Narita 2016 patient body, Plasma in GD 1, Reference values, Animal models of GD
Narita 2016 #560 (continued)
| pre-Tx | post-Tx | pre-Tx | post-Tx | pre-Tx | post-Tx | pre-Tx | post-Tx | pre-Tx | post-Tx | |
|---|---|---|---|---|---|---|---|---|---|---|
| GBA Activity (lymphocyte) (%control) | 13.7 | 43 | 24.7 | 53.2 | 30.1 | 105 | 18.1 | 60.3 | 100.6 | 145 |
| CSF GlcSph (ng/ml) | 18.2 | 16.1 | 26.6 | 15 | 49.1 | 30.4 | 635 | 533 | 146 | 118 |
| CSF GlcSph reduction (%) | 11.5% | 43.6% | 38.1% | 16.1% | 19.2% | |||||
| myoclonus improvement | marked | marked | moderate | marked | marked (at 6m) | |||||
| PLR response | improved | improved | improved | improved | improved (at 6m) | |||||
Plasma in GD 1
About 10% (not exact)
| Brazil (2010 Muller) type Not specified GlcCer plasma | 2016 Murugesan type 1 GlcSph plasma | (Chipeaux, 2017 #559) type 1 GlcSph plasma | |||
|---|---|---|---|---|---|
| (ng/mg protein) | fold increase | (ng/ml) | fold increase | 내가 원문 안 봤으며) Yuta slide 에: 136.4 nM (HC: 1.8 nM...) | |
| normal | 0.67 | 1.5 | |||
| GD wo ERT | 13.7 | 20X | 180.9 | 121X | |
| GD w ERT | 1.23 | 2X | 89 |
| • |
| GD w Eliglutat | NA | NA | 61.4 | 41X (hematologic parameters 들도 ERT 대비 동등 내지 다소 우월이나, 이는 Simulation 이고, 사용기간 짧으니 해석 주의) | |
plasma lyso-GL1 levels correlate with liver volume and spleen volume, platelet counts and age, and independently associated age, serum chitotriosidase, serum CCL18 and splenectomy
2021 WORLDSymposium Skrahina: 언급 없으나 아마 대부분 GD1 인듯, GlcSph: severe mutation 109 vs mild mutation (5 ng/ml/year), with large variability
Experimental
- recent investigations with cultured osteoblasts of a type 1 Gaucher disease-like mouse model led to the hypothesis that glucosylsphingosine may actively contribute to low bone mineral density by interfering with normal osteoblast function, possibly by altered intracellular calcium homeostasis. In addition, a role for glucosylsphingosine in neurologic symptoms of Gaucher patients has been frequently proposed.
- ↑ Ca²⁺ mobilization from intracellular stores although it uses a different mechanism (https://www.matreya.com/Products/sup13supCsub6sub-Glucosylsphingosine_2209.aspx)
= (js: 결국 CSF GlcSph 가 GD에서 증가되어 있는지는 증거 없음)
Tottori univ / Dried blood spot in GD 3
- (2019 Charkhand, two case reports)
- Following ERT 10 yr, 6.5 - 7.4 fold (31, 35.4 ng/ml)
CSF in GD 3
- Following ERT 10 yr, 241.4 fold (0.7 ng/ml, ERT가 Brain 안 들어가니까 여러 플겠지)
If depleted below normal range
- (2016 Marshall) mice, no overt toxicities daily activity and body weight data
- (2016 Zheng) Fabry clinical trial, 4 patients showed below normal range following SRT, ie very low upto 18w (safety mention 없음, lucerastat일 수 있는데 못 찾겠음)
- (2016 Smid) 4명 GD1 환자가 below normal up to 2 y 였는데, 별다른 toxicity기술없음.
Heterozyg
- No change in plasma (2011 Dekker, they don’t have PD,
Animal
- D409V/D409V mice
- No change in plasma (2011 Dekker, they don’t have PD,
- Not increased in brain (2017 Sardi Venglustat)
- Greatly increased in brain (2017 Sardi Venglustat)
- CBE 100mg/kg, 7w, 57BL/6 mice
- Two fold increase in liver ten fold increase in brain → 약 ↓30% (2016 arshall Ibiglustat)
- Greatly increased in liver (2016 arshall Ibiglustat),
- Greatly increased in brain → 약 ↓30%
- Mice, HV
- 정상보다 아래로 감소 가능 (2016 Smid 에 그림으로 잘 나옴)
- Ibiglustat 75% 감소
Reference values
| Healthy person | GD patient | |
|---|---|---|
| Peripheral (plasma) | 1.8 nM | 136.4 nM (Type1) |
| Central (CSF) | < 10 pg/mL | 635 pg/mL (Type2) 60 pg/mL (Type3) |
| Central (Brain) | < 1 ng/mg | 142 ng/mg (Type2) 23.25 ng/mg (Type3) |
위 table 은 reference 들 모두 해결했음.
2019 Lukina Eliglustat (re-shown)
| Biomarker | Normal Range | Baseline | Year 8 | Percent Reduction |
|---|---|---|---|---|
| Glucosylceramide (GL-1) (μg/mL) (n=18) | <2.0 to 6.6 | 12.15 | 2.70 | -80% |
| Plasma glucosylsphingosine (Lyso-GL-1) (ng/mL) (n=16) | <5 | 624 | 47.6 | -92% |
| Chitotriosidase (nmol/hr/mL) (n=17) | <15 to 181 | 8084 | 902 | -91% |
| CCL18 (ng/mL) (n=18) | 17 to 246 | 3560 | 442 | -87% |
Lukina chart x-axis: Years on Eliglustat (0-8); y-axis: Median Percent Change from Baseline (0% to -100%); legend GL-1, CCL18, Chitotriosidase*, Lyso-GL-1.
Animal models of GD
| Generation method | GBA activity | Phenotype | |
|---|---|---|---|
| GBA KO the GBA-/- mouse | mouse insertion of a neo-cassete in exons 9 and 10 in the GBA gene | <4% | glucosylceramide accumulation in the lung, liver, and brain. However, the GBA-/- mouse exhibits neonatal death as a result of a marked transepidermal water loss due to altered skin permeability, (This is likely due to the lesser hydrolytic efficiency of the N370S enzyme toward the longer chain fatty acid acyl moieties on GC in murine skin vs. human13,14,15) |
| RecNcil (L444P/A456P) point mutant mice | A single insertion mutagenesis procedure (SIMP) | <10% | died soon after birth due to compromised skin barrier function |
| L444P/L444P point mutant mice | <20% | died soon after birth due to compromised skin barrier function, ↑ a-syn in striatum | |
| N370 |
| ||
| GBAL444P/L444P;Ugcg+/+ | crossing L444P+/- mice with a mouse bearing a knockout in glucosylceramide synthase (Ugcg). | 15-20% | ↑ improved life span (50% of the mice survive for up to a year), However, these mice lack the typical features of GD such as: ↑ glucosylceramide or Gaucher cells |
| human GBA-L444P heterozygous KI mice (Gba-wt/L444P) human GBA-L444P x 1 copy + mouse Gba-wt x 1 copy (그냥 GBA heteroz carrier 모델이네) | (generated at Shonan) |
[shonan findings]
| |
Cortex GlcSph plot: y-axis Concentration (nM). Caption: Brain injection of α-Syn preformed fibrils (PFFs) is being tried to develop a synopathy model. Injection of AAV9-SNCA can be an alternative approach.. Annotation: 20210125: significant ↑ GlcSph, (1.5-fold) with age-dependence.
hGBA-L444P-tg8 mouse (start)
- The hGBA-L444P-tg8 mouse: 8 copies of human GBA ((no mouse Gba gene) (this mice is ‘hemizygous’ and still called
GBA activator project uses this! this strain expresses human GBA L444P mutant protein only,
(Sanders, 2013 #909)
- Cerebrum: gba activity is 32% control (table2)
- cerebellum: So, =GlcCer, ↑(x2)GlcSph
- So, =GlcCer, ↑(x2, ~7 vs ~12.5 at 45w, at 25w: 6 vs 8) GlcSph
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Animal / CBE row | 2016 arshall Ibiglustat | reads as written; the leading letter of Marshall appears clipped in the source. |
| Reference values inset | unit and Type-label pairing | values are taken verbatim from the visible inset; check before reuse. |
| 2019 Lukina table / Chitotriosidase | 8084 and -91% | values as visible in the inset table; OCR alternates between 8084 and 6084 across earlier captures. |
| hGBA-L444P-tg8 paragraph | (this mice is 'hemizygous' and still called | trailing clause is clipped at the bottom edge of the photo. |