| iv) (Shu, 2019) | c.5096A>G p.Tyr1699Cys | were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34: 95% confidence interval: [1.09, 1.64] per +1 standard deviation: P = 0.006) (Shu, 2019 #2034) OR=13.16 (vs general population (7)) |
A range of clinical presentations have been seen — see Genotype-Phenotype Correlations [Kim et al 2012]
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Penetrance
a. In Ashkenazi Jews with this variant, penetrance is estimated at 25%-30% up to age 80 [Ozelius et al 2006, Goldwurm et al 2007, Marder et al 2015].
b. In North African Berbers, lifetime penetrance is estimated at 45% [Hulihan et al 2008], and the risk to heterozygotes and rarer homozygotes was equivalent [Ishihara et al 2008].
c. In non-Jewish individuals, penetrance associated with this variant is estimated at 42% by age 80 [Lee et al 2017a].
Pathology
SN Neuronal loss in all
LRRK2 protein 은 LB 안에서 발견되기도 함
d. the majority of individuals with LRRK2-PD exhibit LB characteristics [Ross et al 2006].
i. However, a significant subset of individuals with LRRK2-PD, particularly those with the p.Gly2019Ser pathogenic variant, have substantia nigra dopaminergic neuronal loss and gliosis without accompanying Lewy body inclusion
i. Of great interest, the pathology correlates with the extent of nonmotor clinical features. Kalia et al [2015] correlated the presence of Lewy bodies with nonmotor features of cognitive impairment / dementia, anxiety, orthostatic hypotension, and the absence of Lewy bodies with a predominantly motor phenotype.
e. a single LRRK2 case without Lewy bodies has been reported to have small soluble a-syn oligomers within the cortex [41]. A more recent study found significantly lower amounts of insoluble a-syn in four LRRK2 cases with Lewy bodies compared to sporadic Parkinson’s disease cases, suggesting that soluble asyn may be pertinent to LRRK2-related disease [42].
f. Other pathologies reported in LRRK2 cases include tau inclusions of the Alzheimer, progressive supranuclear palsy, and frontotemporal lobar degeneration types, and TAR DNA-binding protein 43 (TDP-43) inclusions.1
Phenotype
AD, late onset of the disease, a slow progression, and a good response to levodopa therapy, as well as Lewy bodies in the brain stem
즉 sporadic PD 와 유사한 장점
(아미 POSTMORTEM 37명) LB 없이도 Motor features 보이고, LB 존재 여부는 Certain motor Sx과 연관되더라. (Kalia & Kalia 2015)
Clinical progression
| (Saunders-Pullman, #2340) | 2018 | Slower UPDRS III motor score progression among those with the LRRK2 mutation vs w/o LRRK2 mutation: (0.689 [0.192]) points per year) vs (1.056 [0.187] points per year, Cognition 도 slower 경향이라는 듯 |
| (Ahamadi, #2341) | 2020 | The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). Js: Fig6 IE G2019S 는 전혀 no progress. For a non-enriched placebo-controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability. Whereas, 85, 93 and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50% and 70% subjects with LRRK2 mutations, respectively. |
Pipeline of LRRK2
Summary (Schneider, 2020 #789)
| Denali | Denali | GSK | Pfizer | Genentech | Biogen/Ionis | Takeda | Takeda | EscapeBio | Neuron23 | Cerevel | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Compound | DNL-201 | DNL-151 | No public data | No public data | No public data | BIIB094/ION859, | G2019S-selective small molecule inhibitor | PROTAC | NEU-723 (small molecule) LRRK2 inhibitor? | ||
| RCT No | NCT03710707 | NCT03976349 | 24% of LRRK2WT PD patients 75 pts: LRRK2WT with gene modifiers (LRRK2-PD) | ||||||||
| Mechanism | LRRK2 inhibition | LRRK2 inhibition | LRRK2 inhibition | LRRK2 inhibition | LRRK2 ASO | ||||||
| Status | Ongoing, recruiting, data expected end of 2019 | Planned | Under development | Under development | Ongoing, • Primary completion date postponed to 20230929 | ||||||
| Phase | 1b | N/a | N/a | N/a | Phase 1 / REASON intrathecal 일걸 | HTS started: Nov. 2019 | PS: N/A | Before PS? | Preclinical | Preclinical | |
| Design | Multicenter, randomized, placebo-controlled | N/a | N/a | N/a | 장점들: Mutant selective, CSF Biomarkers (eg. pS1292, BMP) | NEU-723 has significantly better kinome selectivity vs DNL-151; differentiated from DNL151? | |||||
| Total N of pt | 30 | N/a | N/a | N/a | 62 | ||||||
| LRRK2-PD | √ | N/a | N/a | N/a | √ | ||||||
| Idiopathic | √ | N/a | N/a | N/a | |||||||
| Age | 30-75 | N/a | N/a | N/a | 35-80 | ||||||
| Duration | 28 days | N/a | N/a | N/a | N.d. | ||||||
| Doses Tested | Low / High | N/a | N/a | N/a | Single- and multiple-ascending-dose |
DNL201 (=GNE-7915)
(small molecule) : good review on (Jennings, 2022 #2068)
Clinical trials
| name | Target pt | status | number | design | Tx | Primary outcome m | Secondary | |
|---|---|---|---|---|---|---|---|---|
| 1 | Not registered | HV | completed | SAD MAD | 10 | (Blood) > 90% ↓ LRRK2 kinase activity observed at peak and greater than 50% at trough drug levels at the highest multiple dose, (ie on phosphorylation LRRK2 at Serine 935 and phosphorylation of the LRRK2 substrate Rab10, blood-based bm assay) | ||
| 1b | NCT03710707, a safety & BM study | H&Y 1-3 PD patients (30세 이상) with or without LRRK2 mutation (JS: Included both EOPD & LOPD, for LOPD stratified LRRK2- + ) | completed | 30 (15 Spd, 15 LRRK2-PD) | randomized, 28 day | placebo, low dose, high lodse | Primary outcome: safety, lysosomal BM 뭐 봤네. | Secondary outcome: plasma pharmacokinetics, drug concentration in CSF, and LRRK2 and Rab10 phosphorylation. |
DNL201 LRRK2 PHASE 1 HEALTHY VOLUNTEER CLINICAL TRIAL
| Design | Phase 1 study in healthy volunteers |
|---|---|
| Study Size | N=122 completed |
| Key Endpoints |
Safety: Pulmonary function tests, Routine safety PK: Plasma, CSF, Urine Target engagement: pS935 and pRab10 in whole blood / PBMCs Exploratory endpoints: Lysosomal biomarker in CSF and urine |
Part 1: Single Dose, N=8/cohort (6 active : 2 PBO). Doses (mg): 10, 30, 60 (+elderly), 100, 150, 225.
Part 2: Multiple Dose (10 day), N=10/cohort (8 active: 2 placebo). Doses (mg): 25 BID, 40 QD, 40 BID, 80 mg, 80 mg BID, 150 mg, 150/100 mg BID.
Part 3: Healthy Elderly, N=10/cohort. Dose: 40 mg.
- 122 healthy subjects dosed
- Overall well tolerated up to 100 mg BID in healthy young and up to 80 mg BID in healthy elderly subjects
- Safety parameters included pulmonary function and renal safety parameters
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Pipeline LRRK2-PD eligibility | bullet √ markers | Each √ is rendered as a check mark and applies to the trial column above; the alignment is best-effort given the wide table and visible cell borders. |
| Saunders-Pullman row | 0.689 [0.192] | The [ ] brackets in the source contain a standard error; the visible value is preserved as written. |
| Neuron23 cell | LRRK2WT with gene modifiers (LRRK2-PD) | The cell text is partly obscured by a vertical column boundary; reading is consistent with surrounding context. |