scholarly journals Gene Therapy Targeting the Inner Retina Rescues the Retinal Phenotype in a Mouse Model of CLN3 Batten Disease

2020 ◽  
Vol 31 (13-14) ◽  
pp. 709-718 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Mikel Aristorena ◽  
Ryea Maswood ◽  
Olha Semenyuk ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Batten Disease ◽  
Inner Retina

scholarly journals AAV9 gene therapy restores lifespan and treats pathological and behavioral abnormalities in a mouse model of CLN8-Batten disease

2020 ◽  
Author(s):  
Tyler B. Johnson ◽  
Katherine A. White ◽  
Jacob T. Cain ◽  
Logan Langin ◽  
Melissa A. Pratt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Premature Death ◽  
Gene Therapy Vector ◽  
Behavioral Abnormalities ◽  
Endoplasmic Reticulum Protein ◽  
Biallelic Mutations ◽  
Brain And Spinal Cord

AbstractCLN8 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 (ICV)-delivered self-complementary AAV9 (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 brain and spinal cord from 4 to 24 months, reducing histopathological and behavioral hallmarks of the disease and completely restoring lifespan from 10 months in untreated animals to beyond 24 months of age in treated animals. These results demonstrate, by far, the most successful rescue reported in an animal model of CLN8 disease, and supports gene therapy as a promising therapeutic strategy for this disorder.

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Vol 28 (23) ◽  
pp. 3867-3879 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Herranz-Martin ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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

2020 ◽  
Author(s):  
Tyler B. Johnson ◽  
Katherine A. White ◽  
Jon J. Brudvig ◽  
Jacob T. Cain ◽  
Logan Langin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Batten Disease ◽  
Behavioral Abnormalities

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Martin-Herranz ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

scholarly journals Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuewen Wu ◽  
Li Zhang ◽  
Yihui Li ◽  
Wenjuan Zhang ◽  
Jianjun Wang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Inner Ear ◽  
Viral Vectors ◽  
Survival Rates ◽  
Semicircular Canals ◽  
Dependent Manner ◽  
Syndrome Type ◽  
Dose Dependent

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

Sign in / Sign up

Export Citation Format

Share Document