AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis

This study is designed to run parallel to our currently IRB approved protocol #0810010013 entitled "Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human CLN2 cDNA to Children with Late Infantile Neuronal Ceroid Lipofuscinosis," which will assess the safety and efficacy of the virus AAVrh.10 to deliver the CLN2 gene to children in the early stages of the disease. This current study proposes to assess the safety and efficacy of the administration of the same biologic to children who do not fit the criteria for IRB protocol #0810010013.

The differences between protocol #0810010013 and the proposed "parallel" protocol is that inclusion criteria have been modified to include children with any genotype (not only the 5 most common genotypes as in the currently approved protocol) and/or those who score below a 6 but at least a 1 on the Weill Cornell LINCL scale. The reason for expanding the eligibility criteria is to obtain a range of safety data for all children with LINCL, not only those with limited genotype and/or severity. Only 8 subjects will be administered the gene transfer vector in this "parallel" protocol. Subjects will be accrued through IRB approved protocol #0901010186 entitled, "Genotype-Phenotype Correlations of Late Infantile Neuronal Ceroid Lipofuscinosis (2)." Those who do not fit all criteria for the already approved gene transfer protocol (#0810010013) may have the opportunity to be enrolled in this proposed "parallel protocol" (Figure 1). The subjects in the new protocol will be compared to the 16 treated and 16 untreated children enrolled in IRB protocol #0810010013 and #0901010186, respectively.

Inclusion criteria

.

• Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The study does not limit to one specific genotype (genetic constitution).
• The subject must be between the age of 3 and 18 years.
• Subjects will have an average total score of less than 4 but at least 1, and/or an uncommon genotype defined as any genotype that does not include at least one of the 5 most common mutant CLN2 genotypes: C3670T (nonsense Arg208 to stop), G3556C (intron 7 splice), G5271C (Gln422His), T4396G (aberrant splicing, intron8), and G4655A. The total LINCL score should not be outside the 95th percentile confidence limits for age based on our historic data.
• The subject will not previously have participated in a gene transfer or stem cell study.
• 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, and both parents or legal guardians must give consent for their child's participation.
• Sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment.

Exclusion criteria

.

• Presence of other significant medical or neurological conditions may disqualify the subject from participation in this study, particularly those which would create an unacceptable operative risk or risk to receiving the AAVrh.10CUhCLN2 vector, e.g., malignancy, congenital heart disease, liver or renal failure.
• Subjects without adequate control of seizures.
• Subjects with heart disease that would be a risk for anesthesia or a history of major risk factors for hemorrhage.
• Subjects who cannot participate in MRI studies.
• Concurrent participation in any other FDA approved Investigational New Drug.
• Subjects with history of prolonged bleeding or abnormal platelet function or taking aspirin.
• Renal disease or altered renal function as defined by serum creatinine > 1.5 mg/dl at admission.
• Abnormal serum sodium, potassium calcium, magnesium, phosphate at grade III or IV by Division of AIDS Toxicity Scale
• Hepatic disease or altered liver function as defined by SGPT > 150 U/L, and or T.Bilirubin> 1.3 mg/dL
• Immunosuppression as defined by WBC < 3,000 at admission
• Uncorrected coagulopathy during the baseline period defined as INR > 1.4; PTT > 35 sec; PLT < 150,000/mm3
• Anemia (hemoglobin < 11.0 mg/dl at > 2 years of age, with normal serum iron studies)