SNCA ASO (WAVE)

Single-program entity page for the Takeda–Wave Life Sciences SNCA antisense oligonucleotide (RNase-H ASO targeting SNCA mRNA). 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 ASO (WAVE) is an α-synuclein knockdown program developed under the Takeda–Wave collaboration (Takeda-Wave Collaboration Confidential / Takeda-Wave MAPT/SNCA JPT, footer dated April 29, 2021); the program is captured in source as an intrathecal (IT) RNase-H ASO targeting SNCA mRNA, with WAVE-prefixed clone IDs (WV-36397, WV-37643, WV-39172, WV-42827) evaluated head-to-head against IONIS reference ASOs in A53T SNCA transgenic mice (20240722_181835).

The single source page (20240722_181835) documents the SNCA ASO PK/PD Relationship In Transgenic Mice block (In vitro / In vivo lead-in, Single ICV, 100 ug, A53T SNCA mice → 2w 후 분석: 1.2-1.9x better KD (vs IONIS), 3.5-7.4x better Exposure (vs Ionis); the four-clone PK/PD table in cortex and striatum with t1/2 (week), IC50** (ug/g), Imax, and Projected KD at 8 weeks at 100 ug/g rows; footnotes explaining NE: not estimated, * No concentration change or slight concentration increase over 4 weeks, ** PKPD relationship is based on direct PKPD relationship, *** Indirect model estimate presented as a more conservative estimate as compared direct model estimate (0.05 ug/g), and the projected-KD extrapolation rule); the Clinical Plan Of SNCA ASO (P1b/2 design row with IT, Early PD, 3-4 dose levels will be tested, Q monthly dosing -> Q3 m, sentinel-then-expansion sample-size logic N=2 → N~4/arm → N~15/arm once PD effects on CSF aSyn are noted at <=6 mo, milestone POM will be informed by CSF aSyn. ePOC will be informed by NfL and DaT or VMAT2 imaging at ~ month 12., and the Proposed Ph1b/2 Study diagram with FIH study / Extension study / Q mo dosing / Measure t1/2 / Q 3mo dosing / Dosing / CSF aSyn / DaT scan or VMAT2 PET labels); the PET SNCA ASO biodistribution narrative covering SNCA ASO, HDO PET : a-syn ASO central biodistribution, Takeda Imaging’s radiolabel-development plan to map relative brain ASO concentration in striatum vs cerebral cortex, and the injection- paradigm dependence (cardiac-cycle synchronisation, saline-chaser strategies) drawn from prior ASO experience; and the SNCA ASO Questions block split across Target Population (PD (early vs late) vs MSA?), Target aSyn KD Efficacy (PD priority over MSA, maximal safety-bound KD not sure, MOUSE & NHP translation, mRNA-vs-protein effect on total, p-asyn, oligomeric with staining not done, NDE), PK/PD (NHP spreading-model use for human dose estimation and key go/no-go criteria, the long Phase-2-gating paragraph anchored on initial data expected by July 2020 for an NHP α-syn spreading model to set CSF a-syn reduction targets, and Mouse spreading model ever tested? -> no), and Administration (IT, Frequency (3m, but TAU prefers ICV device, removal is easy)).

Source Scope And Boundary Notes

This entity is a single-source program: only 20240722_181835 carries the program nav root SNCA ASO (WAVE) as its first nav_path entry, and it is the only page indexed under snca-aso-wave. The page is fully included for the SNCA ASO portion of its content; the program nav root is the first nav_path entry, so the strict “first nav_path entry == program nav root” rule applies without exception at the nav-root level.

The same canonical photo also carries unrelated TAK-071 program content (TAK-071 Clinical Plan, TAK-071 Cognition Result Note, TAK-071 Power Table Fragment, plus the body-embedded diagram_tak071_crossover_design.jpg figure asset). That TAK-071 material is out of scope for this entity and remains owned by therapeutic-programs § Entity Backlog Candidates TAK-071 row and by gba-pd-asyn; the canonical TAK-071 nav-root page is 20240722_181839 (note; md). The Evidence Package, Key Source Interpretations, Source Table, and figure-group rows below cover only the SNCA ASO portion of 20240722_181835; the TAK-071 portion of the same page is referenced via Related Pages rather than re-narrated here.

Adjacent material that is excluded from this entity:

• The α-synuclein Tier 1 page SNCA BTV (HDO) (PFR-4067-100) > Executive summary (Ryouta Maeda) (20240722_181831) is the sibling SNCA-knockdown program covered by snca-btv-hdo; the SNCA BTV (HDO) page references SNCA ASO (WAVE) indirectly through its IT ASO/HDO comparison narrative (Team is currently prioritizing HDO ... ASO not excluded ... Timeline for HDO is not significantly different from that for ASO) and through the Ryouta Maeda 20220713 differentiation paragraph against IONIS’s BIIB101, but it does not carry SNCA ASO (WAVE) program data tables. The SNCA BTV (HDO) page is referenced via Related Pages rather than re-narrated here.
• The α-synuclein Tier 1 page aSyn programs > aSyn Propagation Suppressor (20240722_181827) carries portfolio-grid rows that include the SNCA ASO modality in its SM-vs-mAb-vs-ASO/NAM differentiation tables and the broader aSyn programs umbrella. That 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 SNCA ASO row there 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 owned by tak-341. It does not carry SNCA ASO (WAVE) program data tables; 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 a SNCA ASO (WAVE) row; they cover passive antibodies, small-molecule aggregation/propagation modulators, and vaccines rather than ASO-modality programs. They remain owned by alpha-synuclein § Antibody and Immunotherapy Programs and by tak-341 for the TAK-341 / MEDI1341 cross-pipeline rows.
• The IONIS comparator BIIB101 / ION464 (Cole 2021) referenced as the SNCA ASO competitive anchor is recorded on the SNCA BTV (HDO) source page (20240722_181831) rather than on the SNCA ASO (WAVE) source page; per the cross-program rule on therapeutic-programs § Entity Backlog Candidates, IONIS BIIB101 / ION464 is treated as external comparator evidence and is not promoted to a program row on this entity page.

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

Evidence Package

evidence area	source-captured detail	source
SNCA ASO PK/PD lead-in — In vivo design and headline KD/exposure ratios	In vitro / In vivo; Single ICV, 100 ug, A53T SNCA mice, -> 2w 후 분석: 1.2-1.9x better KD (vs IONIS); 3.5-7.4x better Exposure (vs Ionis); followed by the [PK/PD] per-clone table.	20240722_181835
SNCA ASO PK/PD table — cortex rows	Per-clone (WV-36397 / WV-37643 / WV-39172 / WV-42827) cortex t1/2 (week) (2.82 / 3.77 / >4 weeks* / >4 weeks*), IC50** (ug/g) (2.78 / 0.35 / 0.87 / 1.00), Imax (only WV-39172 populated at 0.78; other columns visibly blank), and Projected KD at 8 weeks at 100 ug/g (21% / 68% / 54% / 61%).	20240722_181835
SNCA ASO PK/PD table — striatum rows	Per-clone striatum t1/2 (week) (3.67 / >4 weeks* / 3.80 / 7.86), IC50** (ug/g) (0.67 / NE* / 0.22*** / 0.49), Imax (only WV-39172 populated at 0.62; other columns visibly blank), and Projected KD at 8 weeks at 100 ug/g (26% / NE* / 62% / 56%).	20240722_181835
SNCA ASO PK/PD footnotes	NE: not estimated due lack of enough data for model estimation; * No concentration change or slight concentration increase over 4 weeks; ** PKPD relationship is based on direct PKPD relationship.; *** Indirect model estimate presented as a more conservative estimate as compared direct model estimate (0.05 ug/g); the projected-KD extrapolation footnote Projected based on direct response model except for WV-39172; if t1/2 not available for one matrix, assume t1/2 from the other; if t1/2 not available, assume t1/2 of 6 weeks and use concentration at 6 weeks for extrapolation; deck footer Takeda-Wave Collaboration Confidential / Takeda-Wave MAPT/SNCA JPT / April 29, 2021 / 44.	20240722_181835
Clinical Plan Of SNCA ASO — P1b/2 design row	P1b/2 row design IT, Early PD, 3-4 dose levels will be tested, Q monthly dosing -> Q3 m; sample-size sequencing initially sample size expected to be N=2 sentinel dosing, then N~4/arm; expansion gate when PD effects are noted based on CSF aSyn levels at <=6 mo, expansion to N~15/arm is planned; milestone POM will be informed by CSF aSyn. ePOC will be informed by NfL and DaT or VMAT2 imaging at ~ month 12.; PK/PD column visibly blank in this row.	20240722_181835
Clinical Plan Of SNCA ASO — Proposed Ph1b/2 Study diagram	Visible labels inside the design diagram: Proposed Ph1b/2 Study, FIH study, Extension study, Q mo dosing, Measure t1/2, Q 3mo dosing, Dosing, CSF aSyn, DaT scan or VMAT2 PET. The diagram is preserved as the body-embedded asset diagram_snca_aso_ph1b2_design.jpg because the dosing / sampling schedule is easier to inspect visually than as text alone.	20240722_181835
PET SNCA ASO biodistribution plan	SNCA ASO, HDO PET : a-syn ASO central biodistribution: Takeda Imaging is developing novel methods to radiolabel the a-syn ASO in order to be able to track its CNS biodistribution via PET imaging. If successful, this approach will enable the relative brain concentration of the ASO to be mapped throughout the brain, and hence to inform on parenchymal ASO exposure in the striatum relative to the cerebral cortex.; injection-paradigm dependence This imaging method will also provide a readout that can be used to optimize the injection paradigm to obtain the desired brain penetration and distribution. Studies using this approach with other ASOs have shown that the amount and distribution of IT-injected ASO in the brain can strongly depend on the injection paradigm - strategies such as synchronizing the injection to the cardiac cycle to capitalize on the pulsatile nature of CSF flow or the use of a saline chaser after the ASO injection have been reported to increase brain penetration.	20240722_181835
SNCA ASO Questions — Target Population	PD (early vs late) vs MSA?	20240722_181835
SNCA ASO Questions — Target aSyn KD Efficacy	in PD patients and MSA patients? -> PD is priority. Don't have data in MSA.; maximal KD from safety perspective -> not sure; translation from MOUSE & NHP; mRNA but effect on protein? with sub-bullets total, p-asyn, oligomeric -> staining not done and NDE?.	20240722_181835
SNCA ASO Questions — PK/PD	NHP spreading model will be used for human dose estimation a(and biomarker calibration?)? a Key go/no-go criteria? -> will be used; the Phase-2-gating paragraph A key question is the degree of a-syn reduction that is needed to advance the asset to Phase 2 studies. Studies are ongoing to validate a non-human primate model of a-syn spreading, with initial data expected by July 2020. If successful, this model can be used to test multiple doses of a a-syn ASO to determine which doses are effective in blocking a-syn spreading. In addition, this model will allow CSF a-syn levels to be related quantitatively to the degree of inhibition of spreading in disease relevant brain regions, which will allow target values for CSF a-syn reduction to be set objectively.; Mouse spreading model ever tested? -> no.	20240722_181835
SNCA ASO Questions — Administration	IT, Frequency (3m, but TAU prefers ICV device, removal is easy).	20240722_181835

Key Source Interpretations

interpretation	source
The SNCA ASO PK/PD package is recorded in source as a single-ICV, 100 µg, A53T SNCA-mouse comparison against IONIS reference ASOs, with the headline ratios 1.2-1.9x better KD (vs IONIS) and 3.5-7.4x better Exposure (vs Ionis) framing the program’s KD/exposure differentiation claim. The deck footer attributes the data to the Takeda-Wave Collaboration Confidential / Takeda-Wave MAPT/SNCA JPT package dated April 29, 2021.	20240722_181835
The four-clone PK/PD table records WAVE-prefixed clone IDs (WV-36397, WV-37643, WV-39172, WV-42827) with per-tissue (cortex / striatum) t1/2 (week), IC50** (ug/g), Imax, and Projected KD at 8 weeks at 100 ug/g. Imax is populated only for WV-39172 in both cortex (0.78) and striatum (0.62); the other three clones’ Imax cells are visibly blank in the source and the SNCA PK/PD Imax placement under WV columns is recorded as an Uncertain Span (see Uncertainties Carried From Source) — downstream readers should not infer values for the blank Imax cells. The >4 weeks* and NE* cells carry the asterisk footnotes verbatim.	20240722_181835
The Clinical Plan Of SNCA ASO is recorded as a P1b/2 design with intrathecal administration in early PD, 3–4 dose levels, and a dosing-cadence transition from Q monthly dosing to Q3 m. Sample size is sequenced as N=2 sentinel → N~4/arm → N~15/arm, with the expansion gate triggered when PD effects are noted based on CSF aSyn levels at <=6 mo. The PK/PD column for this row is visibly blank in the source.	20240722_181835
The Phase-1b/2 milestone language separates POM from ePOC: POM will be informed by CSF aSyn, while ePOC will be informed by NfL and DaT or VMAT2 imaging at ~ month 12. This explicitly anchors the program’s biomarker-readout strategy on CSF aSyn (proximal target engagement) and on NfL plus DaT or VMAT2 imaging (distal-effect / progression).	20240722_181835
The PET SNCA ASO axis is framed as a Takeda-Imaging-led radiolabel development effort to map relative brain ASO concentration (striatum vs cerebral cortex) and to optimise the injection paradigm; the source explicitly cites cardiac-cycle synchronisation and saline-chaser strategies as prior-ASO precedents that increase brain penetration. The PET work is described as biodistribution (parenchymal exposure mapping) rather than TE / TO. The parallel HDO PET workstream owned by snca-btv-hdo is referenced indirectly through the shared SNCA ASO, HDO PET heading text.	20240722_181835
The SNCA ASO Questions block records four open-question categories with explicit go/no-go framing: target population (PD (early vs late) vs MSA?), KD efficacy (PD priority over MSA, MOUSE & NHP translation, mRNA-vs-protein effect on total, p-asyn, oligomeric with staining not done, NDE), PK/PD (NHP spreading model used as the human-dose-estimation gating tool with initial data expected by July 2020; mouse spreading model not yet tested), and administration (intrathecal, 3-month frequency with TAU prefers ICV device for removability). The a(and biomarker calibration?)? a Key go/no-go criteria? shorthand is recorded as an Uncertain Span and is preserved verbatim rather than normalised.	20240722_181835
The Phase-2-gating paragraph anchors the human-dose-target derivation on the NHP α-syn spreading model: if validated, the model will be used to test multiple doses to determine which doses block α-syn spreading and to relate CSF a-syn levels quantitatively to disease-relevant brain-region spreading inhibition, allowing CSF a-syn reduction targets to be set objectively. Mouse spreading model ever tested? -> no is recorded verbatim and frames the NHP model as the program’s only spreading-model gating tool at the time of capture.	20240722_181835
Across the program, the source treats Q3 m as the dosing-cadence target for IT administration but flags that TAU prefers ICV device, removal is easy, indicating the route choice within IT (intrathecal lumbar puncture vs ICV-device implant) was unresolved at capture and is delegated to the TAU stakeholder.	20240722_181835

Source Table

stem	nav path	source note	canonical	uncertain spans	embedded images
20240722_181835	SNCA ASO (WAVE) > Clinical plan of SNCA ASO	note	md	7	2

1 source; uncertain_span_count totals 7; embedded_image_count totals 2. Of the two body-embedded figure assets on this page, only the SNCA ASO Proposed Ph1b/2 Study design diagram (data/processed/assets/by-photo/20240722_181835/diagram_snca_aso_ph1b2_design.jpg) is in scope for this entity; the second figure (data/processed/assets/by-photo/20240722_181835/diagram_tak071_crossover_design.jpg) belongs to the TAK-071 portion of the same canonical photo and is out of scope here per Source Scope And Boundary Notes. Both figures are linked rather than re-embedded on this entity page per the 2026-04-29 body-purity decision; the figure-only embeds remain at the canonical by-photo level. The source-note nav_path is inferred from the body content and visible navigation headings, and the source preserves that inference and the Uncertain Spans row labelled navigation path (see Uncertainties Carried From Source below).

Figure / Asset Groups In Source

source

figure group

20240722_181835

SNCA ASO Proposed Ph1b/2 Study design diagram (diagram_snca_aso_ph1b2_design.jpg): visible labels Proposed Ph1b/2 Study, FIH study, Extension study, Q mo dosing, Measure t1/2, Q 3mo dosing, Dosing, CSF aSyn, DaT scan or VMAT2 PET. Preserved as a body-embedded asset because the dosing / sampling schedule is easier to inspect visually than as text alone. The TAK-071 crossover diagram on the same canonical photo (diagram_tak071_crossover_design.jpg) is out of scope for this entity (see Source Scope And Boundary Notes).

Uncertainties Carried From Source

issue	source
nav_path SNCA ASO (WAVE) > Clinical plan of SNCA ASO; related TAK-071 > Clinical plan is inferred from body content and visible navigation headings — the active nav highlight is not crisp in the crop.	20240722_181835
SNCA PK/PD table — Imax placement under WV columns: the Imax values appear centered/merged in the source table and were transcribed as visible (only WV-39172 populated in cortex 0.78 and striatum 0.62), but column alignment should be checked against the image asset before downstream extraction.	20240722_181835
SNCA PK/PD footnotes — final projected-KD footnote marker: the left side of the footnote line is partly clipped / low contrast; wording was reconstructed from visible text plus OCR agreement.	20240722_181835
SNCA ASO Questions — a(and biomarker calibration?)? a Key go/no-go criteria? shorthand with duplicated a is preserved rather than normalised.	20240722_181835

The remaining three Uncertain Spans on the canonical page belong to the TAK-071 portion of 20240722_181835 (TAK-071 row label K-1-02 OC study partial-cut, the Js: Mean & sd 사용시 / Js: LSM 사용시 Korean / English notation, and the highlighted TAK-071 power-table row 0.49 / ? / ? / 36 / 36 / ? / 0.62) and are delegated to the TAK-071 backlog candidate per Source Scope And Boundary Notes; they are not duplicated here.

Related Pages

• alpha-synuclein — α-synuclein topic synthesis (Tier 1); the program-axis narrative for SNCA ASO (WAVE) 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 ASO (WAVE) row that was previously listed as an Entity Backlog Candidate.
• snca-aso-wave — per-nav-root index for SNCA ASO (WAVE) (1 source — the single Clinical plan of SNCA ASO 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 ASO (WAVE) is under Programs and Standalone Nav-Roots / SNCA ASO — antisense oligonucleotide (WAVE Life Sciences).
• source-catalog — all 447 sources in capture order.
• nav-path-index — 376 distinct nav_paths.
• snca-btv-hdo — sibling SNCA- knockdown program entity (HDO modality; same in-house program- entity precedent for an aSyn-knockdown asset; the SNCA BTV (HDO) page records the IT ASO/HDO selection rationale and the IONIS BIIB101 differentiation paragraph).
• tak-341 — sibling α-synuclein program entity (passive-immunotherapy modality; same in-house program-entity precedent for an 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).