AAVRh.10 Administered to Children With Late Infantile Neuronal Ceroid Lipofuscinosis
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Neurology |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 3 - 18 |
| Updated: | 1/19/2019 |
| Start Date: | April 15, 2010 |
| End Date: | December 2022 |
Direct CNS Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human CLN2 cDNA to Children With LINCL With Uncommon Genotypes and/or Moderate to Severe Impairment
The investigators propose to assess the safety and efficacy of a new administration method to
deliver a biologic to children with a form of Batten disease using an experimental gene
transfer procedure. This gene transfer procedure consists of delivering a good copy of the
mutated gene to the nerve cells via a virus. These children are born with genetic changes
called mutations 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 investigators previous clinical trial 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 and
showed small, but significant benefits to the recipient. The investigators currently have an
IRB approved protocol which uses a slightly different virus called AAVrh.10 as the gene
delivery system. This 3rd protocol proposes to use the same virus AAVrh.10 as the gene
delivery system and has expanded the eligibility criteria.
deliver a biologic to children with a form of Batten disease using an experimental gene
transfer procedure. This gene transfer procedure consists of delivering a good copy of the
mutated gene to the nerve cells via a virus. These children are born with genetic changes
called mutations 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 investigators previous clinical trial 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 and
showed small, but significant benefits to the recipient. The investigators currently have an
IRB approved protocol which uses a slightly different virus called AAVrh.10 as the gene
delivery system. This 3rd protocol proposes to use the same virus AAVrh.10 as the gene
delivery system and has expanded the eligibility criteria.
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.
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.
1. Definitive diagnosis of LINCL, based on clinical phenotype and genotype. The study
does not limit to one specific genotype (genetic constitution).
2. The subject must be between the age of 3 and 18 years.
3. 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.
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.
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
T.Bilirubin> 1.3 mg/dL
10. Immunosuppression as defined by WBC < 3,000 at admission
11. Uncorrected coagulopathy during the baseline period defined as INR > 1.4; PTT > 35
sec; PLT < 150,000/mm3
12. Anemia (hemoglobin < 11.0 mg/dl at > 2 years of age, with normal serum iron studies)
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