Pipeline of GD & GBA-PD
Prevail PR001
Preclinical
201906 US SECURI AND COMMISION 에 잘 나옴.
at all 3 doses, vector genomes were detected in the brain and spinal cord 5 weeks postadministration. It was observed that GCase activity was reduced in CBE-treated mice and increased by the highest dose of the therapy in the brain and spinal cord at 5 weeks.
| model | readout | tissue | PR001 dose | visible effect / message |
|---|---|---|---|---|
| CBE mice | GBA activity | cortex | 3.2x10^10 | ↑ normal control보다도 훨씬 더 증가시킴 |
| CBE mice | GlcCer/GlcSph | Cortex | 3.2x10^10 | ↓ normal control에 근접 |
| CBE mice | a-syn | na | ||
| message |
GBA activity를 normal보다 훨씬 더올려야 GlcCer/GlcSph는 normalize됨. GBA activity의 moderate 증가 (ie still below normal control)로는 GlcSph도 moderate감소 밖에 안 됨. 같은 data인데 아래는 다른 dose 제시. | |||
Animal study data by Prevail Therapeutics (CBE treatment)
아래는 6달후! (장기투여는 아님)
No PR001, no CBE: vehicle only, n = 10; No PR001 + CBE: vehicle only + CBE, n = 11; High dose: 3.2 x 10^10 vg PR001 + CBE, n = 10.
Each bar represents the mean ± SEM.
| disease / model field | transcription |
|---|---|
| disease | GD |
| treatment model | CBE (장기투여) |
| age | 2-3 days old |
| genetic model | 4L/PS-NA mice, 3-4 w old |
| mutation note | homozygous point mutation at V394L + saposin C mutation |
| source interpretation | so this is GD mice (prc1, "GBA KI mice with ↓ prosaposin & saposin) |
persistent and durable effects. Six months following ICV administration of a single PR001 dose, GCase activity levels remained significantly increased in the cerebral cortex and a corresponding reduction of lipid accumulation was observed.
(Schiffer, 2020 #1616) strongly enlarged visceral organs that are infiltrated by enlarged leukocytes and macrophages. Furthermore, animals present strong motor deficits that are accompanied by increased glucosylceramide and glucosylsphingosine levels in the brain, astrocytosis and activated microglia in the cortex and hippocampus as well as reduced calbindin levels in the cerebellum. The latter was directly related to a strong Purkinje cell loss. The α-syn IR area was highest in the cerebellum and hippocampus of 5 week old control and 4L/PS-NA animals. In the cerebellum α-syn levels decreased over age in both groups without significant differences between genotypes (Fig 7A). In the hippocampus, only a minor decrease of α-syn levels over age could be observed with the here applied method (Fig 7B).
[Prevail] In these 4L/PS-NA mice, PR001 made increased levels of active GCase, fewer lipids accumulated, and the mice were more mobile on a balance beam. 4L/PS-NA mice also accumulate α-syn. In these mice, and also in A53T α-syn mice made worse with CBE, PR001 halved the amount of insoluble α-syn, we observed vector genome presence and statistically significant increases in GCase activity in the cerebral cortex 14 weeks following PR001 administration.
PR001 Single-Dose Efficacy Study In The Genetic Mouse Model
Single dose efficacy study with PR001 in genetic model 4L/PS-NA.
Dose chosen based on technical and experimental limitation.
administered via ICV injection, as shown in the graphs below
GBA activity는 cortex고, GlcCer/GlcSph는 cerebellum 이고, a-syn 은 cortex이네,
Biodistribution And GCase Activity
No PR001, Control: vehicle only, n = 10; No PR001, 4L/PS-NA: vehicle only, n = 10; Dose 1: 4.3 x 10^9 vg PR001, n = 10; Dose 2: 4.3 x 10^10 vg PR001, n = 10; Dose 3: 1.3 x 10^11 vg PR001, n = 7; Dose 4: 4.3 x 10^11 vg PR001, n = 8.
Each bar represents the mean ± SEM. Values obtained in vehicle only injections without PR001 were indistinguishable from background. P-value: ***p<0.001 by one-way analysis of variance followed by Tukey HSD.
We also observed a dose-dependent trend toward reduced GluSph and GluCer accumulation in the cerebellum 14 weeks following PR001 administered via ICV injection, as shown in the graphs below.
PR001 Observed To Reduce Lipid Accumulation In The Cerebellum In Genetic Mouse Model
No PR001, Control: vehicle only, n = 10; No PR001, 4L/PS-NA: vehicle only, n = 10; Dose 1: 4.3 x 10^9 vg PR001, n = 10; Dose 2: 4.3 x 10^10 vg PR001, n = 10; Dose 3: 1.3 x 10^11 vg PR001, n = 7; Dose 4: 4.3 x 10^11 vg PR001, n = 8.
Each bar represents the mean ± SEM.
| model | GBA activity | GlcCer/GlcSph | a-syn (oligomeric) |
|---|---|---|---|
| 4L/PS-NA mice / PR001 | cortex; 4.3x10^10 (dose 2); ↑15x | cerebellum; 4.3x10^10 (dose 2); = (0.05못 되어서...) | Cortex; 2.4x10^10; ↓60% |
| message | GlcCer/GlcSph 변화 없이도 GBA activity변화만으로 a-syn변화시킴. | ||
insoluble α-Synuclein at 14 weeks after PR001 administration, as depicted in the graph below.
PR001 Observed To Reduce Insoluble α-Synuclein In Genetic Mouse Model
No PR001, Control: vehicle only, n = 5; No PR001, 4L/PS-NA mice: vehicle only, n = 5; PR001, 4L/PS-NA: 2.4 × 10^10 vg PR001, n = 4.
Each bar represents the mean ± SEM.
Uncertain Spans
| location | unresolved text | reason |
|---|---|---|
| CBE source note | 201906 US SECURI AND COMMISION | Source appears misspelled/truncated; likely SEC-related source but not normalized. |
| CBE dose | 3.2x10^10 | High-risk vector-genome dose token. |
| 4L/PS-NA model note | prc1, "GBA KI mice with ↓ prosaposin & saposin | Narrow wrapped source column; quote/abbreviation is unclear. |
| single-dose diagram | dose table values inside the timeline | diagram glyphs are too small to read individually. |
| biodistribution/GCase graphs | exact bar heights and y-axis values | numeric values not directly readable from the plot. |
| lipid accumulation graphs | exact p-value markers and trend brackets | annotation glyphs not directly readable from the plot. |
| summary table | = (0.05못 되어서...) | Korean shorthand is visible but semantically compressed. |
| bottom alpha-syn figure | lower figure continuation | the plot is clipped at the bottom edge of the photo. |