Batten Treatment Report

www.BattenTreatmentReport.com

gene therapy

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease

https://doi.org/10.1016/j.ymthe.2020.09.033

https://pubmed.ncbi.nlm.nih.gov/33010819/

TITLE:
AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease

ALTERNATIVE TITLE:
None

DATE:
Sun, 04 Oct 2020 06:00:00 -0400

AUTHORS:
Tyler B Johnson,Katherine A White,Jon J Brudvig,Jacob T Cain,Logan Langin,Melissa A Pratt,Clarissa D Booth,Derek J Timm,Samantha S Davis,Brandon Meyerink,Shibi Likhite,Kathrin Meyer,Jill M Weimer

SOURCE:
Molecular therapy : the journal of the American Society of Gene Therapy

DESCRIPTION:
CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease…

CONTENT:
Mol Ther. 2020 Sep 24:S1525-0016(20)30490-1. doi: 10.1016/j.ymthe.2020.09.033. Online ahead of print.

ABSTRACT

CLN8 disease is a rare form of neuronal ceroid lipofuscinosis caused by biallelic mutations in the CLN8 gene, which encodes a transmembrane endoplasmic reticulum protein involved in trafficking of lysosomal enzymes. CLN8 disease patients present with myoclonus, tonic-clonic seizures, and progressive declines in cognitive and motor function, with many cases resulting in premature death early in life. There are currently no treatments that can cure the disease or substantially slow disease progression. Using a mouse model of CLN8 disease, we tested the safety and efficacy of an intracerebroventricularly (i.c.v.) delivered self-complementary adeno-associated virus serotype 9 (scAAV9) gene therapy vector driving expression of human CLN8. A single neonatal injection was safe and well tolerated, resulting in robust transgene expression throughout the CNS from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. While it is unclear whether some of these behavioral improvements relate to preserved visual function, improvements in learning/memory, or other central or peripheral benefits, these results demonstrate, by far, the most successful degree of rescue reported in an animal model of CLN8 disease, and they support further development of gene therapy for this disorder.

PMID:33010819 | DOI:10.1016/j.ymthe.2020.09.033

PUBMED ID:
pubmed:33010819

OTHER ID:
pmid:33010819,doi:10.1016/j.ymthe.2020.09.033

PUBLICATION DATE:
Sun, 04 Oct 2020 06:00:00 -0400
2020-10-04

RETRIEVAL DATE :
10/05/20 11:55AM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/33010819/?utm_source=Other&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1nWYA0Nnwr_wLHWsIDX2btUvlzF91Kc2m_rAz6Uc2Ke1bh4s-l&fc=20200622115739&ff=20201005115516&v=2.12.3

LINK – DOI:
https://doi.org/10.1016/j.ymthe.2020.09.033

LINK – FULL TEXT:
Pending

NOTES:
None

Neurogene Announces FDA Orphan Drug Designation for CLN7 Batten Disease Gene Therapy

https://www.businesswire.com/news/home/20200811005348/en/

https://www.neurogene.com/press-releases/neurogene-announces-fda-orphan-drug-designation-for-cln7-batten-disease-gene-therapy/

Neurogene Announces FDA Orphan Drug Designation for CLN7 Batten Disease Gene Therapy
FDA grants Orphan Drug Designation to Neurogene’s adeno-associated virus vector with engineered transgene encoding the human CLN7 gene

August 11, 2020 09:00 AM Eastern Daylight Time
NEW YORK–(BUSINESS WIRE)–Neurogene Inc., a company founded with a mission to bring life-changing genetic medicines to patients and families affected by rare neurological diseases, today announced that the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to adeno-associated virus vector with engineered transgene encoding the human CLN7 gene for patients with CLN7, a form of Batten disease. Batten disease, a common name for a rare class of diseases called neuronal ceroid lipofuscinoses (NCLs), affects an estimated 2-4 out of every 100,000 children in the United States. In July, the company announced it had received Orphan Drug Designation from the FDA for its gene therapy for the treatment of CLN5 Batten disease.

Safety Study of a Gene Transfer Vector (AAV2CUhCLN2) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis [Completed]

https://clinicaltrials.gov/ct2/show/NCT00151216

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

Study Type : Interventional (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study will be carried out in two populations of children with LINCL. Group A will include n= 5 children with a total disability score of 0 to 4 (the severe forms of the disease; the staging based on a modification of the scale of Steinfeld et al. Group B will include n=6 children with a total disability score of 5 to 6, a moderate stage of the disease. All of the study population of 11 children (Group A, n= 5 and Group B, n=6) will receive 3×10^12 particle units of the AAV2CUhCLN2 vector divided among 12 locations delivered through 6 burr holes (2 locations at varying depths through each hole), 3 burr holes per hemisphere. The choice of the locations for the burr holes and needle placement will be on a case-by-case basis due to the diffuse and variable nature of the disease presentation.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : June 2004
Actual Primary Completion Date : June 2019
Actual Study Completion Date : June 2019
Resource links provided by the National Library of Medicine

Gene therapy targeting the inner retina rescues the retinal phenotype in a mouse model of CLN3 Batten disease

https://www.liebertpub.com/doi/10.1089/hum.2020.038

https://doi.org/10.1089/hum.2020.038

https://pubmed.ncbi.nlm.nih.gov/32578444/

TITLE:
Gene therapy targeting the inner retina rescues the retinal phenotype in a mouse model of CLN3 Batten disease

ALTERNATIVE TITLE:
None

DATE:
Wed, 24 Jun 2020 06:00:00 -0400

AUTHORS:
Sophia-Martha Kleine Holthaus,Mikel Aristorena,Ryea Maswood,Olha Semenyuk,Justin Hoke,Aura Hare,Alexander J Smith,Sara E Mole,Robin R Ali

SOURCE:
Human gene therapy

DESCRIPTION:
The neuronal ceroid lipofuscinoses (NCLs), often referred to as Batten disease, are inherited lysosomal storage disorders that represent the most common neurodegeneration during childhood. Symptoms include seizures, vision loss, motor and cognitive decline and premature death. The development of brain-directed treatments for NCLs has made noteworthy progress in recent years. Clinical trials are currently ongoing or planned for different forms of the disease. Despite these promising advances, it…

CONTENT:
Kleine Holthaus SM, et al. Hum Gene Ther 2020.

ABSTRACT

The neuronal ceroid lipofuscinoses (NCLs), often referred to as Batten disease, are inherited lysosomal storage disorders that represent the most common neurodegeneration during childhood. Symptoms include seizures, vision loss, motor and cognitive decline and premature death. The development of brain-directed treatments for NCLs has made noteworthy progress in recent years. Clinical trials are currently ongoing or planned for different forms of the disease. Despite these promising advances, it is unlikely that therapeutic interventions targeting the brain will prevent loss of vision in patients as retinal cells remain untreated and will continue to degenerate. Here, we demonstrate that Cln3Δex7/8 mice, a mouse model of CLN3 Batten disease with juvenile onset, suffer from a decline in inner retinal function resulting from the death of rod bipolar cells, interneurons vital for signal transmission from photoreceptors to ganglion cells in the retina. We also show that this ocular phenotype can be treated by adeno-associated virus (AAV)-mediated expression of CLN3 in cells of the inner retina, leading to significant survival of bipolar cells and preserved retinal function. In contrast, the treatment of photoreceptors, which are lost in patients at late disease stages, was not therapeutic in Cln3Δex7/8 mice, underlining the notion that CLN3 disease is primarily a disease of the inner retina with secondary changes in the outer retina. These data indicate that bipolar cells play a central role in this disease and identify this cell type as an important target for ocular AAV-based gene therapies for CLN3 disease.

PMID:32578444 | DOI:10.1089/hum.2020.038

PUBMED ID:
pubmed:32578444

OTHER ID:
pmid:32578444,doi:10.1089/hum.2020.038

PUBLICATION DATE:
Wed, 24 Jun 2020 06:00:00 -0400
2020-06-25

RETRIEVAL DATE :
06/24/20 01:04PM

LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/32578444/?utm_source=MS-Office&utm_medium=rss&utm_campaign=pubmed-2&utm_content=1nWYA0Nnwr_wLHWsIDX2btUvlzF91Kc2m_rAz6Uc2Ke1bh4s-l&fc=20200622115739&ff=20200624130422&v=2.9.2

LINK – DOI:
https://doi.org/10.1089/hum.2020.038

LINK – FULL TEXT:
Pending

NOTES:
Not sure why this article is dated July 15, 2020 and yet was discovered by the system on June 24, 2020… Hmmm…

Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

https://clinicaltrials.gov/ct2/show/NCT01161576

Safety Study of a Gene Transfer Vector (Rh.10) for Children With Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

Go to sections
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: We chose an initial dose two fold lower of 9.0×10^11 genome copies/subject (Group A). Initially, the study plan was to proceed to Group B, which would receive a higher dose of 1.8×10^12 genome copies if the initial dose was well tolerated. However, after assessing the MRI images of the first 6 children who received the dose of 9.0×10^11 gc, we discovered that 4 of the 6 subjects at 6 months and 1 of the 6 subjects at 12 months exhibited varying degrees of T2 hyperintensities related to diffusion restriction at the sites of vector deposition. Although there are no clinical correlates to these MRI findings, we have decided to lower the dose by ½ log to 2.85×10^11 gc for the remaining subjects to be enrolled in protocol #0810010013. The volume of the drug solution will be the same as in Group A, but the concentration of the vector will be ½ log less.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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 (LINCL)
Study Start Date : August 2010
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : August 2032

Gene Therapy (AT-GTX-502) for Children With CLN3 Batten Disease

https://clinicaltrials.gov/ct2/show/NCT03770572

Gene Therapy for Children With CLN3 Batten Disease

Study Description
Go to sections
Brief Summary:
This is a phase 1/2, open-label, single dose, dose-escalation clinical trial to evaluate the safety and efficacy of AT-GTX-502 (previous NCH Code: scAAV9.P546.CLN3) delivered intrathecally into the lumbar spinal cord region of subjects with CLN3 Batten disease.

Condition or disease Intervention/treatment Phase
CLN3
Batten Disease
Genetic: AT-GTX-502
Phase 1
Phase 2

Detailed Description:
This is a phase 1/2, open-label, single-dose, dose-escalation study of AT-GTX-502 administered intrathecally into the lumbar spinal cord region of pediatric patients with CLN3 Batten disease.

This study consists of a one-time injection of AT-GTX-502 with follow-up visits on Day 7, 14, 21, and 30, followed by every 3 months through 1 year post-dose, and then every 6 months through the second and third years. There are two Cohorts with a low dose and a high dose.

The primary outcome for this clinical study is to evaluate safety. The co-primary objective is to determine the efficacy of AT-GTX-502 as measured by United Batten Disease Rating Scale (UBDRS) physical subscale.

The secondary outcome measures include Pediatric Quality of Life (PedsQL) inventory, seizure subscale of the UBDRS and global impression subscale of the UBDRS.

The exploratory outcome measures include visual impairment assessment, cognitive evaluations, Brain magnetic resonance imaging (MRI), electroencephalogram (EEG), electrocardiogram (ECG) and echocardiogram (ECHO).

For more information about this study, please contact Amicus Therapeutics Patient Advocacy at clinicaltrials@amicusrx.com or +1 609-662-2000.

Study Design
Go to sections
Study Type : Interventional (Clinical Trial)
Estimated Enrollment : 7 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description:
Single Treatment Group (AAV9-CLN3) – 2 Cohort Assignment (Low-dose, High-dose)

Dose escalation in this study will begin with low-dose, determined to be the minimal efficacious dose as determined in non-clinical studies. Dose escalation to a high-dose (2x the minimally effective dose (MED) as evaluated in Cohort 1) will proceed as part of Cohort 2 of the study upon demonstration of safety of the low-dose in Cohort 1 of the study.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/IIa Gene Transfer Clinical Trial for Juvenile Neuronal Ceroid Lipofuscinosis, Delivering the CLN3 Gene by Self-Complementary AAV9
Actual Study Start Date : November 13, 2018
Estimated Primary Completion Date : June 2023
Estimated Study Completion Date : September 2023

Experimental gene therapies for the NCLs

https://www.sciencedirect.com/science/article/abs/pii/S0925443920301174?via%3Dihub

Review
Experimental gene therapies for the NCLs
Centro de Biología Molecular Severo Ochoa (UAM-CSIC) and Departamento de Biología Molecular,Universidad Autónoma de Madrid (UAM), Madrid, Spain
Received 6 November 2019, Revised 16 March 2020, Accepted 17 March 2020, Available online 24 March 2020.

Long-Term Follow-Up of AT-GTX-501 scAAV9 Gene Transfer in Subjects With CLN6 Batten Disease

https://clinicaltrials.gov/ct2/show/NCT04273243

Long-Term Follow Up of CLN6 Batten Disease Subjects Following Gene Transfer
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.

ClinicalTrials.gov Identifier: NCT04273243
Recruitment Status : Recruiting
First Posted : February 18, 2020
Last Update Posted : February 26, 2020
See Contacts and Locations
Sponsor:
Amicus Therapeutics
Information provided by (Responsible Party):
Amicus Therapeutics

Study DetailsTabular ViewNo Results PostedDisclaimerHow to Read a Study Record
Study Description
Go to sections
Brief Summary:
This is a long-term safety and efficacy study in subjects with CLN6 Batten disease who previously received a single intrathecal administration of AT-GTX-501.

Condition or disease Intervention/treatment
CLN6
Batten Disease
Genetic: AT-GTX-501

Detailed Description:
This is a long-term safety and efficacy study in subjects with CLN6 Batten disease who previously received a single intrathecal administration of AT-GTX-501. The assessments described in this long-term follow-up (LTFU) study (AT GTX 501 02) are performed following and in addition to the initial 2 years of assessments in the treatment study (AT-GTX-501-01). In this LTFU study, subjects complete safety and efficacy assessments throughout the study’s 13-year duration. Combining the duration of the initial treatment study and this LTFU study, the overall duration reflects a follow-up period up-to 15 years since gene transfer via AT-GTX-501.

The primary outcome for this study is to assess the long-term safety of AT-GTX-501 in subjects with CLN6 Batten disease.

The secondary outcome measure of this study is to assess the long-term efficacy of AT-GTX-501 in subjects with CLN6 Batten disease.

Study Design
Go to sections
Study Type : Observational
Estimated Enrollment : 13 participants
Observational Model: Case-Only
Time Perspective: Prospective
Official Title: Long-Term Follow-Up of AT-GTX-501 scAAV9 Gene Transfer in Subjects With CLN6 Batten Disease
Actual Study Start Date : January 24, 2020
Estimated Primary Completion Date : January 2035
Estimated Study Completion Date : January 2035

The CLN3 gene and protein: What we know

https://onlinelibrary.wiley.com/doi/full/10.1002/mgg3.859

https://pubmed.ncbi.nlm.nih.gov/31568712/

REVIEW ARTICLE Open Access
The CLN3 gene and protein: What we know
Myriam Mirza Anna Vainshtein Alberto DiRonza Uma Chandrachud Luke J. Haslett Michela Palmieri Stephan Storch Janos Groh Niv Dobzinski Gennaro Napolitano … See all authors
First published: 30 September 2019 https://doi.org/10.1002/mgg3.859Citations: 6
Correspondence
Danielle M. Kerkovich, Principal Scientist, Beyond Batten Disease Foundation, P.O. Box 50221, Austin, TX 78763.
Email: dkerkovich@beyondbatten.org

Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease

https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(19)30311-9

https://linkinghub.elsevier.com/retrieve/pii/S1525001619303119

https://pubmed.ncbi.nlm.nih.gov/31331814/

Gene Therapy Corrects Brain and Behavioral Pathologies in CLN6-Batten Disease
Jacob T. Cain, Shibi Likhite, Katherine A. White, Derek J. Timm, Samantha S. Davis, Tyler B. Johnson, Cassandra N. Dennys-Rivers, Federica Rinaldi, Dario Motti, Sarah Corcoran, Pablo Morales, Christopher Pierson, Stephanie M. Hughes, Stella Y. Lee, Brian K. Kaspar, Kathrin Meyer, Jill M. Weimer
Mol Ther. 2019 Oct 2; 27(10): 1836–1847. Published online 2019 Jul 10.
PMCID: PMC6822284

Back to top