study of sar421869 in participants with retinitis pigmentosa associated with usher syndrome type 1b

Conditions: Usher Syndrome; Retinitis Pigmentosa

Summary: to evaluate the safety and tolerability of ascending doses of subretinal injections of sar421869 in participants with usher syndrome type 1b. to evaluate for possible biological activity of sar421869.

following screening procedures, the gene transfer agent were injected once only under the retina by an opthalmic surgeon under anesthesia. participants then had regular follow-up visits where general health examinations, blood tests and ophthalmic examinations including best corrected visual acuity, slit lamp examination, intraocular pressure, fundoscopy, autofluorescence, optical coherence tomography, perimetry and electroretinogram were undertaken. at the end of the study, the participants were invited to enter in an open-label safety study for long-term follow-up visits (at least once every six months) including ophthalmological examinations and recording of adverse events (aes) were continued for 5 years; then the investigator followed the participants by telephone for a subsequent 10 years at a minimum interval of once a year to monitor delayed aes.

Eligibility criteria:
inclusion criteria: * clinical and molecular diagnosis of retinitis pigmentosa associated with usher syndrome type 1b, caused by at least one pathogenic myosin 7a gene (myo7a) mutation on both alleles, confirmed by direct sequencing and co-segregation analysis within the participant's family. * suitable verbal/auditory and/or tactile sign language communication (in the opinion of the investigator) as to allow written informed consent to be obtained. * women of childbearing potential had a negative pregnancy test at screening and at baseline, and agree to use an effective form of contraception such as the contraceptive pill or intra uterine device for at least three months following sar421869 administration, or be surgically sterile or postmenopausal, with the last menstrual period being over two years prior to enrolment. * males of reproductive potential agreed with their partner to use two forms of contraception, including one barrier method for at least three months following sar421869 administration if their partner was of childbearing capacity, or must be surgically sterile. * participants agreed to not donate blood, organs, tissues or cells for at least three months following sar421869 administration. exclusion criteria: * presence of significant ocular abnormalities in the study eye that in the opinion of the investigator would preclude the planned surgery, effective safety follow-up, or interfere with the interpretation of study outcome measures (e.g., glaucoma, corneal or significant lens opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization). * any pre-existing factor or past history of eye disease in children that might predispose to an increased risk of surgical complications in the study eye (e.g., trauma, previous surgery, uveitis, congenital, developmental or structural abnormalities). * concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter ocular function (e.g., malignancies, diabetes, juvenile rheumatoid arthritis or sickle cell disease). * any contraindication to pupil dilation in either eye. * contraindications to use of anesthesia (local or general, as appropriate). * treatment with intravitreal, subtenon, or periocular steroid within 4 months of the screening visit. * any known allergy to any component of the delivery vehicle or diagnostic agents used during the study (e.g., fluorescein, dilation drops), or medications planned for use during the peri-operative period, particularly topical, injected or systemic corticosteroids. * life-threatening illness. * alcohol or other substance abuse. * history of malignancy within a five year period or have had a positive cancer screening test within a one year period of the screening visit. * laboratory test abnormalities or abnormalities in electrocardiogram or chest x-ray, that in the opinion of the principal investigator, are clinically significant and would make the participant unsuitable for participation in the study. * intercurrent illness or infection 28 days prior to sar421869 administration. * concurrent anti-retroviral therapy that would inactivate the investigational agent. * current treatment with immunosuppressant therapies. * pre-menopausal or non-surgically sterile women who were unwilling to use an effective form of contraception such as the contraceptive pill or intrauterine device. * men or women who did not agree to use barrier contraception as specified in the inclusion criteria. * pregnant or breastfeeding women. * history of any investigational agent within 28 days prior to sar421869 administration. * participation in a prior gene transfer therapy study. * enrolment in any other clinical study, for any condition, including those relating to usher syndrome type 1b, throughout the duration of the sar421869 study. * current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery. * past medical history of hiv, or hepatitis a, b or c. * inability to comply with the study protocol. * any ocular surgery including laser and cataract surgery with intraocular lens implantation, aphakia or prior vitrectomy, in the study eye within 6 months of screening.

Keywords: usher syndrome retinitis pigmentosa usher syndrome associated retinitis pigmentosa