gene therapy clinical trial for the treatment of leber's hereditary optic neuropathy associated with nd1 mutations

Conditions: Leber Hereditary Optic Neuropathy (LHON)

Summary: the objective of this clinical study is to evaluate the safety, tolerability and preliminary efficacy of nfs-02 in the treatment of lhon caused by mitochondrial nd1 gene mutation. this study will enroll subjects aged ≥ 18 years old and ≤ 75 years old to receive a single unilateral intravitreal (ivt) injection of nfs-02 to evaluate its safety, tolerability and preliminary efficacy. the clinical manifestations of all subjects are to be reduced visual acuity caused by lhon associated with nd1 mutation, with laboratory test showing g3460a mutation (a clia-certified laboratory) and reduced visual acuity lasted for \> 6 months and \< 10 years.

at the dose-finding stage, the principle is that the safety review committee (src) will decide whether to make dose adjustment based on the safety data of the starting dose. the starting dose is 1.5×108 vg, 0.05 ml eye/dose. the safety of the starting dose will be reviewed by the src, and dose escalation or de-escalation is by recommendation of the src. the safety of the starting dose will first be performed in 6 evaluable subjects. criteria for dose modification: dose escalation: if drug-related dose-limiting toxicity (dlt) events are observed in \< 2 of the 6 evaluable subjects within 6 weeks after the dosing of nfs-02 at the starting dose, the dose can be escalated to 5.0×108 vg, 0.05 ml eye/dose after the approval by src. if drug-related dose-limiting toxicity (dlt) events are observed in \< 2 of the 6 evaluable subjects within 6 weeks after the dosing of nfs-02 at the 5.0×108 vg, 0.05 ml eye/dose, the dose can be escalated to 1.5×109 vg, 0.05 ml eye/dose after the approval by src. dose de-escalation: if drug-related dose-limiting toxicity (dlt) events are observed in ≥ 2 of the 6 evaluable subjects within 6 weeks after the dosing of nfs-02 at the starting dose, the dose can be de-escalated to 5.0×107 vg, 0.05 ml eye/dose after the approval by src. enrollment sequence: * the enrollment sequence of any dose group (6 subjects) is that the 2nd subject and the 3rd subject will be enrolled at least 7 days after the enrollment of the 1st subject. * the 4th, 5th and 6th subjects will be enrolled at least 7 days after the enrollment of the 2nd and the 3rd subjects. the 7-day interval is to avoid acute safety events to the greatest possible extent.

Eligibility criteria:
inclusion criteria: age 1. age at the time of signing the informed consent form: the age of the subjects must be ≥ 18 years old and ≤ 75 years old type of subject and disease characteristics 2. the clinical manifested vision loss due to lhon, and any eye bcva ≥ 0.5 logmar 3. the genotype testing result shows the presence of g3460a mutation in the nd1 gene, and the absence of the other primary lhon associated mutations in the mitochondrial dna (mtdna) (nd4 \[g11778a\] or nd6 \[t14484c\]) (confirmed by a clia-certified international laboratory) 4. the vision loss in the eye with worse visual acuity lasted \> 6 months and \< 10 years at screening 5. pupils can be adequately dilated for a thorough ocular examination and visual acuity test 6. each eye of the subject must maintain at least hand motion visual acuity (va) (≤ 2.3 logmar) as defined in the ocular/vision examination manual (operating manual for refraction and va examinations) in this study 7. willingness to comply with the clinical study protocol and 5 years of long-term follow-up after administration sex 8. male or female 1. male subjects: a male subject must agree to take contraceptive measures at least 6 months after the treatment visit, see appendix 5 for details 2. female subjects: a female subject is eligible to participate if she is not pregnant (see appendix 5), not breastfeeding, and at least one of the following conditions applies: i) not a woman of childbearing potential (wocbp) as defined in appendix 5 ii) a wocbp who agrees to follow the contraception guidance in appendix 5 for at least 6 months after the treatment visit informed consent 9. written informed consent form must be obtained from the subject or his/her parent/legal guardian before any study-related procedures is performed (see section 10.2) 10. if the subject is legally blind (\> 1.0 logmar or the readings of decimal visual acuity chart \< 0.1), an impartial witness must be present throughout the informed consent process and discussion process. exclusion criteria: 1. any known allergy and/or hypersensitivity to the study drug or its constituents 2. contraindication to ivt injection in any eye 3. ivt drug delivery to any eye within 30 days prior to the screening visit 4. history of vitrectomy in either eye 5. narrow anterior chamber angle in any eye contra-indicating pupillary dilation 6. presence of disorders or diseases of the eye or adnexa, excluding lhon, which may interfere with visual or ocular assessments, including spectral-domain optical coherence tomography (sd-oct), during the study 7. presence of known/documented mutations, other than the lhon-related mutation, which are known to cause pathology of the optic nerve, retina, or afferent visual system 8. presence of systemic or ocular/vision diseases, disorders, or pathologies, other than lhon, known to cause or be associated with vision loss, or whose associated treatment(s) or therapy(ies) is/are known to cause or be associated with vision loss 9. presence of optic neuropathy from any cause other than lhon 10. presence of illness or disease that, in the opinion of the investigator, include symptoms and/or the associated treatments that can alter visual function, for instance cancers or pathology of the central nervous system (cns), including multiple sclerosis (diagnosis of multiple sclerosis must be based on the 2010 revisions to the mcdonald criteria) (polman c h et al., 2011), and/or diseases or conditions that affect the safety of subjects participating in the study 11. history of recurrent uveitis (idiopathic or immune-related) or active ocular inflammation 12. participated in another clinical study and receive an imp within 90 days prior to the screening visit a) exceptions: subjects who have completed the clinical study of idebenone as imp \> 90 days prior to the screening visit and has completely discontinued idebenone at least 7 days prior to dosing are still eligible to participate in the study. 13. any eye has previously received ocular gene therapy 14. subjects who refused to stop using idebenone 15. have undergone clinical-related ocular surgery (per investigator's assessment) within 90 days prior to the screening visit 16. female subjects who are breastfeeding or plan to breastfeed within the first 6 months after the administration of nfs-02 injection 17. history of drug or alcohol abuse (including heavy smoking, i.e., \> 20 cigarettes per day or \> 20 pack-years \[equivalent to one pack a day for 20 years or 2 packs a day for 10 years\]) 18. human immunodeficiency virus (hiv) antibody, syphilis antibody and hcv antibody positive are excluded; hepatitis b test that shows a clinically significant active infection requiring treatment (defined as the presence of hepatitis b core antibody \[hbcab\] positive or hepatitis b surface antigen \[hbsag\] positive, and hepatitis b virus deoxyribonucleic acid \[hbv-dna\]) \> 1000 copies/ml or according to local laboratory method above lower limit of quantitative detection) are excluded 19. unable to tolerate or unable or unwilling to comply with all the protocol requirements 20. subjects from the study site fail to comply with or do not agree to comply with local and institutional guidelines for suspected 2019 novel coronavirus (covid-19) infection/testing 21. any other exclusions determined by the investigator