Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative
lysosomal storage disease with no known therapy. There are estimated to be 200 to 300
children in the USA at any one time with the disease. LINCL is a genetic disease resulting
from mutations in the CLN2 gene. The CLN2 gene encodes a protein tripeptidyl peptidase-I
(TPP-I) which is absent/deficient in children with LINCL. This absence/deficiency of TPP-I
results in lysosomal storage and subsequent cell death (especially neurons). The children
with LINCL are chronically ill, with a progressive CNS disorder that invariably results in
death, typically by age 8 to 12.

This clinical study will evaluate the concept that persistent expression of the normal CLN2
cDNA in the CNS will result in the production of sufficient amounts of TPP-I to prevent
further loss of neurons, and hence limit disease progression. To assess this concept, an
adeno-associated virus vector encoding the normal human CLN2 gene (AAV2CUhCLN2) will be used
as a vehicle to deliver and express the human CLN2 cDNA in the brain of children with LINCL.
The proposed study will include 11 individuals and will be divided into two parts. Group A,
to be studied first, will include 5 individuals with the severe form of the disease. Group B
of the trial will include 6 individuals with a moderate form of the disease. Following direct
intracranial administration of the vector, there will be neurological assessment using the
LINCL clinical rating scale and magnetic resonance imaging/magnetic resonance spectroscopy
assessment of the CNS in regions of vector administration. The data generated will help
evaluate two hypotheses: (1) that it is safe to carry out direct intracranial administration
of the AAV2CUhCLN2 vector to the CNS of individuals with LINCL; and (2) that administration
of the AAV2CUhCLN2 vector will slow down or halt the progression of the disease in the
central nervous system.

Inclusion Criteria:

- A definitive diagnosis of late infantile neuronal ceroid lipofuscinosis, based on
clinical phenotype and genotype, with CLN2 gene mutations known to be associated with
the disease.

- All subjects will be naive, i.e., they have not previously participated in a gene
therapy study for LINCL.

- Parents of study participants must agree to comply in good faith with the conditions
of the study, including attending all of the required baseline and follow-up
assessments.

- Both parents or legal guardians must give consent for their child's participation in
the research study.

- For group A, subjects will have a LINCL average total disability score 0 to 4, the
severe form of the disease.

- For group B, subjects will have a LINCL average total disability score 5 to 6, a
moderate form of the disease.

Exclusion criteria

- Other significant medical or neurological conditions may disqualify the patient from
participation in this study, particularly those which would create an unacceptable
operative risk or risk to receiving the AAV2CUhCLN2 vector. Examples include
malignancy (other than skin cancer), congenital heart disease, liver or renal failure,
or seropositive for HIV. Each case will be individually reviewed and the final
decision shall rest with the Eligibility Committee comprised on three physicians other
than the Principal Investigator, including a pediatric neurosurgeon, pediatric
neurologist and general pediatrician.

- Individuals without adequate control of seizures (i.e., a seizure score <3 on the CNS
Disability Scoring System for Late Infantile Neuronal Ceroid Lipofuscinosis).

- Individuals with heart disease that would be a risk for anesthesia.

- History of hemorrhage or major risk factors for hemorrhage (e.g., abnormally low
platelet counts).

- Concurrent participation in any other FDA approved Investigational New Drug clinical
protocol is not allowed, although the Principal Investigator will work with other
doctors to accommodate specific requests (e.g., a study of nutritional supplements
probably would not be a disqualification).

- Individuals who have a (1) heart pacemaker and/or related implants, (2) metal
fragment/chip in the eye or other sites, (3) an aneurysm clip in their brain, and (4)
metallic inner ear implants.