Zhang et al. 2022 — Lanosterol depot delivery in cynomolgus-monkey cataracts
TL;DR
Nine older female cynomolgus monkeys comprised three untreated clear-lens references, three with bilateral naturally occurring cortical cataract, and three with bilateral nuclear cataract. Both eyes of each cataractous animal received a subconjunctival lanosterol–thermogel depot; there was no vehicle, sham-injection, or untreated-cataract arm. Mean cortical LOCS III grade fell from C3.0 at baseline to C2.5 at day 14 and then rebounded by day 21, while mean nuclear grade was N2.8 both at baseline and day 14.1 With only three animals per subtype and no cataract control, this is an exploratory exposure-linked time trend, not controlled evidence that lanosterol—topical or otherwise—reverses cataract. gap/needs-replication gap/needs-human-replication
Design
- Selection and groups: 40 monkeys aged 18–22 years were screened. Nine females selected partly for cooperation and anesthesia response entered the study: three without cataract, three with bilateral cortical cataract, and three with bilateral nuclear cataract. Assignment was based on phenotype, not randomization.
- Delivery: the formulation contained 1.6 mg lanosterol per 1 mL of 25% (w/w) PLGA₁₇₀₀–PEG₁₅₀₀–PLGA₁₇₀₀ thermogel plus fluorescein. Each cataractous eye received 0.1 mL by superior-temporal subconjunctival injection—0.16 mg lanosterol per eye—followed by topical levofloxacin for one week.
- Follow-up: standardized dilated photographs and aqueous-humor sampling were obtained at baseline and days 7, 14, and 21. Cortical opacity was assessed by retroillumination and nuclear opacity by slit-lamp images; two described “blind-test” examiners graded LOCS III images, but the information concealed from them and handling of paired ratings were not reported.
- Terminal measures: all lenses were removed at day 21 and separated into cortex and nucleus for soluble-protein, crystallin, total-antioxidant-capacity, and GSSG/GSH assays.
- Controls: the three clear-lens animals were untreated reference animals, not a vehicle/sham control. No cataractous animal was left untreated or given blank thermogel.
Results
Exposure and opacity time course
Depot fluorescein declined over follow-up and was seldom detectable at day 21. LC–MS showed that aqueous-humor lanosterol peaked at day 14: 31.61 ± 6.50 ng/mL in cortical-cataract eyes and 28.58 ± 9.14 ng/mL in nuclear-cataract eyes, compared with 9.04 ± 5.19 and 12.01 ± 2.81 ng/mL at day 7 and 8.28 ± 3.12 and 4.92 ± 1.51 ng/mL at day 21. The reported time-course P-values were 0.002 and 0.005, respectively.1 These measurements establish aqueous exposure, not lanosterol concentration within the lens; fluorescein disappearance is also not a direct lanosterol assay.
The six cortical-cataract eyes averaged C3.0 at baseline and C2.5 at day 14. The opacity-reduction rate at day 14 was reported as greater than at day 21 (P<0.05, exact value not supplied), when opacity had rebounded toward baseline. The six nuclear-cataract eyes averaged N2.8 both before treatment and at day 14, with no significant time-course change through day 21.1 The paper did not report an active-versus-control opacity comparison because no cataract control existed.
Terminal protein and redox measures
At day 21, cortical tissue from treated cortical-cataract lenses had a higher soluble-protein/total-protein ratio than untreated clear controls (77.6% versus 66.9%, P=0.012) and a higher soluble-α-crystallin/total-protein ratio (54.6% versus 46.9%, P=0.039). No significant β- or γ-crystallin-solubility difference was reported. The paper states that these assays used “a subset” of lenses but gives no sample count.1
Total antioxidant capacity was higher in cortex and nucleus of the treated cataract groups than in clear controls. The GSSG/GSH ratio was lower in cortex from the treated cortical-cataract group, but higher in nuclei from both treated cataract groups. Because these were terminal cross-sectional comparisons of treated diseased lenses against untreated clear lenses, baseline disease differences and treatment effects cannot be separated.1
Interpretation
The study is useful mainly as a delivery and subtype signal. Aqueous exposure and manually graded cortical opacity moved on similar time courses, while the nuclear group showed little change. Temporal concordance does not establish causality: without an untreated or vehicle-treated cataract group, natural fluctuation, repeated-procedure effects, measurement drift, and regression to the mean cannot be separated from treatment.
Both eyes of each treated monkey received the same intervention, creating six measured eyes but only three independent animals per subtype. The paper reports repeated-measures ANOVA but does not state whether the inferential unit was eye or animal or whether within-animal correlation was modeled. Sample sizes for terminal biochemical assays were also unreported. No power calculation, exact cortical-opacity P-value, confidence interval, or multiplicity adjustment was supplied, and the opacity endpoint remained a manually graded ordinal score.
The invasive sustained-release route cannot be generalized to ordinary topical eye drops or to the chemically undisclosed zoc2017217 program. Follow-up lasted only 21 days, the apparent cortical change was not sustained, and no visual-acuity or other functional outcome was measured.
Extrapolation to humans
| Dimension | Status | Notes |
|---|---|---|
| Pathway conserved in humans? | yes | Lanosterol and crystallins are shared, but tissue exposure was engineered. |
| Disease phenotype conserved? | partial | Naturally occurring adult-onset primate cataract is relevant, but there were only three animals per subtype and no cataract control. |
| Replicated in humans? | no | No human treatment arm was performed. |
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Footnotes
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Zhang K, He W, Du Y, Zhou Y, Wu X, Zhu J, Zhu X, Zhang K, Lu Y · doi:10.1093/pcmedi/pbac021 · PMID:36196296 · PMCID:PMC9523460 · nine female cynomolgus monkeys (18 eyes), with three animals per clear-lens/cortical-cataract/nuclear-cataract group · nonrandomized, uncontrolled active-treatment study using bilateral subconjunctival lanosterol–thermogel depots · Precision Clinical Medicine 2022;5(3):pbac021. ↩ ↩2 ↩3 ↩4 ↩5