Phase I/II Study of SAR422459 in Patients With Stargardt's Macular Degeneration

The total duration per patient is up to 52 weeks, which includes a 4 week screening period
and a 48 weeks study period.

At the end of the study, the patient will be invited to enter in an open-label safety study
(LTS13588) and long-term follow-up visits including ophthalmological examinations and
recording of adverse events for up to 15 years.

Inclusion Criteria:

- Signed and dated written informed consent obtained from the patient and/or the
patient's legally acceptable representative.

- Diagnosis of Stargardt's Macular Degeneration (SMD), with at least one pathogenic
mutant ABCA4 allele on each chromosome.

- Women of childbearing potential must have a negative pregnancy test at Day -1, and
agree to use an effective form of contraception for at least three months, or be
surgically sterile or postmenopausal, with the last menstrual period being over two
years prior to enrollment.

- Males must agree with their partner to use two forms of contraception for at least
three months following SAR422459 administration.

- Patients must agree to not donate blood, organs, tissues or cells for at least three
months following SAR422459 administration.

- Patients enrolled in France must be affiliated to or benefit from a social security
regimen.

Specific Inclusion Criteria Patient Group A:

- Patients (18 years or older) with advanced Stargardt's Macular Degeneration.

- Visual acuity ≤20/200 in the worst eye.

- Severe cone-rod dysfunction with no detectable or severely abnormal full-field
electroretinogram responses.

Specific Inclusion Criteria Patient Group B:

- Patients (18 years or older) with Stargardt's Macular Degeneration.

- Visual Acuity ≤20/200 in the worst eye.

- Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Patient Group C:

- Patients (18 years or older) with Stargardt's Macular Degeneration.

- Visual acuity ≤20/100 in the worst eye.

- Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Patient Group D:

- Symptomatic patients (from 6 years to 26 years old) with early or childhood-onset SMD
(age at disease onset <18 years) with at least one pathogenic mutant ABCA4 allele on
each chromosome confirmed by direct sequencing and co-segregation analysis within the
patient's family.

- Visual acuity of ≥20/200 in both eyes at the time of the screening visit.

- Patients are anticipated to experience rapid deterioration in visual function and/or
retinal structure as determined by an annual progression rate in at least one of the
following parameters occurring in at least one eye (assessments recorded up to 2 years
prior to the screening visit date may be considered to document evidence of rapid
deterioration):

- Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).

- Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.

- Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by
>14 dB-sr as assessed by static perimetry.

- Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a
rate of ≥0.5 mm^2.

- Enlargement in the area of central macular retinal thinning/photoreceptor loss by
ocular coherence tomography at a rate of ≥0.5 mm^2.

- All eligible patients must demonstrate an ability to understand, willingness to
cooperate and ability to reliably perform required study procedures as judged and
confirmed by the study investigator.

Specific inclusion criteria Patient Group E:

- Symptomatic patients (between 6 years and 17 years old) with early or childhood-onset
SMD with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by
direct sequencing and co-segregation analysis within the patient's family.

- Visual acuity of ≥20/100 in both eyes at the time of screening visit.

- Patients are anticipated to experience rapid deterioration in visual function and/or
retinal structure as determined by an annual progression rate in at least one of the
following parameters occurring in at least one eye (assessments recorded up to 2 years
prior to the screening visit date may be considered to document evidence of rapid
deterioration):

- Loss of ≥1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).

- Reduction in macular mean sensitivity of ≥1.2 dB as assessed by microperimetry.

- Reduction in macular mean sensitivity of ≥5 dB or reduction in hill of vision by
>14 dB-sr as assessed by static perimetry.

- Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a
rate of ≥0.5 mm^2.

- Enlargement in the area of central macular retinal thinning/photoreceptor loss by
ocular coherence tomography at a rate of ≥0.5 mm^2.

- All eligible patients must demonstrate an ability to understand, willingness to
cooperate and ability to reliably perform required study procedures as judged and
confirmed by the study investigator.

Exclusion Criteria:

- Pre-existing eye conditions that would preclude the planned surgery or interfere with
the interpretation of study endpoints.

- Cataract surgery with intraocular lens implantation within 6 months of enrolment.

- Aphakia or prior vitrectomy in the study eye.

- Concomitant systemic diseases including those in which the disease itself, or the
treatment for the disease, can alter ocular function.

- Any intraocular surgery or laser in either eye planned within 6 months of Day 0.

- Any contraindication to pupil dilation in either eye.

- Any known allergy to any component of the delivery vehicle or diagnostic agents used
during the study, or medications planned for use in the perioperative period
particularly topical, injected or systemic corticosteroids.

- Any injectable intravitreal treatment to the treated eye or intravitreal device in the
treated eye within 6 months prior to screening.

- Any periocular injections of corticosteroids to the treated eye within 4 months prior
to screening.

- Laboratory test abnormalities or abnormalities in electrocardiogram, chest X-rays that
in the opinion of the Principal Investigator would make the patient unsuitable for
participation in the study.

- Significant intercurrent illness or infection during the 28 days prior to enrolment.

- Pre-menopausal or non-surgically sterile women who are unwilling to use an effective
form of contraception such as the contraceptive pill or intrauterine device.

- Alcohol or other substance abuse.

- Contraindications to use of anesthesia (local or general, as appropriate).

- Concurrent anti-retroviral therapy that would inactivate the investigational agent.

- History of any investigational agent within 28 days prior to SAR422459 administration.

- Participation in a prior ocular gene transfer therapy study.

- Enrolment in any other clinical treatment study throughout the duration of the
SAR422459 study.

- Current or anticipated treatment with anticoagulant therapy or the use of
anticoagulation therapy within the four weeks prior to surgery.

- A past medical history of human immunodeficiency virus (HIV) or hepatitis A, B, or C
infection.

- Women who are pregnant or are breastfeeding.

- History or signs consistent with unilateral amblyopia (strabismic, anisometropic, or
stimulus deprivation).