NG101 Gene Therapy for Age-Related Macular Degeneration
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Neuracle Genetics, Inc
Must be taking: Anti-VEGF injections
Must not be taking: Anticoagulant therapy
Disqualifiers: Diabetes, Glaucoma, Retinal detachment, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will evaluate the safety, tolerability, and preliminary efficacy of NG101 AAV gene therapy administered by subretinal injections into a single selected eye as a single selected dose for patients with wet age-related macular degeneration (wAMD).
Will I have to stop taking my current medications?
The trial requires that you stop taking any anticoagulant therapy (blood thinners) that is medically necessary at least 2 weeks before the NG101 injection, except for low-dose aspirin used for prevention.
What data supports the effectiveness of the NG101 treatment for age-related macular degeneration?
Gene therapy approaches, like those used in early phase clinical trials for neovascular age-related macular degeneration, have shown promising results in delivering antiangiogenic proteins, which help reduce the need for frequent injections and related complications.
12345What safety data exists for NG101 gene therapy for age-related macular degeneration?
Gene therapy using rAAV.sFlt-1 for age-related macular degeneration has shown a favorable safety profile in early clinical trials, with no drug-related adverse events reported. Some mild, procedure-related side effects were noted, such as cataracts, which were resolved with surgery.
26789How is the NG101 treatment different from other treatments for age-related macular degeneration?
NG101 is a gene therapy that aims to provide a long-term solution for age-related macular degeneration by delivering anti-angiogenic proteins to the eye, potentially reducing the need for frequent injections that are common with current treatments.
2361011Eligibility Criteria
This trial is for individuals aged 50 to 89 with wet age-related macular degeneration (wAMD) in one eye, who have had at least three anti-VEGF injections in the past six months. Participants must have undergone cataract surgery and not be pregnant or able to become pregnant without contraception. They should not have any severe systemic diseases, uncontrolled glaucoma, recent ocular surgeries, other retinal diseases, or be on certain anticoagulants.Inclusion Criteria
My vision in the study eye is between 20/63 and 20/400, mainly due to wet AMD.
I've had 3 or more anti-VEGF injections in one eye within the last 6 months.
I am using effective birth control or am not able to have children, and I have a negative pregnancy test.
+5 more
Exclusion Criteria
Any medically uncontrolled diabetes, defined as HbA1C > 8.0
My study eye has had a retinal detachment.
I have had eye melanoma in the past.
+19 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1 week
1 visit (in-person)
Treatment
Participants receive a single subretinal injection of NG101 AAV gene therapy
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
260 weeks
Multiple visits (in-person) at Weeks 24, 52, 104, 156, 208, and 260
Long-term follow-up
Extended monitoring for adverse events and efficacy
260 weeks
Participant Groups
The study tests NG101 AAV gene therapy given as a single dose through subretinal injection into one eye of patients with wAMD. It aims to assess the treatment's safety and initial effectiveness in improving vision affected by this condition.
3Treatment groups
Experimental Treatment
Group I: NG101 Gene Therapy Group 3Experimental Treatment1 Intervention
Single subretinal injection of 8x10\^9 vector genomes of NG101 AAV gene therapy
Group II: NG101 Gene Therapy Group 2Experimental Treatment1 Intervention
Single subretinal injection of 3x10\^9 vector genomes of NG101 AAV gene therapy
Group III: NG101 Gene Therapy Group 1Experimental Treatment1 Intervention
Single subretinal injection of 1x10\^9 vector genomes of NG101 AAV gene therapy
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Vancouver Coastal Health Research InstituteVancouver, Canada
Cincinnati Eye InstituteCincinnati, OH
Sunnybrook Ophthalmology and Vision ServicesToronto, Canada
Vitreous Retina Macula Specialists of TorontoToronto, Canada
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Who Is Running the Clinical Trial?
Neuracle Genetics, IncLead Sponsor
ORA, Inc.Industry Sponsor
References
Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration. [2022]We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD).
Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. [2021]Age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness in the developed world. Antivascular endothelial growth factor therapy has transformed the management and outcome of neovascular AMD (nAMD), although the need for repeated intravitreal injections-even lifelong-and the related complications, high drug costs, frequent clinic visits and repeated imaging have resulted in an enormous burden both to healthcare systems and patients. The application of gene therapy approaches for sustained delivery of a range of antiangiogenic proteins has the promise of helping to address these aforementioned challenges. A number of early phase clinical trials of gene therapy in nAMD have provided encouraging results, with many more ongoing or anticipated. There remain significant areas of controversy, including regarding the optimal treatment targets, routes of administration and potential safety concerns. In this review we aim to provide an update of the current status of gene therapy for nAMD and briefly discuss future prospects.
Viral-mediated FGF-2 treatment of the constant light damage model of photoreceptor degeneration. [2019]These experiments evaluate overexpression of basic fibroblast growth factor (FGF-2) as a treatment to decrease photoreceptor cell death in the constant light damage model of retinal degeneration. Increased FGF-2 expression was accomplished by gene transfer to the retina via injection into the subretinal space of a recombinant adeno-associated virus (rAAV), containing the FGF-2 gene. Rescue effects were assessed by morphometry and electroretinographic analysis.
Three-Year Follow-Up of Phase 1 and 2a rAAV.sFLT-1 Subretinal Gene Therapy Trials for Exudative Age-Related Macular Degeneration. [2020]To assess the safety and the 3-year results of combined phase 1 and 2a randomized controlled trials of rAAV.sFLT-1 gene therapy (GT) for wet age-related macular degeneration.
Emerging therapies and their delivery for treating age-related macular degeneration. [2022]Age-related macular degeneration (AMD) is the most common cause of blindness in the Western world and is characterised in its latter stages by retinal cell death and neovascularisation and earlier stages with the loss of parainflammatory homeostasis. Patients with neovascular AMD (nAMD) are treated with frequent intraocular injections of anti-vascular endothelial growth factor (VEGF) therapies, which are not only unpopular with patients but carry risks of sight-threatening complications. A minority of patients are unresponsive with no alternative treatment available, and some patients who respond initially eventually develop a tolerance to treatment. New therapeutics with improved delivery methods and sustainability of clinical effects are required, in particular for non-neovascular AMD (90% of cases and no current approved treatments). There are age-related and disease-related changes that occur which can affect ocular drug delivery. Here, we review the latest emerging therapies for AMD, their delivery routes and implications for translating to clinical practice. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.
Preclinical evaluation of KH631, a novel rAAV8 gene therapy product for neovascular age-related macular degeneration. [2023]The upregulation of vascular endothelial growth factor (VEGF) is strongly associated with the development of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD). Currently, the standard treatment for nAMD involves frequent intravitreal injections of anti-VEGF agents, which inhibit the growth of new blood vessels and prevent leakage. However, this treatment regimen places a significant burden on patients, their families, and healthcare providers due to the need for repeated visits to the clinic for injections. Gene therapy, which enables the sustained expression of anti-VEGF proteins after a single injection, can dramatically reduce the treatment burden. KH631 is a recombinant adeno-associated virus 8 vector that encodes a human VEGF receptor fusion protein, and it is being developed as a long-term treatment for nAMD. In preclinical studies using non-human primates, subretinal administration of KH631 at a low dose of 3 × 108 vg/eye resulted in remarkable retention of the transgene product in the retina and prevented the formation and progression of grade IV CNV lesions. Furthermore, sustained transgene expression was observed for more than 96 weeks. These findings suggest that a single subretinal injection of KH631 has the potential to offer a one-time, low-dose treatment for nAMD patients.
Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomised clinical trial. [2022]Neovascular, or wet, age-related macular degeneration causes central vision loss and represents a major health problem in elderly people, and is currently treated with frequent intraocular injections of anti-VEGF protein. Gene therapy might enable long-term anti-VEGF therapy from a single treatment. We tested the safety of rAAV.sFLT-1 in treatment of wet age-related macular degeneration with a single subretinal injection.
AAV cis-regulatory sequences are correlated with ocular toxicity. [2020]Adeno-associated viral vectors (AAVs) have become popular for gene therapy, given their many advantages, including their reduced inflammatory profile compared with that of other viruses. However, even in areas of immune privilege such as the eye, AAV vectors are capable of eliciting host-cell responses. To investigate the effects of such responses on several ocular cell types, we tested multiple AAV genome structures and capsid types using subretinal injections in mice. Assays of morphology, inflammation, and physiology were performed. Pathological effects on photoreceptors and the retinal pigment epithelium (RPE) were observed. Müller glia and microglia were activated, and the proinflammatory cytokines TNF-α and IL-1β were up-regulated. There was a strong correlation between cis-regulatory sequences and toxicity. AAVs with any one of three broadly active promoters, or an RPE-specific promoter, were toxic, while AAVs with four different photoreceptor-specific promoters were not toxic at the highest doses tested. There was little correlation between toxicity and transgene, capsid type, preparation method, or cellular contaminants within a preparation. The toxic effect was dose-dependent, with the RPE being more sensitive than photoreceptors. Our results suggest that ocular AAV toxicity is associated with certain AAV cis-regulatory sequences and/or their activity and that retinal damage occurs due to responses by the RPE and/or microglia. By applying multiple, sensitive assays of toxicity, AAV vectors can be designed so that they can be used safely at high dose, potentially providing greater therapeutic efficacy.
Gene Therapy for Age-Related Macular Degeneration. [2017]The purpose of this article was to evaluate safety and signals of efficacy of gene therapy with subretinal rAAV.sFlt-1 for wet age-related macular degeneration (wet AMD). A phase 1 dose-escalating single-center controlled unmasked human clinical trial was followed up by extension of the protocol to a phase 2A single-center trial. rAAV.sFlt-1 vector was used to deliver a naturally occurring anti-vascular endothelial growth factor agent, sFlt-1, into the subretinal space. In phase 1, step 1 randomized 3 subjects to low-dose rAAV.sFlt-1 (1 × 10 vector genomes) and 1 subject to the control arm; step 2 randomized an additional 3 subjects to treatment with high-dose rAAV.sFlt-1 (1 × 10 vector genomes) and 1 subject to the control arm. Follow-up studies demonstrated that rAAV.sFlt-1 was well tolerated with a favorable safety profile in these elderly subjects with wet AMD. Subretinal injection was highly reproducible, and no drug-related adverse events were reported. Procedure-related adverse events were mild and self-resolving. Two phakic patients developed cataract and underwent cataract surgery. Four of the 6 patients responded better than the small control group in this study and historical controls in terms of maintaining vision and a relatively dry retina with zero ranibizumab retreatments per annum. Two patients required 1 ranibizumab injection over the 52-week follow-up period. rAAV.sFlt-1 gene therapy may prove to be a potential adjunct or alternative to conventional intravitreal injection for patients with wet AMD by providing extended delivery of a naturally occurring antiangiogenic protein.
Gene therapy for age-related macular degeneration. [2018]In neovascular age related macular degeneration (nAMD), gene therapy to chronically express anti-vascular endothelial growth factor (VEGF) proteins could ameliorate the treatment burden of chronic intravitreal therapy and improve limited visual outcomes associated with 'real world' undertreatment. Areas covered: In this review, the authors assess the evolution of gene therapy for AMD. Adeno-associated virus (AAV) vectors can transduce retinal pigment epithelium; one such early application was a phase I trial of AAV2-delivered pigment epithelium derived factor gene in advanced nAMD. Subsequently, gene therapy for AMD shifted to the investigation of soluble fms-like tyrosine kinase-1 (sFLT-1), an endogenously expressed VEGF inhibitor, binding and neutralizing VEGF-A. After some disappointing results, research has centered on novel vectors, including optimized AAV2, AAV8 and lentivirus, as well as genes encoding other anti-angiogenic proteins, including ranibizumab, aflibercept, angiostatin and endostatin. Also, gene therapy targeting the complement system is being investigated for geographic atrophy due to non-neovascular AMD. Expert opinion: The success of gene therapy for AMD will depend on the selection of the most appropriate therapeutic protein and its level of chronic expression. Future investigations will center on optimizing vector, promoter and delivery methods, and evaluating the risks of the chronic expression of anti-angiogenic or anti-complement proteins.
Engineering of PEDF-Expressing Primary Pigment Epithelial Cells by the SB Transposon System Delivered by pFAR4 Plasmids. [2022]Neovascular age-related macular degeneration (nvAMD) is characterized by choroidal blood vessels growing into the subretinal space, leading to retinal pigment epithelial (RPE) cell degeneration and vision loss. Vessel growth results from an imbalance of pro-angiogenic (e.g., vascular endothelial growth factor [VEGF]) and anti-angiogenic factors (e.g., pigment epithelium-derived factor [PEDF]). Current treatment using intravitreal injections of anti-VEGF antibodies improves vision in about 30% of patients but may be accompanied by side effects and non-compliance. To avoid the difficulties posed by frequent intravitreal injections, we have proposed the transplantation of pigment epithelial cells modified to overexpress human PEDF. Stable transgene integration and expression is ensured by the hyperactive Sleeping Beauty transposon system delivered by pFAR4 miniplasmids, which have a backbone free of antibiotic resistance markers. We demonstrated efficient expression of the PEDF gene and an optimized PEDF cDNA sequence in as few as 5 × 103 primary cells. At 3 weeks post-transfection, PEDF secretion was significantly elevated and long-term follow-up indicated a more stable secretion by cells transfected with the optimized PEDF transgene. Analysis of transgene insertion sites in human RPE cells showed an almost random genomic distribution. The results represent an important contribution toward a clinical trial aiming at a non-viral gene therapy of nvAMD.