This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis pigmentosa caused by RPGR mutations.

Approximately 12 participants, who were not part of the Phase 1/2 (HORIZON) study, will be enrolled into the dose expansion portion of the study. These participants will be randomized in a 1:1 ratio to 1 of 2 treatment groups (i.e., Group 1 [low dose] and Group 2 [high dose]). Each participant will receive the assigned dose of AGTC-501 in one eye on a single occasion.

Inclusion Criteria:

• Provide written informed consent or assent (per local regulation), prior to the conduct of any study-related procedure. Subjects who provide assent must have a parent, guardian, or legal representative provide written informed consent.
• Be between 8 and 50 years of age (inclusive) at the time of informed consent and assent (as applicable).
• Be male and have at least one documented pathogenic or likely pathogenic variant in the RPGR gene
• Have a clinical diagnosis of XLRP.
• Have a BCVA no better than 75 letters and no worse than 35 letters based on an ETDRS chart at each screening visit.
• Be able to perform all tests of visual and retinal function and structure in both eyes based on the subject's reliability, and fixation, per the investigator's discretion.
• Have detectable baseline mean macular sensitivity measured by (MAIA) microperimetry, as determined by the investigator and confirmed by the Central Reading Center (CRC).
• Have detectable EZ line in both eyes as assessed by SD-OCT and confirmed by the CRC.

Exclusion Criteria:

• Have other known disease-causing mutations documented in the subject's medical history or identified through a retinal dystrophy gene panel, that in the opinion of the investigator would interfere with the potential therapeutic effect of the study agent or the quality of the assessments.

• For subjects with herpes simplex virus (HSV):

  1. Have history of oral or genital herpes and unable and/or unwilling to utilize prophylactic antiviral medication.
  2. Have a history of ocular herpes.
  3. Have active oral or genital herpes or are currently receiving treatment for HSV infection.

• Have complicating systemic diseases (e.g., medical conditions causing immunosuppression, active systemic infection) that would preclude the gene transfer or ocular surgery.

• Have known sensitivity or allergy to systemic corticosteroids or other immunosuppressive medications.

• Have used anti-coagulant agents that may alter coagulation

• Have received any vaccination/immunization within 28 days prior to screening and/or during screening with the exception of the influenza vaccine, which is only exclusionary if they have received the influenza vaccine within 28 days prior to randomization.

• Have used systemic corticosteroids or other immunosuppressive medications within 3 months prior to screening and/or intend to use during screening.

• Have previously received any AAV gene therapy product, stem cell therapy, cell-based therapy, or similar biologics.

Ocular Exclusion Criteria (Either Eye):

• Have pre-existing eye conditions that would preclude the planned surgery, interfere with the interpretation of study endpoints, or increase the risk of surgical complications
• Have significant media opacity impacting evaluation of the retina or vitreous.
• Had intraocular surgery within 90 days of study treatment administration.
• Have any active ocular/intraocular infection or inflammation
• Have a history of steroid-induced raised IOP of >25 mmHg following corticosteroid exposure, despite topical IOP-lowering pharmacologic therapy.
• Have any artificial retinal implant or prosthesis.
• Have absence of clear ocular media and/or inadequate pupil dilation to facilitate good quality OCT images.
• Have any history of rhegmatogenous retinal detachment.
• Have myopia (spherical equivalent) exceeding -10 diopters (or axial length of >30 mm if PI deems it appropriate to measure) or presence of pathologic myopia in the study eye.
• Have passed the Low Contrast Ora-VNC™ mobility course in either eye or binocularly at any screening visit.

The Phase 2 study is a masked study; therefore, neither the investigator nor the subject will know the dose assignment. Both the subject and the investigator will know which eye received treatment.

Masking will continue until the Month 12 data analysis is performed.