Jinyuan Wang, Jinlu Zhang, Shicheng Yu, Hongyan Li, Shaohong Chen, Jingting Luo, Haibo Wang, Yuxia Guan, Haihan Zhang, Shiyi Yin, Huili Wang, Heping Li, Junle Liu, Jingyuan Zhu, Qiong Yang, Ying Sha, Chuan Zhang, Yuhang Yang, Xuan Yang, Xifang Zhang, Xiuli Zhao, Likun Wang, Liping Yang, Wenbin Wei | Signal Transduction and Targeted Therapy | Vol. 9, Issue 95 | 24 April 2024 | https://doi.org/10.1038/s41392-024-01806-3
Abstract
Bietti crystalline corneoretinal dystrophy is an inherited retinal disease caused by mutations in CYP4V2, which results in blindness in the working-age population, and there is currently no available treatment. Here, we report the results of the first-in-human clinical trial (NCT04722107) of gene therapy for Bietti crystalline corneoretinal dystrophy, including 12 participants who were followed up for 180–365 days. This open-label, single-arm exploratory trial aimed to assess the safety and efficacy of a recombinant adeno-associated-virus-serotype-2/8 vector encoding the human CYP4V2 protein (rAAV2/8-hCYP4V2). Participants received a single unilateral subretinal injection of 7.5 × 1010 vector genomes of rAAV2/8-hCYP4V2. Overall, 73 treatment-emergent adverse events were reported, with the majority (98.6%) being of mild or moderate intensity and considered to be procedure- or corticosteroid-related; no treatment-related serious adverse events or local/systemic immune toxicities were observed. Compared with that measured at baseline, 77.8% of the treated eyes showed improvement in best-corrected visual acuity (BCVA) on day 180, with a mean ± standard deviation increase of 9.0 ± 10.8 letters in the 9 eyes analyzed (p = 0.021). By day 365, 80% of the treated eyes showed an increase in BCVA, with a mean increase of 11.0 ± 10.6 letters in the 5 eyes assessed (p = 0.125). Importantly, the patients’ improvement observed using multifocal electroretinogram, microperimetry, and Visual Function Questionnaire-25 further supported the beneficial effects of the treatment. We conclude that the favorable safety profile and visual improvements identified in this trial encourage the continued development of rAAV2/8-hCYP4V2 (named ZVS101e).
Introduction
Bietti crystalline corneoretinal dystrophy (BCD) is an inherited retinal degenerative disorder characterized by the presence of yellow-white crystalline deposits in the retina, which are accompanied by the progressive atrophy of the retinal pigment epithelium (RPE), photoreceptors, and choriocapillaris. Patients with BCD commonly exhibit clinical symptoms in their 20s or 30s, which include progressive night blindness, reduced visual acuity, restricted visual field, and impaired color vision.1 According to a natural history study, the best-corrected visual acuity (BCVA) of patients with BCD typically declines by an average of 4.5 letters per year.2 By the age of 50–60 years, most individuals with BCD experience severe visual and visual field impairments, resulting in legal blindness.3 The worldwide prevalence of BCD is 1/576,000;4 however, the condition is more common in East Asia.5 In China, the prevalence of retinitis pigmentosa is 1/3784,6 with BCD accounting for 15% of these cases;7 thus, the prevalence of BCD in China is estimated to be ~1/25,000. Currently, no treatment is available for BCD.
BCD is a specific type of retinitis pigmentosa with autosomal recessive inheritance caused by mutations in CYP4V2.8 The CYP4V2 protein is produced in multiple body tissues but is particularly abundant in the RPE.9,10 CYP4V2 is an omega 3-polyunsaturated medium-chain fatty acid hydroxylase that hydrolyzes docosahexaenoic and eicosapentaenoic acid in the eye.9 The photoreceptor outer segment contains large amounts of lipids that can be esterified to form docosahexaenoic acid, eicosapentaenoic acid, and other fatty acids. Physiologically, the RPE engulfs the portion of the photoreceptor outer segment that is undergoing shedding, and the disc lipids are metabolized in the RPE and transferred to the inner segment for the biosynthesis of new discs. This process of lipid recycling promotes disc regeneration while maintaining photoreceptor function. CYP4V2 mutations disrupt lipid metabolism and RPE-mediated lipid recirculation, thus impairing the regeneration of photoreceptor membrane discs, which leads to photoreceptor damage and, ultimately, retinal degeneration.11,12
RPE65 gene replacement therapy was approved for marketing in 2017, as it represented a notable advance in clinical medicine and offered the potential to correct many other inherited retinal dystrophies (IRDs) caused by mutations that lead to functional impairment, including BCD. Adeno-associated virus (AAV)-mediated gene therapy has shown promising efficacy in several in vivo or in vitro BCD models.12,13,14,15 In particular, the recombinant AAV2/8–human CYP4V2 (rAAV-hCYP4V2) vector, which produces the functional wild-type human CYP4V2 protein (patent no. CN113106124B), has been found to be efficient in an induced pluripotent stem cells-derived RPE from a patient with BCD as well as in a Cyp4v3-knockout mouse model,14 providing the basis for a clinical trial for this gene therapy.
Here, we report an investigator-initiated trial of gene replacement therapy for BCD. This is the first clinical trial on BCD worldwide with a focus on assessing the safety and preliminary clinical efficacy of rAAV2/8-hCYP4V2, which will offer unprecedented prospects for addressing unmet medical needs in the management of BCD.
Results
Participant characteristics and intervention
A total of 12 participants were enrolled in this study; the first 6 participants were followed up for 365 days, and the remaining 6 participants were followed up for 180 days. Their median age was 40 years (SD, 8.2 years; range, 27–50 years), and half of them were female (Table 1). One eye per patient was selected for treatment with rAAV2/8-hCYP4V2. The median baseline visual acuity letter score in the treated eyes was 30.6 (Snellen equivalent, ~20/200; Table 1). Most participants exhibited widespread RPE and choriocapillaris atrophy, as well as ellipsoid zone disruption and extensive loss (Supplementary Figs. 1 and 2). The investigational product (rAAV2/8-hCYP4V2, also known as ZVS101e) was successfully injected into the subretinal space through one or two injection sites (retinotomies) per participant, with the fovea included in the administration area in 3 participants (R004, R007, and R008; Supplementary Fig. 2). The injected viral particles were fully absorbed within 24 hours. In 2 participants, R004 and R008, macular holes developed 1 day after surgery and healed 15 days after surgery (Supplementary Figs. 3 and 4). Participant R005 developed cataracts 1 day after the surgery and underwent lens replacement surgery 9 months after the intervention. Participant R002 was excluded from the efficacy analysis due to an accidental head trauma that occurred 27 days after surgery.
Product safety
73 treatment-emergent adverse events (TEAEs) were reported in the 12 participants, including 24 ocular TEAEs and 49 systemic TEAEs. Ocular TEAEs were consistent with vitrectomy and subretinal injection procedures (Table 2). 2 serious adverse events occurred in 2 participants: R002 experienced a decrease in visual acuity due to head trauma by an accidental fall, and R005 developed cataracts after subretinal injection and underwent standard lens replacement surgery. The most common adverse event was coronavirus disease (COVID-19), followed by hypercholesterolemia and leukocytosis. No suspected unexpected serious adverse reaction was observed, and most of the TEAEs were mild (94.5%) or moderate (4.1%). 5 TEAEs (6.8%), including hyperlipidemia (4/73, 5.5%) and hypercholesterolemia (1/73, 1.4%), were considered to be possibly related to both the investigational product and corticosteroids; 32 TEAEs (43.8%) were considered to be related to corticosteroids; and 23 TEAEs (31.5%) were considered to be related to the procedure. Therefore, our analysis demonstrated that a single unilateral subretinal rAAV2/8-hCYP4V2 administration is safe and well-tolerated.
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