A first-in-human, open label, dose escalation trial to evaluate the safety, tolerability and pharmacodynamics of a single dose of AXV-101 in patients with Bardet-Biedl syndrome 1 (BBS1) bi-allelic mutations and retinal degeneration
Bardet-Biedl syndrome 1 (BBS1) mutation affecting multiple organs, including the eyes and vision
Up to 12 children between the ages of 4 to 17 years with BBS1 with deteriorating eyesight will be enrolled on the study. The study consists of two parts (cohort 1 and cohort 2): Cohort 1 participants (n = 3) will be given a dose of 3 x 10^11 viral genomes AXV-101 Cohort 2 participants (n = 9) will be given a dose of 5 x 10^11 viral genomes of AXV-101 The children will be followed up for a total of 5 years at set timepoints (up to 19 hospital visits) to check the safety and effectiveness of the study drug.
To be eligible to participate in this trial, an individual must meet all the following criteria: 1. Male or female participants aged 4 to 17 years (inclusive). 2. Able to provide written informed consent: 2.1. Parent(s)/guardian(s) prior to the initiation of any study-specific procedures for participants who are under the age of 18 2.2. Participants aged 6-17 years of age may (according to the judgement of the investigator) provide their written assent; consent will also be required from the legal guardian of the participant. 2.3. Participants aged below 6 years of age will not be required to sign an assent form; however, their views should be considered; consent will be required from the legal guardian of the participant. 3. Participant with a confirmed diagnosis of bi-allelic BBS1 mutations. Molecular diagnosis/genetic testing will have been undertaken by an accredited laboratory using an assay that has the relevant mark of conformity and is used as per its intended use. UK diagnostic genetic laboratories must conform to the Association for Clinical Genomic Science (ACGS) and adopt the ACMG guidelines for the determination of pathogenicity. US diagnostic genetic laboratories must be CLIA-approved. 4. Participants with presentation of retinal degeneration (evidence of early Rod-Cone Dystrophy, Cone-Rod Dystrophy or Night vision loss [nyctalopia]) 5. Participants with sufficient viable retinal cells as determined by OCT. Participants must have either: 5.1. A measurable area of intact ellipsoid within the posterior pole - minimum 1500 microns horizontal width 5.2. ≥3-disc areas of retina without atrophy or pigmentary degeneration within the posterior pole; or 5.3. Remaining visual field within 30 degrees of fixation as measured by a III4e isopter or equivalent. 6. Post-pubertal male participants and female participants of childbearing potential must be willing to comply with the contraceptive requirements
An individual who meets any of the following criteria will be excluded from participation in this trial: 1. A fully blind participant. 2. Participant or participant’s legal guardian is unable or unwilling to meet the requirements of the study, or unable to provide written informed consent/assent 3. Participant has been administered any investigational medicinal product (IMP) during the last 6 months prior to individual enrolment of the participant and/or within five half-lives of the previous IMP, whichever is longer 4. Other than as required per protocol, the participant has received immune-modulating agents within 90 days before dosing (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed) 5. Glucocorticoid intolerance 6. Use of other concomitant medications to manage chronic conditions must have been stable for at least 30 days before dosing 7. Presence of severe diabetes or uncontrolled blood glucose 8. Presence of active infection or recent severe infection (elevated WBC) 9. Participant with any prior intraocular surgery in either eye within 6 months 10. Participant with any known sensitivity to AXV-101, its excipients and the medications planned for use in the peri-operative period 11. Participant with significant renal, liver or haematological disease as defined by: 12. Laboratory evidence of liver disease (aspartate aminotransferase greater than two times the upper limit of normal [ULN] of the testing laboratory). 13. Laboratory evidence of renal disease (eGFR<30). 14. Laboratory evidence of haematological disease (absolute neutrophil count < 1,500/mm3; haemoglobin < 0.9 times the lower limit of normal [LLN] of the testing laboratory, by sex; or platelet count < 140,000/mm3). 15. Any pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of the study or the safety of the participant. Active uveitis or intraocular inflammation (infectious or non-