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 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 Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1273 ◽  
Author(s):  
Matthew J. Haney ◽  
Yuling Zhao ◽  
Yeon S. Jin ◽  
Elena V. Batrakova
Keyword(s):  
Mouse Model ◽  
Extracellular Vesicles ◽  
Broad Class ◽  
Batten Disease ◽  
Drug Carriers ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Enzyme Replacement ◽  
Daunting Task ◽  
The Brain

CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs). Herein, we incorporated TPP1 into EVs released by immune cells, macrophages, and examined biodistribution and therapeutic efficacy of EV-TPP1 in BD mouse model, using various routes of administration. Administration through intrathecal and intranasal routes resulted in high TPP1 accumulation in the brain, decreased neurodegeneration and neuroinflammation, and reduced aggregation of lysosomal storage material in BD mouse model, CLN2 knock-out mice. Parenteral intravenous and intraperitoneal administrations led to TPP1 delivery to peripheral organs: liver, kidney, spleen, and lungs. A combination of intrathecal and intraperitoneal EV-TPP1 injections significantly prolonged lifespan in BD mice. Overall, the optimization of treatment strategies is crucial for successful applications of EVs-based therapeutics for BD.

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 Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6235
Author(s):  
Ahmed Morsy ◽  
Angelica V. Carmona ◽  
Paul C. Trippier
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Induced Pluripotent Stem Cell ◽  
Epileptic Seizures ◽  
Premature Death ◽  
Model Systems ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Phenotypic Screening ◽  
Lysosomal Storage ◽  
Induced Pluripotent

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

scholarly journals Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease

2016 ◽  
Vol 24 (12) ◽  
pp. 2054-2063 ◽  
Author(s):  
Marialuisa Alliegro ◽  
Rita Ferla ◽  
Edoardo Nusco ◽  
Chiara De Leonibus ◽  
Carmine Settembre ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Disease ◽  
Low Dose ◽  
Storage Disease ◽  
Lysosomal Storage ◽  
Enzyme Replacement

scholarly journals Fabry disease, a complex pathology not easy to diagnose

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Paolo Colomba ◽  
Simone Scalia ◽  
Giuseppe Cammarata ◽  
Carmela Zizzo ◽  
Daniele Francofonte ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Vascular Endothelium ◽  
Clinical Manifestations ◽  
Premature Death ◽  
Lysosomal Storage ◽  
Familial Data ◽  
Enzyme Replacement ◽  
Cerebrovascular Complications ◽  
Cellular Events

Fabry disease is a multisystemic lysosomal storage disorder, inherited in an X-linked manner. It is a defect of metabolism of the glycosphingolipids, due to the reduction or absence of the activity of lysosomal enzyme α-galactosidase A. This reduction of activity causes the storage of globotriaosylceramide and derivatives in the lysosomes, triggering a cascade of cellular events, mainly in vascular endothelium. These events are the responsible for the systemic clinical manifestations and the renal, cardiac and cerebrovascular complications, or a combination of them. The symptomatology can lead to the premature death of patient between the fourth or fifth decade of life. The first symptoms can occur at different ages, generally in childhood, with different severity and course. Fabry disease is suspected on the basis of clinical and anamnestic-familial data, and it is confirmed by enzymatic and genetic assays. However, Fabry disease could be a pathology more complex than previously considered, and the diagnostic tests that are currently in use could be not always sufficient to confirm the clinical diagnosis. Probably, other factors could be also involved in the onset of symptomatology. In the last years, the knowledge of the disease is considerably increased but other studies are necessary to make a prompt and reliable diagnosis. An early diagnosis of Fabry disease is essential for the beginning of the enzyme replacement therapy, which can contribute to arrest its progression and improve the quality of life of patients.

scholarly journals Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joan Bertolin ◽  
Víctor Sánchez ◽  
Albert Ribera ◽  
Maria Luisa Jaén ◽  
Miquel Garcia ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vector ◽  
Keratan Sulfate ◽  
Whole Body ◽  
Mucopolysaccharidosis Type ◽  
Lysosomal Storage ◽  
Peripheral Tissues ◽  
Enzyme Replacement ◽  
Morquio A ◽  
Mucopolysaccharidosis Type Iva

AbstractMucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

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