Leber congenital amaurosis (LCA) is a rare inherited retinal disease present from birth that causes severe vision loss. It is caused by mutations in genes critical for the visual cycle, preventing the retina from responding normally to light. Diagnosis involves assessing lack of retinal response on electroretinogram and genetic testing to identify the specific mutation. While currently no treatment can restore lost vision, gene therapy targeting the RPE65 gene has been approved for LCA type 2 based on clinical trials demonstrating improved light sensitivity.

2.  It is rare inherited retinal degenerative
disease usually autosomal recessive
 Genetic condition that causes severe loss of
vision at birth or early childhood.
 LCA is the most serious and early form of
IRD (Inherited Retinal Dystropies) and it
occurs in approximately 5% of IRD total
cases.

4.  The disease was first described by Theodor
Karl Gustav von Leber in 1869.
 In 1957, a non-recordable ERG was
identified as a common feature essential for
diagnosis of LCA by Franceschetti and
Dieterle .
 At the same time, in 1957, a Swedish study
identified the disease to be of autosomal
recessive inheritance.

5.  LCA causes childhood blindness in one of
every 33,330 people.
 Leber congenital amaurosis (LCA) is the
most severe kind of disease accounting for
approximately 5% of the whole retinal
dystrophies and 20% of the children that
study in blind schools.

6.  LCA is an autosomal recessive disease. This means that
both parents must be carriers of the defective gene that
causes LCA.
 In the table below, each parent has one red defective gene
(A) paired with one black non-defective gene (B)
 The risk for two carrier parents to both pass the defective
gene and have an affected child is 25% with each pregnancy.
 The risk to have a child who is a carrier like the parents is
50% with each pregnancy.
 The chance for a child to receive normal genes from both
parents and be genetically normal for that particular trait is
25%.

7. 1 2 3 4
Mother AB -> A A B B
Father AB -> A B A B
Child
AA
(LCA)
AB
(carrier)
AB
(carrier)
BB
(normal)

8.  LCA can result from mutations in at least 27 genes, all of
which are necessary for normal vision.
 Twenty-four of the genes associated with LCA cause only
recessive disease.
 Two genes (IMPDH1 and OTX2) are known to cause
dominant disease.
 One gene (CRX) is known to cause either dominant or
recessive disease, depending on the specific mutation.
 Mutations in the CEP290, CRB1, GUCY2D, and RPE65
genes are the most common causes of the disorder, while
mutations in the other genes generally account for a
smaller percentage of cases.

9. Type Gene % of cases
LCA 1 GUCY2D 12
LCA 2 RPE65 6
LCA 3 SPATA7 Unknown
LCA 4 AIPL1 5
LCA 5 Lebercillin 2
LCA 6 RPGRIP1 4
LCA 7 CRX 1
LCA 8 CRB1 10
LCA 9 Unknown Unknown
LCA 10 CEP290 15
LCA 11 IMPDH1 8
LCA 12 RD3 0.1
LCA 13 RDH12 3
% of patients affected by mutation in various genes causing LCA:

10.  The pathophysiology of LCA is related to the
inability of the eye to undergo
phototransduction due to a disruption of the Visual
Cycle.
 The Visual Cycle is a series of enzymatic reactions
between the retinal pigment epithelium (RPE)and
the neurosensory retina to metabolize dietary
vitamin A into 11-cis retinal to generate
photopigment.
 Without 11-cis retinal, the phototransduction
cascade cannot be initialized; thus, visual neuronal
signals are not propagated to the visual cortex.

11.  A dysfunctional mutation of any of the genes
encoding for proteins that catalyze any of the
series of enzymatic reactions to generate 11-
cis retinal can block the Visual Cycle and
lead to symptoms of LCA.
 As such, there are over eleven known
variants of this disease, each linked to a
specific genetic mutation.

12. Signs
A decrease in visual responsiveness at birth is the first sign of the
disease.
Absence or reduction of the electrical activity of the retina
A cone shape to the front of the eye (keratoconus).
Rapid, involuntary eye movements (nystagmus);
Clouding of the lenses of the eyes (cataracts); and/or
Unusual sensitivity to light (photophobia);
Abnormal or absent pupillary response
Crossed eyes (strabismus);
Nyctalopia

13.  Electroretinogram (ERG):
ERG measures electrical response of retina
which are standard or absent in LCA.
Normal ERG responses rule out a diagnosis of
LCA.
 Autofluorescence measures lipofuscin
accumulation in RPE which is related to shed
photoreceptor disc elements. Amount of
autofluorescence in LCA varies by subtype.

14.  The utilization of newer diagnostic tools as
optical coherence tomography (OCT), join to
electrophysiological test (ERG) support the
diagnosis.
 However, at present, genetic-molecular
testing is necessary to obtain a definitive
diagnosis of retinal dystrophies through
pathogenic variants identification.

15.  At present, their is no medicine available for
this disease
 Surgery is also not available
 New approach has been taken for treating
LCA, that is 'Gene Therapy'
 Gene therapy has found to be a perfect cure
for treatment of LCA

16.  Voretigene neparvovec (Luxturna) is an
novel gene therapy for the treatment of Leber's
congenital amaurosis type 2 caused by RPE65
(Retinal Pigment Epithelium 65 kDA protein)
 It is the first in vivo gene therapy approved by
the FDA on October 12, 2017
 Voretigene neparvovec is an AAV2 vector
containing human RPE65 cDNA with a
modified Kozak sequence.
 It is given as an subretinal injection.

18.  The product voretigene neparvovec is designed to deliver a
normal copy of the gene encoding the human retinal pigment
epithelial 65 kDa protein (hRPE65) to cells of the retina in
persons lacking a normal functional version of RPE65.
 The AAV2 capsid components of voretigene neparvovec
facilitate cell surface binding, entry, and delivery of the vector
genome packaged within the capsid to the nucleus of the cell.
 Once in the nucleus, the genome is uncoated and replicated by
cellular DNA polymerases into a double stranded genome,
which subsequently forms extrachromosomal concatemers
(multiple copies of the same DNA sequence arranged end to
end in tandem, may be circular or linear ) of the expression
cassette.

19.  Phase I studies
o Phase I studies was conducted in two ways:
Study 101:
o Study 101 was an open-label, dose-
exploration safety study.
o In this study, subject received subretinal
injection of voretigene neparvovec (first-
treated eyes).

20. Study 102:
 In Study 102, treated Study 101 subjects
subsequently received a subretinal injection
of voretigene neparvovec in the contralateral
eye (second-treated eyes).
 The interval between the first- and second-
eye injections ranged from 1.7 to 4.6 years.
 Multi-luminance mobility testing (MLMT) is
used to determine the result

21.  Phase 3 Study:
 Study 301 was an open-label, randomized
study.
 In the treatment group received subretinal
injections of voretigene neparvovec in both
eyes.
 In Study 302 injection interval between the
two eyes of each subject varied from 7 days
to 21 days

22.  Multi-luminance mobility testing (MLMT) is
used to determine the result
 MLMT score was significant showing the
drug of having the activity

23.  Ocular Adverse Events : Conjunctival
hyperemia, Cataract development, retinal
tear, eye pain.
 Serious Adverse Events : Irreversible optic
atrophy due to sustained increased IOP
 Systemic Adverse Events : Leukocytosis,
Fever, Nausea, Vomitting

24.  The drug Luxturna (Vortigene Neperavovec)
has been approved by FDA for the treatment
of RPE65 mutated disease i.e; Leber
Congenital Amaurosis type 2 on October
12th, 2017