scholarly journals Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

2021 ◽  
Vol 8 ◽  
Author(s):  
Gibran Nasir ◽  
Rajiv Chopra ◽  
Fiona Elwood ◽  
Seemin S. Ahmed
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Lysosomal Enzyme ◽  
Metabolic Disorder ◽  
Clinical Treatment ◽  
Krabbe Disease ◽  
Toxic Metabolite ◽  
Promising Strategy ◽  
Cellular Pathways ◽  
Functional Deficiency

Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination. Although there is currently no effective therapy for Krabbe disease, recent gene therapy-based approaches in animal models have indicated a promising outlook for clinical treatment. This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this devastating pediatric disease.

Role of animal models in gene therapy

Gene Therapy ◽  
2020 ◽  
pp. 155-167
Author(s):  
Julia R. Dorin ◽  
David J. Porteous
Keyword(s):  
Gene Therapy ◽  
Animal Models

scholarly journals Can early treatment of twitcher mice with high dose AAVrh10-GALC eliminate the need for BMT?

Bioimpacts ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 135-146
Author(s):  
Mohammad A Rafi ◽  
Paola Luzi ◽  
David A Wenger
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Viral Vector ◽  
Krabbe Disease ◽  
High Dose ◽  
Restriction Enzyme Digestion ◽  
Hematopoietic Stem ◽  
Galc Gene

Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for pre-symptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four- and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.

scholarly journals Gene therapy for CNS diseases – Krabbe disease

Bioimpacts ◽  
2016 ◽  
Vol 6 (2) ◽  
pp. 69-70 ◽  
Author(s):  
Mohammad A. Rafi
Keyword(s):  
Gene Therapy ◽  
Krabbe Disease ◽  
Cns Diseases

Gene Therapy: Paving New Roads in the Treatment of Hemophilia

2019 ◽  
Vol 45 (07) ◽  
pp. 743-750 ◽  
Author(s):  
Gabriela G. Yamaguti-Hayakawa ◽  
Margareth C. Ozelo
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Pediatric Patients ◽  
Viral Vector ◽  
Monogenic Disease ◽  
Adeno Associated Virus ◽  
Underlying Liver Disease ◽  
Experimental Animal Models ◽  
The Road ◽  
Gene Therapy Application

AbstractHemophilia is a monogenic disease with robust clinicolaboratory correlations of severity. These attributes coupled with the availability of experimental animal models have made it an attractive model for gene therapy. The road from animal models to human clinical studies has heralded significant successes, but major issues concerning a previous immunity against adeno-associated virus and transgene optimization remain to be fully resolved. Despite significant advances in gene therapy application, many questions remain pertaining to its use in specific populations such as those with factor inhibitors, those with underlying liver disease, and pediatric patients. Here, the authors provide an update on viral vector and transgene improvements, review the results of recently published gene therapy clinical trials for hemophilia, and discuss the main challenges facing investigators in the field.

scholarly journals Improving Precise CRISPR Genome Editing by Small Molecules: Is there a Magic Potion?

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1318 ◽  
Author(s):  
Nadja Bischoff ◽  
Sandra Wimberger ◽  
Marcello Maresca ◽  
Cord Brakebusch
Keyword(s):  
Gene Therapy ◽  
Dna Repair ◽  
Animal Models ◽  
Molecular Biology ◽  
Small Molecules ◽  
Genome Editing ◽  
Drug Targets ◽  
Targeted Mutagenesis ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing has become a standard method in molecular biology, for the establishment of genetically modified cellular and animal models, for the identification and validation of drug targets in animals, and is heavily tested for use in gene therapy of humans. While the efficiency of CRISPR mediated gene targeting is much higher than of classical targeted mutagenesis, the efficiency of CRISPR genome editing to introduce defined changes into the genome is still low. Overcoming this problem will have a great impact on the use of CRISPR genome editing in academic and industrial research and the clinic. This review will present efforts to achieve this goal by small molecules, which modify the DNA repair mechanisms to facilitate the precise alteration of the genome.

Animal Models for Prenatal Gene Therapy: The Sheep Model

2012 ◽  
pp. 219-248 ◽  
Author(s):  
Khalil N. Abi-Nader ◽  
Michael Boyd ◽  
Alan W. Flake ◽  
Vedanta Mehta ◽  
Donald Peebles ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Animal Models ◽  
Sheep Model
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