LRRK2 Pipeline

This topic page reorganises the 4 source notes filed under lrrk2 into reading-order axes. It does not replace the by-photo Markdown; every claim links back to a source note or the canonical transcription. Where a source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Overview

The corpus’s LRRK2 chapter is a tight late-document pipeline cluster that anchors the Denali / Genentech / Biogen kinase-inhibitor and ASO arc and the Schneider 2020 #789 cross-sponsor pipeline matrix. Four overlapping axes organise the 4 sources, one source per axis: (1) DNL201 (=GNE-7…) — Genentech / Denali small-molecule kinase inhibitor with the Pipeline-of-LRRK2 Schneider 2020 matrix, the LRRK2- PD penetrance / pathology / phenotype / clinical-progression bullets, and the DNL201 LRRK2 PHASE 1 HEALTHY VOLUNTEER CLINICAL TRIAL slide block (20240722_183407); (2) DNL151 (=BIIB12…) — Biogen / Denali backup small-molecule with the Jennings 2022 #2283 DNL201 preclinical matrix, the LIGHTHOUSE / LUMA / NCT04056689 / NCT04557800 trial table, and the BIIB094 (=ION859) Biogen ASO preclinical row (20240722_183410); (3) Other LRRK2 Pipeline — REASON Phase 1b NCT03976349 trial-row tail, eight-company Other-LRRK2-pipeline table, and the LRRK2 Prevalence / Protein / Lysosome > Structure of Lysosome > Ion channels and Transporters table tail (20240722_183413); (4) Animal Models + Inflammation and LRRK2 — Longitudinal cohort- comparison wide-table tail, Animal-models-of-LRRK2 a–g bullets, the Figure 1 LRRK2 144-kb chromosome-12q12 / Ankyrin / LRR / Roc / COR / MAPKKK / WD40 domain schematic, and the Inflammation and LRRK2 section heading whose body bullets continue onto _183404 (20240722_183401).

The LRRK2-side Mutation chapter (_183404 — LRRK2 MOA evidence table, Mitophagy and LRRK2 two-row table, LRRK2 Pathogenic Variants 4-column reference table, G2019S / G2385R / R1628P risk profile, Armadillo-Ankyrin-LRR-Roc-COR-Kinase-WD40 protein-domain schematic) is filed under genetics-pathway by nav root and narrated on genetics-pathway § LRRK2-Side Mutation Chapter; this topic cross-links it rather than re-narrating. DNL151 / DNL201 entity-page promotion is explicitly deferred to v1.x backlog per therapeutic-programs § Entity Backlog Candidates.

Source Boundary / Delegation

This topic is bounded inside sections/lrrk2 and includes exactly the 4 sources listed in lrrk2. Adjacent material that overlaps in content but is owned elsewhere:

boundary	adjacent material	owned by
_183404 LRRK2-side Mutation chapter — LRRK2 MOA evidence table, Mitophagy and LRRK2 table, LRRK2 Pathogenic Variants reference table, protein-domain schematic, G2019S / G2385R / R1628P risk profile, and Inflammation and LRRK2 body bullets that begin on the bottom edge of _183401 and continue onto _183404	_183404 is filed under sections/genetics-pathway by its Mutation nav root; this topic cross-links rather than re-narrates	genetics-pathway § LRRK2-Side Mutation Chapter
_183413 Lysosome > Structure of Lysosome > Ion channels and Transporters table tail; the row continues onto _183416	lysosomal-membrane / ion-channel / transporter biology	lysosome-autophagy § Lysosomal Enzymes, Transporters, and Lysosomal Changes in PD
BMP urine / CSF biomarker readouts on DNL201 NCT03710707 (_183407) and DNL151/BIIB122 NCT04056689 (_183410); pS935 / pT73 Rab10 / Cathepsin / lysosomal-proteolysis / lysosomal-enlargement biomarker rows; the Jennings 2022 #2283 DNL201 AHA-labeling assay on _183419; the Denali R&D-Day LRRK2-inhibitor → ↓ BMP correction note on _183423; the ETV:IDS (=DNL310) brain-BMP-rescue Mice-row note on _183410	lysosomal-membrane biomarker biology and BMP BMP change in diseases row	lysosome-autophagy § Assessment of Lysosome / § Macroautophagy / Microautophagy / CMA / BMP
_183401 Inflammation and LRRK2 section heading and _183407 Pathology Kalia & Kalia 2015 LB-correlation-with-nonmotor-features bullet	inflammation / NLRP3 / Complement / microglia disease-side biology	inflammation / nlrp3-inhibitor
_183413 2019S and R1441C mutations → post-synaptic calcium imbalance → ↑ mitochondrial clearance from dendrites by mitophagy bullet and the Mitophagy and LRRK2 two-row table on _183404	mitophagy / Parkin biology / 31P MRS	mitochondria / parkin
_183407 LRRK2-PD penetrance / pathology / phenotype / clinical-progression genetics bullets (Saunders-Pullman 2018 #2340, Ahamadi 2020 #2341, Ozelius 2006 / Hulihan 2008 / Lee 2017a penetrance) and the variant-pathogenicity / ACMG-AMP framework that LRRK2 G2019S / G2385R / R1628P calls consume	LRRK2-PD genetics methodology	genetics-pathway
_183407 pS910 / pS935 14-3-3 binding-site EC50 bullets and references to LRRK2_opportunity, status & plans_con_Feb 2023_vF.pdf (Ambagon) p.12 / p.13	molecular-biology / phosphosite vocabulary	molecular-biology
AAV / capsid / promoter / route-of-administration / FDA-CTGT-2021 GT-safety vocabulary	PK / PD / GT / pharmacology	pk-gt-pharmacology · molecular-biology § GT Safety Appendix (_184756)
pS935 / pRab10 / urine BMP / lysosomal-BM / MDS-UPDRS / DATScan / VMAT outcome measures and [BIOMARKER] validation framework	biomarker validation and outcome measures	biomarkers-outcomes
Schneider 2020 #789 cross-sponsor pipeline matrix and Pipeline-of-PD LRRK2 row on _184324 / _184327 / _184330 / _184333	program-routing map	therapeutic-programs
DNL151 (=BIIB12…) and DNL201 (=GNE-7…) entity-page promotion — per-program timeline, decision tree, sample-size logic, biomarker plan, competitor landscape	not promoted in this pass; remains v1.x backlog candidate	v1.x backlog (no entities/programs/dnl151.md / dnl201.md created)

_183404 is not included in the Source Table below; it stays in genetics-pathway § LRRK2-Side Mutation Chapter. No new entity page is created in this pass; promotion follows the precedent in therapeutic-programs § Entity Backlog Candidates.

Source Coverage

4 source notes are assigned to the lrrk2 section, one per first-level nav_path cluster:

nav root (first nav_path entry)	sources	covered axis
Pipeline of LRRK2	1	DNL201 (=GNE-7…) — Genentech / Denali
DNL151 (=BIIB12...)	1	DNL151 (=BIIB12…) — Biogen / Denali (incl. BIIB094 ASO row)
LRRK2 Clinical trials	1	Other LRRK2 Pipeline + LRRK2 Prevalence / Protein / Lysosome tail
Longitudinal	1	Animal Models + Inflammation and LRRK2

For exact nav_path strings and headings see lrrk2 and the by-nav indexes listed in related_topics_by_nav. The DNL151 (=BIIB12...) nav-root preserves the Word navigation pane’s own truncation verbatim.

Across the 4 sources, source-note frontmatter records 12 uncertain_span_count entries and 0 body-embedded figure assets. The zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md): the Figure 1 LRRK2 chromosome-12q12 / domain schematic, Schneider 2020 #789 cross-sponsor matrix, DNL201 Phase 1 HV slide-style block, R&D Day randomization diagram, R&D Day brain-vs-PBMC two-panel slide, and Ion-channels-and-Transporters wide table are all kept as evidence rather than embedded. The 12 uncertain spans are retained as review targets.

DNL201 (=GNE-7…) — Genentech / Denali

20240722_183407 anchors the chapter. The page tail-ends an LRRK2-PD genetics block (Penetrance — Ozelius 2006 Ashkenazi 25–30% / Hulihan 2008 North African Berber 45% / Lee 2017a non-Jewish 42% by age 80; Pathology — Ross 2006 LB majority and the p.Gly2019Ser SN-loss-without-LB subset, soluble vs insoluble aSyn, tau / PSP / FTLD / TDP-43 inclusions; Phenotype with the Korean inline annotations LRRK2 protein 은 LB 안에서 발견되기도 함 and the Kalia & Kalia 2015 LB-correlation-with-nonmotor-features quote; Clinical progression — Saunders-Pullman 2018 #2340 and Ahamadi 2020 #2341 enriched-trial sample-size arithmetic with the Js: Fig6 IE G2019S 는 전혀 no progress. annotation), then carries the Pipeline of LRRK2 > Summary (Schneider, 2020 #789) wide cross-sponsor matrix covering Denali (DNL-201, DNL-151), GSK / Pfizer / Genentech (No public data), Biogen-Ionis (BIIB094 / ION859), Takeda (G2019S-selective SM, PROTAC), EscapeBio, Neuron23 (NEU-723), and Cerevel. The DNL201 (=GNE-7915) Clinical-trials sub-table (Jennings 2022 #2068 review, NCT03710707 1b safety / BM study) and the DNL201 LRRK2 PHASE 1 HEALTHY VOLUNTEER CLINICAL TRIAL slide-style block (Part 1 SAD / Part 2 MAD / Part 3 Healthy Elderly with the dose-escalation diagram and N=122 completed) close the page; specific cell values (RCT IDs, dose tokens, eligibility ticks, trial-arm Ns) stay on the canonical page rather than being re-quoted here. 3 Uncertain Spans.

DNL151 (=BIIB12…) — Biogen / Denali

20240722_183410 opens with the tail of the DNL201 NCT03710707 trials sub-table from _183407 (Secondary outcome bullets, Target engagement Blood / PBMC pS935 / pRab10, Lysosomal biomarkers in CSF and urine, Exploratory DaTscan substudy, Clinical Endpoints MDS-UPDRS Part III) and the R&D Day randomization diagram (DNL201 High Dose N=12 / Low Dose N=10 / PBO N=8). The Preclinical sub-table reproduces the Jennings 2022 #2283 DNL201-preclinical matrix (Tx / ↓ pS935 LRRK2 / ↓ pT73 Rab10 / ↓ Cells with enlarged lysosome / ↑ lysosomal protein degradation across HEK293 / H4 / primary astrocytes / fibroblasts from healthy controls and Gaucher-disease GBA carriers / Human PBMC ex vivo / human iPSC-derived microglia ex vivo), an In-vitro G2019S : ↑ LAMP2 (IF) row, the NHP R&D Day slide pair (LRRK2 INHIBITION IN PBMCs PREDICTS BRAIN LRRK2 INHIBITION callout; brain-vs-PBMC pS935/LRRK2 bar chart and CSF/Plasma exposure curve), and the Mice row note preserved verbatim (Cf) ETV:IDS (=DNL310)으로 Mouse brain BMP 감소 봤으나 DN;201로 본 건 없네. DNL151 (=BIIB122 , backup to DNL201, collaboration with BIOGEN)(small molecule)).

The Clinical trials sub-table covers LIGHTHOUSE (started 202209, discontinued 20230611 due to complexity / 2031 timeline; ~400 participants; DNL151/BIIB122 vs Placebo; 96-week minimum; MDS-UPDRS primary; Centogene / ROPAD recruitment), LUMA (planned for iPD with LRRK2-carrier amendment, ~640 participants, 48-week minimum), NCT04056689 (ongoing PD H&Y 1-3, 34 participants, 3 doses vs placebo RCT DB 42 days; primary target engagement ↓ pS935 in whole blood and secondary dose-dependent ↓ pRab10 / urine BMP across 90 / 130 / 300 mg oral doses for 28 days), and NCT04557800 (ongoing HV, N=184, 15–300 mg QD up to 28 days or 400 mg BID up to 14 days). The Preclinical (BIIB094) sub-section names BIIB094 (=ION859) (=IONIS-BIIB7Rx) (Biogen) (ASO) and the single-row preclinical note LRRK2 ASOs to the brains of mice reduced LRRK2 protein levels and Nlrp3-induced LRRK2 inclusions [67]. Specific cell values (RCT IDs, dose tokens, Ns, endpoint deltas) stay on the canonical page. 3 Uncertain Spans. The ETV:IDS (=DNL310) Mice-row note is delegated per the boundary table.

Other LRRK2 Pipeline

20240722_183413 carries the tail of a Clinical-trials table whose Phase 2 row only shows ongoing and whose Phase 1b row anchors NCT03976349 (REASON) — intrathecal H&Y 1-3 PD, 62 participants SAD/MAD, Safety primary, magenta-highlighted Secondary cell PK, (lysosomal BM 미언급). The Other LRRK2 pipeline wide table follows with eight companies: E-SCAPE Bio (ESB5070 G2019S-selective SM), Neuron23 (NEU-723 best-in- class SM, $100M Series C in Mar 2022), Arrien (ARN-1104 G2019S- selective SM), Oncodesign / Servier (macrocycle SM), CerevelTx (licensed from Pfizer, G2019S SM), Genosco (G-969, likely discontinued), NeuBase Therapeutics (Antisense, likely discontinued), and Brenig Therapeutics (BT-0267, ACS Spring 2024 New Orleans safety data, entering human trials by end of 2024).

The page continues into LRRK2 Prevalence (autosomal-dominant 5–15% / sporadic 1–3%; G2019S 1% sporadic / 4% familial; population-frequency bullets including Moroccan Berber / Sephardi Jew / Southern European samples), LRRK2 Protein (2527 aa / 286 kDa; cytoplasm + mitochondrial outer membrane; low abundance with kidney / lung / peripheral immune expression; kinase activity; macroautophagy effects; calcium / mitophagy effects of G2019S / R1441C; Parkin / GBA / 14-3-3 interactions including pS910 / pS935 binding-site EC50 bullets), and the Lysosome > Structure of Lysosome > Ion channels and Transporters wide row group whose table continues onto _183416. Specific cell values, bullet references, and binding-site EC50 numbers stay on the canonical page. 3 Uncertain Spans. The Lysosome / Ion-channels-and-Transporters table tail is delegated per the boundary table.

Animal Models + Inflammation and LRRK2

20240722_183401 opens with the lower portion of the Longitudinal cohort-comparison wide table that started on _183358 (DATScan / Motor tracking / Cognition / sMRI / Effect size / CSF / Blood / Publication-Resource rows; AMP-PD = PPMI + PDBP block; Huh 2020 / Stoker 2020 / Minett 2018 / Crilia 2016 / Malek 2018 / Davis 2016 yellow-highlighted MDS-UPDRS- III Mean(SD) cell / Firbank 2017 / Nombela 2014 citation columns; Korean meta-commentary in the Stoker / AMP-PD cells preserved verbatim). The 4 LRRK2 > Animal models of LRRK2 alphabetic bullets a–g cover BAC transgenic / neuron-specific adenoviral G2019S / AAV-G2019S 50% SNc loss findings and a five-functional-domain summary (LRRK2 51 exons / 144 kb genomic region). The bottom of the page carries the Figure 1 LRRK2 chromosome-12q12 / Ankyrin / LRR / Roc / COR / MAPKKK / WD40 domain schematic — preserved as body_r05_c01 / body_r05_c02 evidence rather than embedded because the crops include transcribable bullet text and the Figure 1 caption. The Inflammation and LRRK2 section heading is visible; body bullets (Kunisada hiPS-microglia, Dong Hwan Ho 2018 TNFα, MOA evidence table, Mitophagy and LRRK2 two-row table) begin on _183404 and are owned by genetics-pathway § LRRK2-Side Mutation Chapter per the boundary table. 3 Uncertain Spans.

Source Table

All 4 sources, in capture-time order, with the per-page uncertain-span and embedded-image counts copied verbatim from source-note quality_metrics. nav path is the full nav_path recorded in the source note (joined by >).

stem	nav path / heading	source note	canonical	uncertain spans	embedded images
20240722_183401	Longitudinal > 4 LRRK2 > Animal models of LRRK2 > Inflammation and LRRK2	note	md	3	0
20240722_183407	Pipeline of LRRK2 > Summary (Schneider…) > DNL201 (=GNE-7…) > Clinical trials	note	md	3	0
20240722_183410	DNL151 (=BIIB12…) > Clinical trials > Preclinical	note	md	3	0
20240722_183413	LRRK2 Clinical trials > Other LRRK2 pipeline > Prevalence > Protein > Lysosome > Structure of Lysosome > Ion channels and Transporters	note	md	3	0

Totals across the 4 sources: uncertain_span_count = 12, embedded_image_count = 0. These are review surface area; the zero-figure-embed count reflects the 2026-04-29 body-purity decision.

Uncertainties Carried Forward

Specific uncertainty hot spots worth checking on the canonical pages before any downstream extraction (each axis section above counts the per-page totals; this list captures the cross-page issues):

• _183401 Longitudinal long descriptor cell that spans many narrow columns of the wide table (column placement collapsed in the HTML rendering; original text preserved verbatim); Davis 2016 #192 Mean (SD) Annual change of MDS-UPDRS-III 3.4 (7.7) / 2.0 (6.6) pairing ambiguity; Inflammation and LRRK2 section heading visible at the bottom edge with body bullets continuing onto _183404 (section break across photos rather than a value uncertainty).
• _183407 Schneider 2020 #789 matrix √ LRRK2-PD / Idiopathic eligibility ticks rendered with best-effort alignment across a wide table; Saunders-Pullman row 0.689 [0.192] standard-error bracket preserved as written; Neuron23 cell text partly obscured by a vertical column boundary.
• _183410 improved urine BMP by 20% / 60% at low / high dose direction may be flipped on the small slide visual; LIGHTHOUSE row o o 10,000 participants double-bullet appears intentional in the source’s nested list; BIIB094 row Nlrp3-induced LRRK2 inclusions [67] interpreted from a faint footer reference; Mice-row note preserves the DN;201 typographic anomaly verbatim.
• _183413 REASON Phase 2 row partial visibility (only ongoing cell visible; other columns may have content cut off at the top edge); Brenig Therapeutics row preserves the source-typography he superior safety profile (he likely should be The); Ion channels and Transporters ABC [ATP binding cassette] transporters, row group has only the header cell visible at the bottom edge and continues onto _183416.

Related Pages

• lrrk2 — section index for all 4 sources
• genetics-pathway — sibling topic; owns the LRRK2-Side Mutation Chapter (_183404) that this topic cross-links rather than re-narrates; also owns LRRK2-PD penetrance / pathogenicity / PRS methodology
• lysosome-autophagy — sibling topic; owns the Ion-channels-and-Transporters chapter that the _183413 table tail extends into (continuing onto _183416); the BMP BMP change in diseases row context; the Jennings 2022 #2283 DNL201 AHA-labeling assay on _183419; the Denali R&D-Day LRRK2-inhibitor → ↓ BMP correction note on _183423
• inflammation / nlrp3-inhibitor — own microglia / TNFα / NLRP3 / Complement / pyroptosis disease-side biology
• mitochondria / parkin / parkn-gt — own mitophagy / PINK1 / pS65-Ub / parkin-mediated autophagy
• pk-gt-pharmacology / molecular-biology — sibling topics; ETV:IDS (=DNL310) Mice-row note on _183410, AAV / capsid / GT-safety vocabulary, phosphosite vocabulary (pS910 / pS935 / pS1292 / pT73 Rab10), GT Safety Appendix on _184756
• biomarkers-outcomes — sibling topic; [BIOMARKER] framework, plasma-vs-blood / serum / CSF analyte selection, MDS-UPDRS / DATScan / VMAT outcome measures
• clinical-pd — sibling topic; Pipeline-of-PD comparator inventory and LRRK2-PD vs iPD eligibility distinctions
• therapeutic-programs — program-routing map; DNL151 / DNL201 row owner page is now topics/lrrk2 (status topic-only); entity-page promotion remains an Entity Backlog Candidate
• alpha-synuclein — sibling topic (Tier 1); LRRK2-PD pathology bullets on _183407 reference soluble vs insoluble aSyn in LRRK2 cases
• genetics-pathway — sibling section; _183404 is filed there by nav root
• lysosome-autophagy — sibling section; the Ion-channels-and-Transporters table tail on _183413 continues onto _183416 which lives there
• longitudinal — Longitudinal first-nav_path index
• pipeline-of-lrrk2 — Pipeline of LRRK2 first-nav_path index
• dnl151-biib12 — DNL151 (=BIIB12...) first-nav_path index (Word-truncation preserved)
• lrrk2-clinical-trials — LRRK2 Clinical trials first-nav_path index
• source-catalog — all 447 sources in capture order
• nav-path-index — 376 distinct nav_paths