safety study of a gene transfer vector (rh.10) for children with late infantile neuronal ceroid lipofuscinosis (lincl)

Conditions: Batten Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis

Summary: this is a proposed follow up study on the investigators previous gene transfer human clinical trial entitled "administration of a replication deficient adeno-associated virus gene transfer vector expressing the human cln2 cdna to the brain of children with late infantile neuronal ceroid lipofuscinosis" (weill cornell irb# 0401007010). as in the previous study, the investigators propose to administer a biologic by direct gene transfer into the brain and assess its safety on children with a fatal genetic disease of the central nervous system (cns). the disease is late infantile neuronal ceroid lipofuscinosis (lincl, a form of batten disease). this will be accomplished by using delivery of a gene (method called gene transfer) to administer to the brain an experimental drug called aavrh.10cuhcln2, a gene transfer vector.

the investigators propose to assess a new drug to treat children with a form of batten disease called late infantile neuronal ceroid lipofuscinosis (lincl). these children are born with genetic changes called mutations in their cln2 gene that result in the inability of the brain to properly recycle proteins. the recycling failure leads to death of the nerve cells in the brain and progressive loss of brain function. children with batten disease are normal at birth but by age 2 to 4 have motor and vision problems which progress rapidly to death at age approximately 10 years old. there are no therapies available to treat the disease. the experimental gene transfer procedure treatment the investigators propose consists of augmenting the abnormal gene by a good copy. a virus is used to deliver the good gene to the nerve cells. since the disease is due to an abnormal cln2 gene, the aim of this study is to add a normal copy of the cln2 gene to the brain of affected children to try to reverse death of cells in the brain. previously the investigators have used a virus called adeno-associated virus 2 (aav2) as the gene delivery system. that study showed that viral delivery of the gene was safe. we now propose to use a slightly different virus called aavrh.10 as a gene delivery system and use 2 different doses of the virus. children with batten disease will get the drug injected into the brain and will receive extensive neurological assessment at intervals to determine if the transfer slows the rate of progress of the disease. the primary aims of the study are: (1) to assess the hypothesis that direct administration of aavrh.10cuhcln2 to the brain of children with lincl can be achieved safely and with minimal toxicity; and (2) to evaluate the hypothesis that direct administration of aavrh.10cuhcln2 to the brain of children with lincl will slow down or halt progression of the disease as assessed by neurological rating scales and quantitative mri (primary variables). the investigators have recently completed a study in which the normal copy of the gene was surgically delivered to 12 locations in the brain in 10 children with lincl. the children were assessed by a number of neurological and imaging parameters prior to and after gene transfer. the data demonstrated that the gene transfer was well tolerated and had a small impact on the progression of the disease and suggested that higher doses and a better delivery system may provide greater benefit. the previous study used the viral gene transfer vector adeno-associated virus type 2 (aav2) at a dose of 2,000,000,000,000 molecules of the drug (2 x 10\^12 particle units). the investigators now propose a very similar study with delivery of the identical payload with a slightly different viral gene delivery system based on the virus aavrh.10.

Eligibility criteria:
inclusion criteria: all individuals who meet the following criteria will be included without bias as to a gender or race/ethnicity. each case will be individually reviewed with the eligibility committee comprised of 3 physicians other than the pi, including a pediatric neurosurgeon, pediatric neurologist and general pediatrician. 1. definitive diagnosis of lincl, based on clinical phenotype and genotype. the genotype must include at least one of the 5 most common cln2 mutant genotypes: c3670t (nonsense arg208 to stop), g3556c (intron 7 splice), g5271c (gln422his), t4396g (aberrant splicing, intron 8) and g4655a (cys365tyr). if either parental allele is r447h, the patient will not be included in the study. these account for a total of 83% of the mutations in the study by sleat et al and 82% of the mutations in our studies. the study does not limit to one specific genotype (genetic constitution) since our data regarding the natural history of the disease and the studies of steinfeld, show that, for these 5 genotypes (genetic constitution), lincl subjects have similar clinical course. 2. the subject must be between the age of 2 and 18 years. 3. subjects will have an average total score of 4 - 12 on the weill-cornell lincl scale, and the total score should not be outside the 95th percentile confidence limits for age based on our historic data. 4. the subject will not previously have participated in a gene transfer or stem cell study. 5. 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. 6. sexually active subjects will have to use contraception during the treatment and for 2 months after completion of the treatment. 7. if asymptomatic (i.e - an lincl score of 12), has one older sibling who has a positive genotype and has clinical manifestations of the disease. exclusion criteria: 1. 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. 2. subjects without adequate control of seizures. 3. subjects with heart disease that would be a risk for anesthesia or a history of major risk factors for hemorrhage. 4. subjects who cannot participate in mri studies. 5. concurrent participation in any other fda approved investigational new drug. 6. subjects with history of prolonged bleeding or abnormal platelet function or taking aspirin. 7. renal disease or altered renal function as defined by serum creatinine \> 1.5 mg/dl at admission. 8. abnormal serum sodium, potassium calcium, magnesium, phosphate at grade iii or iv by division of aids toxicity scale. 9. hepatic disease or altered liver function as defined by sgpt \> 150 u/l, and or total bilirubin \> 1.3 mg/dl 10. immunosuppression as defined by wbc \< 3,000/µl at admission 11. uncorrected coagulopathy during the baseline period defined as inr \> 1.4; ptt \> 35 sec; plt \< 100,000/mm3. 12. anemia (hemoglobin \ 2 years of age, with normal serum iron studies).

Keywords: batten disease late infantile neuronal lipofuscinosis gene transfer