Study treatment emergent adverse events. NightstaRx Limited hopes

Study NCT03116113 began in July of 2017 and looked at the safety and
efficacy of AAV vector expression in patients with XLRP caused by mutation in
the RPGR-ORF15 gene. Preclinical studies showed successful therapeutic effect
of AAV vectors in proof-of-concept studies of XLRP canine models (34), and the
studies showed no toxicity in biodistribution and toxicology tests. In this
study, a team from the University of Pennsylvania created AAV vectors carrying
RPGRorf15 cDNA and conducted an efficacy study in RPGR knock-out mouse. (35)
Vectors were subretinally injected into the knockout mouse at varying doses and
they were then monitored for retinal function and changes by ERG and OCT. They
found preservation of retinal structure and function both with mouse and human
RPGRor15 vector administration, and OCT showed preservation of the outer layer
in vector-injected retina. Now in this human trial, 15 males 18 or older with XLRP
caused by mutations in RPGR have been recruited to be treated with a single,
subretinal administration of a low dose of AAV-RPGR in the affected eye. Two
other cohorts of 5 patients each will test the medium and high doses. Success
of the study will be measured by low incidences of dose limiting toxocities and
incidences of treatment emergent adverse events. NightstaRx Limited hopes to
release results of this trial by 2019. (40)

Study NCT03252847 is similar to the previous trial in that
it looks at the safety and efficacy of subretinal administration of AAV with
XLRP caused by mutations in RPGR. This trial, however, focuses on
AAV2/5-hRKp.RPGR and compares both adults and children by recruiting 36
participants of young and adult men. They will be divided into 3 cohorts with
low, intermediate, or high subretinal dosages of the vector, respectively.

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Success of the study will be measured by low incidence of adverse events
related to subretinal administration of AAV-RPGR, and this safety component is defined
as absence of ATIMP-related safety events; Dr. James Bainbridge at UCL and
MeiraGTx hopes to release results of this trial by
2020. (41)

Study NCT03374657, though it doesn’t start until 2018,
looks at the maximum tolerated dose of a recombinant AAV8 vector called CPK850,
as determined by the single ascending dose ranging portion of the study. They
also want to look at the safety and potential efficacy of the vector on
possibly improving visual function in patients with RLBP1 RP due to biallelic
mutations in RLBP1 gene. They recruited 15 participants ranging in age from
18-70, and formed five cohorts in ascending dosage level of the subretinal
injection to the study eye. Success of the study will be measured by low number
of participants with adverse events, serious adverse events, and deaths.

It will also be measured by a high number of responders in dark adaptation.

Novartis Pharmaceuticals hopes to release results of this trial by 2025. (42)

Study NCT03326336,
which also doesn’t start until 2018, hopes to look at the safety and
tolerability of a recombinant AAV vector drug product derived from rAAV2.7m8
named GS030-DP (drug product) after being administered via intravitreal
injection and repeated light stimulation using their patented device in
patients with non-syndromic RP. This is different from all other trials, as
they are not only studying patients with non-syndromic RP, but they are
studying intravitreal injection. Administration of AAV into the vitreous has
not been previously successful as it is difficult for the viral vectors to
reach the target bleb in the outer retinal layer, as the viscous vitreous fluid
often prevents much of the vectors from reaching the target location.

Subretinal injections, however, allow for a specific injection directly into
the targeted location. Unfortunately, subretinal injection causes posterior
vitreous detachment and is many-folds more invasive of a procedure than
intravitreal injections, as the former often requires local anesthesia whereas
the latter can be done in an office setting in the period of 5-10 minutes. This
trial recruited 18 participants ranging from 18-75 years old, and divided into
four groups, with the first three groups containing three patients each at
ascending dosages, and the last group containing 3-9 participants at the
highest well-tolerated dose, as determined by results from the previous three
groups. Success of the study will be measured by the
safety and tolerability of the GS030 treatment after 1 year. GenSight
Biologics hopes to release results of this trial by 2024. (43)

Lastly, study
NCT033281 focuses on the safety and efficacy of AAV2/5 hPDE6B subretinal
injection in patients with RP arising from mutations in the PDE6B gene. This is
the only RP study looking at mutations in the PDE6B gene have success the study
will be measured by low incidences of ocular and non-ocular adverse events.

They recruited 12 participants, all 18 years of age or older, and administered
the lowest dose of AAV2/5-hPDE6B vector into one cohort and highest dose into the
second cohort. The third cohort will receive unilateral, subretinal
administration of the confirmatory dose. Horama S. A. hopes to release results
of this trial by 2022. (44)

There have also
been other clinical trials not currently listed on and some
of which target slightly different aspects of RP than we are focusing on. In
the first clinical safety study (NCT01482195), six patients received submacular
injection of AAV2-VMD2-hMERTK, and three patients displayed significant improvement.

(36) Two years after treatment, however, the improvement declined and retinal
thickness did not improve. In another clinical study (NCT02341807), researchers
used AAV5, which has a higher tropism for photoreceptors than the previously
used AAV2, and found improvements in retinal thickness. (37) Lastly, ciliary
neurotrophic factor (CNTF) has been studied for photoreceptor degeneration
inhibition, which can delay ganglion death through AAV delivery and delay
vision loss. Phase I (NCT00063765) confirmed its safety, and phase II for early
RP (NCT00447980) and late RP (NCT00447993) are currently underway. (38)



Age-related macular degeneration
(AMD) is a leading cause of irreversible vision loss (visual acuity 20/2000 or
worse) in the developed world. It Different from LCA and RP, which are mainly
inherited diseases, AMD is greatly affected by older age, smoking, diet and
exercise, in conjunction with race and genetics. as smoking doubles the risk


Etiology: risk factors interplay to
modify the Bruch membrane/choroid complex, RPE, and photoreceptor cells. The
mechanism of development is not fully understood, but we do know the process of
neovascularization is driven by the upregulation of angiogenic cytokines,
specifically VEGF. (for wet)


 most likely to occur after age 50

It destroys the macula (sharp,
central vision)