significantly different from that for ASO although some additional works are needed for HDO.	20240722_181831
Ryouta Maeda 202104 note — IT rationale and dosing frequency	System to IT due to low exposure in CNS. PLAN: no cholesterol ligand. Still system option by transferrin (peptidream, Denali). Expected dosing frequency: Every 1-3 m.	20240722_181831
Ryouta Maeda 20200702 / 20200908 note — biomarker plan	Briefly, I think PD marker is total a-syn in CSF and disease progression marker is oligomer a-syn in CSF. If TE marker is needed, SNCA mRNA in plasma NDE is suitable same as MAPT HDO PJ. 20200908: Oligomer aSyn is also important (rather than RT-Quic). Reason: This should be used in vivo assay -> 다른 commercial kit 쓰면 될 테니 이건 이유 아닐걸? NDE is important.	20240722_181831
Ryouta Maeda 20220713 note — IONIS BIIB101 differentiation, Wave discontinuation, MAPT HDO IT failure	(in this case it would be important how we differentiate from Ionis IT SNCA ASO, BIIB101. Any thoughts?) We currently think that it might be potency, because there is no report about issues of BIIB101 such as efficacy, safety or duration. But it would be difficult. There are two candidate ASOs from the literature and they showed potent KD efficacy in NHP. Now we are evaluating the KD activity of our HDOs and these IONIS ASOs in model mice by ICV administration to confirm whether our HDOs would show more potent KD activity than that of IONIS's ASOs at least in mice. (can you briefly help me better understand why the Wave collaboration was discontinued?) We don't know the reason of discontinuation of Wave collaboration because of firewall. (can you briefly help me better understand why MAPT HDO IT failed?) MAPT IT HDO PJ could successfully identify the molecule for NHP study. However, we could not appropriately evaluate PK/PD in NHP by IT administration due to technical issues of IT administration at domestic CRO. When we considered the competitiveness with IONIS-MAPTRX and timing of IT asset generation, we decided to focus on BTV asset generation based on business decision. HDO - IT, BTV - IV/SC. To be determined: both in parallel? Or focus on one? 아마: If our HDO (IT) could clearly overcome and differentiate from IONIS's ASO, in terms of KD potency in model mice (by ICV administration) -> then we would focus on HDO asset generation. If not -> develop BTV.	20240722_181831
20230630 Differentiation Table — open questions	Differentiation against IONIS's clinical candidate, hASO2, on KD depth and duration in model mice (~the end of September 2023); comparator anchor BIIB101 / ION464: Cole 2021; competing-area question Main competing area?; sub-questions Target KO?, PD vs MSA?, When PE expected?.	20240722_181831
Sharefolder URL	https://mytakeda.sharepoint.com/sites/InterACT-RAD-Pipeline/NS%20DDU_SCNA%20HDO/Shared%20Documents/Forms/AllItems.aspx?RootFolder=%2Fsites%2FInterACT%2DRAD%2DPipeline%2FNS%20DDU%5FSCNA%20HDO%2FShared%20Documents%2FMeetings&FolderCTID=0x012000D7F9E92FDE58334CB1FADE7001FC1232&View=%7B212C47DA%2D0A74%2D43B7%2DA7AD%2DBCF640FA2E81%7D — preserved verbatim because SCNA/SNCA, percent-encoding, and the long View token are visually ambiguous (see Uncertainties below).	20240722_181831
Translation table — aSyn readouts and biomarker axes	PK row Exposure; TE / exposure rows ↓ aSyn m RNA with three sub-questions (Does it knock down both WT and mutant aSyn? -> it acts on intro, so if the mutation is in exon, then it works.; Does it knock down all forms (monomeric, phosphorylated, oligomeric?) -> yes, because it acts on m RNA. Shall ARNU look at these various forms?; Regional? Deep structure 잠입어려우니 cortex에 더 효과? Shall ARNU do histology?); protein / neuroprotection row ↓ aSyn protein; neuroprotection; Shall ARNU count neurons in various regions? Correlation between these two?; BM row TfR1 PET; ASO; NDE m RNA (from SNCA ASO PRC narrative for PE).; BM row aSyn / imaging readouts aSyn spreading NHP?; P aSyn; RT Quic; Total aSyn CSF; Asyn PET (QST); BM row other readouts Retinal BM?; MIBG?; DATscan; Vmri for LBD.	20240722_181831
HDO PET Needs And Questions — purpose, caveat, lead	ASOs have notoriously poor penetration in deep brain structures (basal ganglia) and other subcortical structures. Lowering of mHTT in patient lumbar CSF as "distal" biomarker of target engagement does not establish origin of this PD effect (spinal cord, cortex, other?). Purpose: visualise drug distribution (not TE, TO). Caveat: it is uncertain how to quantify? How much is enough?; development stage currently similar efforts for ASOs led by Paul McQuade.	20240722_181831
Paul McQuade 20200923 technical questions — HDO PET feasibility	Platform note Paul McQuade: 20200923: this is (theoretically) platform, as long as we use cholesterol-tagging too. And we can start from the step 3.; Q1 Does the plasma/brain ratio of HDO change over time (안 변하면 굳이 pet 필요 없다는 의미 인듯.; Is there differential clearance between these tissues, i.e does it clear slower from the brain than plasma. This would allow for Imaging to potentially quantify non-invasively brain accumulation of these constructs.); Q2 Impact chemical modification has on HDO pk profile (radioisotope붙여도 pk나 tissue distribution등이 안 변해야 함.; Compare modified and non-modified ASO/HDO; -> Tomimatsu: 20200923: we are doing cold studies, will get results Jan 2021.); Q3 How long is needed to be able to image the labeled HDOs, this will impact imaging strategy (Up to 6 h (F), up to 10 days (I, Zr) or >10 days (Pre-targeting)); Q4 Clinical transability of imaging approach (Correct preclinical model; Dosimetry).	20240722_181831
HDO PET Development Workflow (20200521 flowchart)	Step 1: PK study to compare plasma-to-brain ratios of HDOs over time → Does plasma-to-brain ratio change over time? (No -> Terminate PET effort; Yes -> Step 2); Step 2: Impact of chemical modification on HDOs → Does modification significantly impact HDO PK? (No -> Step 3); Step 3: Optimize PET Imaging protocol in rodents → Can PET quantify regional brain uptake of HDOs? (Yes -> Step 4); Step 4: Optimize PET Imaging protocol in preclinical species → Is imaging method clinically translatable? (Yes -> Continue PET effort).	20240722_181831

Key Source Interpretations

interpretation	source
The program plan is recorded in source as a six-column LGE / PE:IT / PE:BTV / CN / CS / IND matrix, with the LGE marker 2018 (?) carrying its question mark verbatim and PE:IT slated within FY2022 while PE:BTV is described as would be difficult because of lack of preparation for peptide ligand selection and animal model. The CN / CS / IND cells are blank in the visible photo; downstream readers should not infer values for those cells from the IT or BTV columns.	20240722_181831
The DMPK MTV row records team prioritisation of HDO over ASO based on tool-molecule data — long plasma duration, better biodistribution, and TfR-conjugated HDO out-distributing TfR-conjugated ASO — while explicitly stating that ASO is not excluded and that selection between ASO and HDO will be made by direct comparison. The HDO timeline is recorded as not significantly different from that for ASO although some additional works are needed for HDO.	20240722_181831
Ryouta Maeda’s 202104 note records the route choice as systemic-to-IT driven by low CNS exposure, with no cholesterol ligand as the plan and Still system option by transferrin (peptidream, Denali) as the systemic alternative. The expected dosing frequency is recorded as Every 1-3 m.	20240722_181831
The biomarker plan in source separates PD marker (total a-syn in CSF) from disease-progression marker (oligomer a-syn in CSF) and proposes SNCA mRNA in plasma NDE as the TE marker analogous to MAPT HDO PJ; the 20200908 follow-up records Oligomer aSyn is also important (rather than RT-Quic) and flags NDE as important, with the inline JS aside 다른 commercial kit 쓰면 될 테니 이건 이유 아닐걸? preserved verbatim.	20240722_181831
Differentiation against IONIS’s IT SNCA ASO BIIB101 is described in source as likely a potency play (no reported BIIB101 issues on efficacy, safety, or duration); the program is evaluating its HDOs alongside two literature ASOs in model mice by ICV administration to test whether HDOs achieve more potent KD than IONIS ASOs.	20240722_181831
The Wave-collaboration discontinuation reason is recorded as unknown to the source author (firewall); the MAPT HDO IT failure is recorded as a domestic-CRO IT-administration technical issue rather than a molecular failure (MAPT IT HDO PJ could successfully identify the molecule for NHP study. However, we could not appropriately evaluate PK/PD in NHP by IT administration due to technical issues of IT administration at domestic CRO), with the business decision recorded as a pivot to BTV asset generation. The same passage records the IT-vs-BTV gating rule If our HDO (IT) could clearly overcome and differentiate from IONIS's ASO, in terms of KD potency in model mice (by ICV administration) -> then we would focus on HDO asset generation. If not -> develop BTV.	20240722_181831
The 20230630 differentiation question list anchors competitive evaluation on IONIS's clinical candidate, hASO2, on KD depth and duration in model mice (~the end of September 2023) with BIIB101 / ION464: Cole 2021 as the literature anchor; sub-questions Target KO?, PD vs MSA?, and When PE expected? are listed without resolved answers in the visible photo.	20240722_181831
The Translation table records aSyn-mRNA knockdown as the TE / exposure axis with three open sub-questions (WT vs mutant via intronic action, monomer / phosphorylated / oligomeric form coverage, regional / cortex penetration), pairs ↓ aSyn protein with neuroprotection as the protein-and-neuroprotection axis, and lists candidate biomarkers TfR1 PET, ASO NDE mRNA (from SNCA ASO PRC narrative for PE), aSyn spreading NHP, P aSyn, RT Quic, Total aSyn CSF, Asyn PET (QST), Retinal BM, MIBG, DATscan, and Vmri for LBD.	20240722_181831
The HDO PET workstream’s stated purpose is visualise drug distribution (not TE, TO), with an explicit caveat that quantification methodology is uncertain (it is uncertain how to quantify? How much is enough?); the program references parallel ASO PET work led by Paul McQuade as the comparator effort and adopts the four 20200923 Paul McQuade technical questions and the 20200521 Step 1–4 workflow as the program’s HDO PET feasibility decision tree.	20240722_181831

Source Table

stem	nav path	source note	canonical	uncertain spans	embedded images
20240722_181831	SNCA BTV (HDO) (PFR-4067-100) > Executive summary (Ryouta Maeda)	note	md	10	1

1 source; uncertain_span_count totals 10; embedded_image_count totals 1. The single body-embedded figure asset is the HDO PET Development Workflow flowchart (20200521) at data/processed/assets/by-photo/20240722_181831/figure_hdo_pet_workflow.jpg. The figure is linked rather than re-embedded on this entity page per the 2026-04-29 body-purity decision; the figure-only embed remains at the canonical by-photo level. The source-note nav_path is inferred from the body heading and statusbar nav headings; the source preserves that inference and the Uncertain Spans row labelled nav path (see Uncertainties Carried From Source below).

Figure / Asset Groups In Source

source

figure group

20240722_181831

HDO PET Development Workflow flowchart (figure_hdo_pet_workflow.jpg, dated 20200521): Step 1 plasma-to-brain PK gate → Step 2 chemical-modification PK impact → Step 3 rodent PET imaging protocol → Step 4 preclinical-species translatability. The photographed page cuts the diagram near the lower edge; the visible nodes were retained but continuation below the photo cannot be ruled out (see Uncertainties Carried From Source).

Uncertainties Carried From Source

issue	source
nav_path SNCA BTV (HDO) (PFR-4067-100) > Executive summary (Ryouta Maeda) is inferred from the body heading and nearby nav headings; the statusbar also shows nearby SNCA ASO (WAVE) and Executive summary (Ashina, Shuntaro), so the body heading is treated as stronger evidence but the inference is recorded.	20240722_181831
Page label Page 34 of 40 is agreed by Apple Vision and PaddleOCR but nearby pages may have different statusbar counts depending on the active Word/document state.	20240722_181831
SNCA BTV phase-table cells preserve visible spelling/spacing where the source itself or OCR is ambiguous: aSn, m RNA, b/c, and the NHP biodistribution befoe CN typo.	20240722_181831
DMPK MTV row tokens TfR construct, tool molecules, and long duration in plasma are readable but line wrapping and spacing are cramped — re-check before downstream extraction.	20240722_181831
Ryouta Maeda 20220713 paragraph carries high-risk drug / program names (Ionis IT SNCA ASO, BIIB101) and the IONIS ASO potency claim; visually readable but should be reviewed before KB extraction.	20240722_181831
SharePoint URL has SCNA vs SNCA ambiguity and a long View token; the URL is wrapped and partly near the page edge. Do not normalize without manual check.	20240722_181831
Translation-table intro token could mean intron; source text appears as intro, so it is left unchanged.	20240722_181831
Translation-table tokens Vmri for LBD and Asyn PET (QST) carry small text and OCR disagreement on exact capitalisation / letters.	20240722_181831
HDO PET questions tokens Clinical transability and isotope labels (F), (I, Zr) are preserved as visible text; likely intended wording / notation may need correction.	20240722_181831
HDO PET workflow flowchart bottom is clipped near the lower edge of the photographed page; visible nodes were retained but continuation below the photo cannot be ruled out.	20240722_181831

Related Pages

• alpha-synuclein — α-synuclein topic synthesis (Tier 1); the program-axis narrative for SNCA BTV (HDO) (PFR-4067-100) lives under § Antibody and Immunotherapy Programs / SNCA-Knockdown Programs, with the umbrella view at § SNCA-Knockdown Programs (umbrella).
• therapeutic-programs — program-routing map; this entity page is the canonical owner for the SNCA BTV (HDO) (PFR-4067-100) row that was previously listed as an Entity Backlog Candidate.
• snca-btv-hdo-pfr-4067-100 — per-nav-root index for SNCA BTV (HDO) (PFR-4067-100) (1 source — the single Executive summary page).
• gba-pd-asyn — section index containing the single source used here.
• alpha-synuclein-source-boundary — α-synuclein Tier 1 / Tier 2 / Tier 3 inclusion-and-delegation map; SNCA BTV (HDO) is under Programs and Standalone Nav-Roots.
• source-catalog — all 447 sources in capture order.
• nav-path-index — 376 distinct nav_paths.
• tak-341 — sibling α-synuclein program entity (passive-immunotherapy modality; same in-house program-entity precedent for an aSyn-knockdown / aSyn-targeting asset).
• parkn-gt — sibling program entity (different modality class; same in-house program-entity precedent).
• nlrp3-inhibitor — sibling program entity (small-molecule modality; same program-entity precedent).
• pr001 — pilot-scope GBA gene-therapy program entity (sibling within the GBA-PD pilot).