Clinical trials
| name | Target pt | status | number | design | Tx | Primary outcome m | Secondary | |
|---|---|---|---|---|---|---|---|---|
| 2 | ongoing | • | ||||||
| 1b | NCT03976349 (REASON) | Intrathecal, H&Y 1-3 PD, Diagnosed with PD in the last 7 years | expected primary completion date in December 2022 | 62 | SAD | • | ||
| MAD | Safety | • PK, (lysosomal BM 미언급) | ||||||
| 1b | • |
Other LRRK2 pipeline
| E-SCAPE Bio | Small molecule G2019S selective inhibitor ESB5070 | IND, start target engagement Phase I by YE 2022 |
| Neuron23 | Small molecule bestin class LRRK2i NEU-723 | IND, start Phase I by YE 2022 ($100M Series C in Mar 2022) |
| ArrienPharmaceuticals | Small molecule G2019S selective inhibitor ARN-1104 | Preclinical / IND-ready – looking to partner to continue |
| Oncodesign (license to Servier) | Small molecule macrocycle LRRK2i | Pre-IND |
| CerevelTx (licensed from Pfizer) | Small molecule G2019S inhibitor | Lead Optimization |
| Genosco | Small molecule G-969 | Preclinical – not on the company website, likely discontinued |
| NeuBase Therapeutics | Antisense | Preclinical – not on the company website, likely discontinued |
| Brenig Therapeutics, | LRRK2 inhibitor (BT-0267) | presented new safety data on its LRRK2 inhibitor drug candidate at the ACS Spring 2024 Conference at the New Orleans Ernest N. Morial Convention Center, on March 17th, 2024. he superior safety profile of LRRK2 Inhibitor BT-0267 with an exceptional plasma ratio, in vivo efficacy of BT-0267 in brain and no visible lung and kidney morphological changes compared to other LRRK2 inhibitor candidates. BT-0267 will be entering human clinical trials by the end of 2024. |
Prevalence
a. the most common cause of autosomal dominant PD accounting for 5–15% of dominant familial PD b. 1–3% of sporadic PD c. G2019S, alone accounts for 1% of sporadic and 4% of familial PD patients [44]. d. In general population i. (, 2008 #2035) 1/46 in our sample of North African Arabs, the most elevated carrier incidence (1/30) being found in Moroccan Berbers. An elevated incidence (1/72) is also found in our sample of Sephardi Jews. These results contrast with the ones we found (1/1550) in a sample of 3100 healthy subjects originating from 15 populations of southern Europe.
Protein
p. Human LRRK2 is 2527 amino acids in length and a molecular weight of 286 kDa. q. Location i. Largely in the cytoplasm but also associates with the mitochondrial outer membrane. 다른 의견: is localized to membranes. b. Expression i. LRRK2 is a low-abundance protein ii. other tissues, particularly the kidney, lung, and a subtype of peripheral immune cells, robustly express LRRK2 (→ safety concern for LRRK2 inibition) Function r. a kinase s. KO of LRRK2 → No effect on DA neuronal development or maintenance t. Expression of LRRK2 mutants implicated in autosomal dominant Parkinson’s disease → ↓ macroautophagy → shortening and simplification of the dendritic tree in cultured neurons.[8] u. 2019S and R1441C mutations → post-synaptic calcium imbalance → ↑ mitochondrial clearance from dendrites by mitophagy Interaction v. Parkin iii. Parkin increases protein aggregation induced by LRRK2 overexpression iv. LRRK2 interacts with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2 (wiki) w. GBA v. reduced GCase activity in dopaminergic neurons derived from PD patients with LRRK2 mutations and increased GCase activity induced by inhibition of LRRK2 kinase activity [62]. x. 14-3-3 ii. Binding sites
- See ‘LRRK2_opportunity, status & plans_con_Feb 2023_vF.pdf’ (Ambagon) p.13
a. Two primary binding sites: i. pS910 (14-3-3γ EC50 = 2.5 µM, 14-3-3σ EC50 = 27.7 µM) ii. pS935 (14-3-3γ EC50 = 19.8 µM, 14-3-3σ EC50 = 183.7 µM) iii. Consequence of binding 1. See ‘LRRK2_opportunity, status & plans_con_Feb 2023_vF.pdf’ (Ambagon) p.12
Lysosome
Structure of Lysosome
ix) Lysosomal membrane a. Membrane integral proteins i. Most abundant in the lysosomal membrane, and thus important for its integrity, are the lysosomal associated membrane proteins type-1 and -2 (LAMP-1, LAMP-2/SCARB2). b. Membrane channels i. transmembrane protein 175 (TMEM175), a potassium channel, or the sialic acid transporter, Sialin, c. Membrane transporters i. lysosomal cholesterol transporter Niemann-Pick Type C1 (NPC1),
Ion channels and Transporters
| Ion channels (passive transport) | Ligand-gated ion channels (ligand binding → energy generation → gate opening) | the pentameric ion channels (pLGICs, also called Cys-loop receptors) : activated by several neurotransmitters | nicotinic acetylcholine receptors (nAChRs), γ-aminobutyric acid type A/C receptors (GABAA/CRs), glycine receptors (GlyRs), 5-hydroxytryptamine type 3 receptors (5-HT3Rs), and zinc-activated ion channels |
| the ionotropic glutamate receptors (iGluRs), activated by the neurotransmitter glutamate, | comprising three main subtypes, namely GRIN/NMDAR (glutamate ionotropic receptor NMDA type), GRIA/AMPAR (glutamate ionotropic receptor AMPA type), and GRIK/kainate (glutamate ionotropic receptor kainate type). The iGluRs are permeable to both K+ and Na+ to depolarize the postsynaptic membrane, and in some cases to divalent cations, such as Ca2+. | ||
| nucleotide-gated channels |
x) ATP-activated ion channels : P2RX/P2X receptor (purinergic receptor P2X) channels ): In response to the binding of ATP they can transport cations including Na+, K+ and Ca2+ xi) CFTR (CF transmembrane conductance regulator: only opened after phosphorylation by PRKA/PKA (protein kinase cAMP-activated) to control the influx and efflux Cyclic nucleotide-activated ion channels | ||
| Proton gated channels, | Calcium-activated channels Calcium-activated potassium channels | ||
| calcium-activated channels, | |||
| KCNJ/Kir and SCNN1/ENaC KCNJ/Kir (potassium inwardly rectifying channel | |||
| Calcium channels | In plasma membrane | most members of the TRP (transient receptor potential) family; Cav (voltage Ca2+ gated channels), P2RX, and the calcium release-activated calcium channels | |
| On ER and lysosome |
| ||
| Sarcoplasmic/ER | ITPR/InsP3R (inositol 1,4,5-trisphosphate receptor), RYR (ryanodine receptor), several members of the TRP family TPCN/TPC (two pore segment channel) proteins [13]. | ||
| Voltage-gated ion channels | voltage-gated Na+ channels (Nav), and ), (specific to Na+, ) | ||
| voltage-gated K+ channels (Kv), (specific to K+) | |||
| Cav ((specific to Ca2+) | high-voltage activated (including L-, P/Q-, N-, and R-type) low-voltage-activated (including T-type) channels | ||
| voltage-gated proton channels (Hv) ((specific to H+) | balances the intracellular pH. | ||
| CLCN/ClC family and | |||
| KCNK/K2PK2P (potassium two pore domain channel subfamily K) | |||
| VRACs and VDACs | |||
| Gap junction channels | |||
| TMEM175 | a novel K+-selective ion channel expressed in both endosomes and lysosomes that regulates lysosomal pH stability, motility and organelle fusion [29]. The pores of TMEM175-dependent channels can be blocked by zinc ion and 4-aminopyridine | ||
| ABC [ATP binding cassette] transporters, | |||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Clinical trials / Phase 2 row | only the cell ongoing is filled; other columns are empty in this slice; the row may have additional content cut off at the top edge of the photo. | partial row visible. |
Other LRRK2 pipeline / Brenig Therapeutics row text | reads presented new safety data on its LRRK2 inhibitor drug candidate at the ACS Spring 2024 Conference at the New Orleans Ernest N. Morial Convention Center, on March 17th, 2024. he superior safety profile of LRRK2 Inhibitor BT-0267 with an exceptional plasma ratio, in vivo efficacy of BT-0267 in brain and no visible lung and kidney morphological changes compared to other LRRK2 inhibitor candidates. BT-0267 will be entering human clinical trials by the end of 2024. (the word he likely should be The but is preserved as written). | source typography preserved including likely typo. |
Ion channels and Transporters table / right-most sub-class column | several rows have empty right-most cells. | row group ABC [ATP binding cassette] transporters, only header cell is visible at the bottom edge of this photo. |