Opening the door to gene therapy for ophthalmology diseases- industry analysis and challenges

Hereditary retinal malnutrition (IRDS) includes a series of rare diseases associated with genetic defects that cause sexual retinal degenerationPatients from the beginning of childhood to middle age, gradually serious, two-sided irreversible vision lossThere are more than 200 genetic defects associated with the most common IRDSThe first gene treatment approved by the FDA, the voreti gene neparvovec (Luxturna; Spark Pharmaceuticals), is approved for use in adults or children RPE65 due to a mutation in the dual allele of the binary gene caused by IRDSThe treatment was approved by the European Medicines Agency (EMA) in November 2018, and these landmark decisions will further open the door to gene therapy for ophthalmic diseasesgene therapy is ideal for patients with IRD because lesions are easy to detect and, to some extent, the eye is an immune "privileged" organ: clinical trials have shown that viral vectors used to transmit the required genes, such as adeno-associated viruses (AAVs) and slow viruses, are used in the treatment of eye diseases without significant immune responses or systemic adverse reactionsthe most common IRDinclude pigmented retinitis, vasculature, Leiber hereditary optic neuropathy (LHON), Leiber Congenital Black Haze (LCA), Stargardt disease, anticolor alitching and X-chain retinal fissure (XLRS); Treatment studies are also under way for retinal vascular disease and geriatric macular degeneration (AMD), although these diseases are not related to a single genetic defect in which cells are genetically modified to produce proteins that block the pathogenic pathwayIRDS gene therapy is opening up a broader market for products in the field of ophthalmologyLuxturna is treated by injecting drugs under the retina to treat patients with living retinal cells, so patients with more serious conditions are not suitable for Luxturna treatmentAlthough 41 patients have undergone safety and efficacy assessments, Spark Pharma will conduct a post-market study to determine the long-term safety of the treatmentKnown side effects are mainly related to the injection process itself, including eye inflammation, redness and painindustry analysisthe way in which ophthalmology gene therapy is administered depends on the location of the target cellsIn most IRDS, the defective gene affects the outer retina, the retinal pigment epithelial (RPE) and the underlying fluff membrane layerIn these cases, the virus vector is transmitted to the lower retina gapLHON treatment to the retinal nerve cell as the target, the carrier into the glass cavity, better penetrate the inner layer of the retinaSimilarly, there is retinal weakness in patients with XLRS, and the treatment of glass is the preferred method for treating XLRS diseasethere are currently 25 gene therapy in Phase sie-I, II or III (Table 1)These include a range of eye diseases, such as retinal pigmentation and LCA, as well as malignant melanoma and vine melanomaApplied Gene Technologies (AGTC) and Meira GTx are leading the way in ophthalmology gene therapy, with five and four treatments under development, respectivelyPhase II was the most intense in research therapy, with 19 therapies at this stage, 5 for retinal pigmentation, 4 for color blindness and 2 for LCAMost therapies inare designed to restore the expression of mutant genes (i.eCHM, codeD RAB-accompanied protein 1 (REP1), CNGA, CNGB, RPE65, RS1, or RPGR)Notable exceptions include AMD's treatment, which targets the pathological mechanism of the disease, gene therapy encoding a therapeutic molecule to inhibit angiogenesis or inhibit cell death, and RST-001 gene coding synthesis channel vision alfalfa 2, a gene with photosensitivityNightStar's AAV2-REP1, which is used to treat vasculature, is the only gene therapy currently in stage III and is most likely to be approved for saleNSR-REP1 (AAV2-REP1) is an AAV2 carrier containing complementary DNA from recombinant humans that produces REP1 in the eyeThe Phase III study is expected to complete global recruitment of 140 patients by the first quarter of 2020Table 1the challenges of gene therapy
while the first gene therapies (Glybera, Imlygic, and Luxa) have successfully overcome clinical development already, there are still significant challenges in production, clinical research design, long-term safety research, and the commercialization of future gene therapyBefore the relevant research and development organizations can obtain FDA approval for a new experimental drug (IND), gene therapy requires a well-controlled production process and quality validation analysis test, which is determined by the inherent complexity and potential variability of the production cycle In early preclinical basic research, more biodistributional studies are needed to ensure that GMs are expressed in the expected way and not passed on to non-target tissues To help overcome these early development challenges, the FDA encourages gene therapy developers to communicate with them early by holding an interactive meeting and conducting targeted consultations prior to an IND meeting careful planning of clinical development in order to avoid delays or additional research needs Based on The results of Phase i and II studies, the approval of gene therapy tends to accelerate; For gene therapy based on viral vectors, anticarrier antibodies need to be screened because they greatly limit the population of drug application, and this limitation should be included in the cost and time prediction table FDA and investors are increasingly looking for patient-related treatment data that can be obtained in clinical studies as a major endpoint of research (such as turnLuxa) or as supplementary evidence Obtaining patient data on an ongoing basis and conducting long-term safety follow-up provides the efficiency and synergies required for a business strategy References: 1.Luxturna FDAlabel: 2 Nature Reviews Discovery Drug original title: Ophthalmology - Slowly Opening the Door to Gene Therapy for Ophthalmology Diseases