Gene therapy for CNS diseases – Krabbe disease

Although gene therapy for CNS diseases shows promise in cell and animal investigations, most human trials have failed to satisfy the requisite requirements. Finding novel techniques to boost the efficacy of gene therapy in treating CNS diseases is still crucial. A growing number of clinical trials have proved the efficacy and safety of using AAV vectors, making AAV vector research a gene therapy hotspot. However, due to the presence of the BBB, many siRNA and DNA with potential therapeutic value are difficult to transport from peripheral circulation to the brain using AAV vectors, limiting the clinical impact of gene therapy drugs in the CNS and posing a major challenge to the field of CNS gene therapy. In early studies, AAV9 was considered the most effective AAV serotype for getting through the blood-brain barrier and transduction to central nervous system cells following intravenous injection. Aavrh10 isolated from rhesus monkeys was equal to, if not superior to, AAV9. AAV-PHP.B, a newly built capsid, exhibits 40-fold greater efficacy than AAV9 in astrocyte and neuron transduction. AAV-PHP.eB, a modified AAV-PHP.B variety, was identified to retain PHP.B's AAV-capacity to transduce astrocytes while enhancing neuronal transduction. While the four serotypes AAV9, AAVrh10, AAV-PHP.B, and AAV-PHP.eB have been validated to penetrate mice's BBB following intravenous injection, the number of AAV vectors that can do so is low. Moreover, the manner in which AAV vectors penetrate the BBB remains unclear. To promote efficient gene therapy for CNS diseases, it is still important to test new vectors with more efficient crossing abilities and understand their crossing processes. In addition to technical challenges, AAV vectors in treating CNS diseases may be limited by cautious attitudes to innovative treatments. Continued advances in AAV vector research, together with early clinical trial outcomes, might help researchers achieve the full potential of AAV-based CNS disease therapies.

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Future Prospects of Gene Therapy for Treating CNS Diseases

Central Nervous System Diseases ◽

10.1007/978-1-59259-691-1_24 ◽

2000 ◽

pp. 485-508

Author(s):

Daniel A. Peterson ◽

Jasodhara Ray ◽

Fred H. Gage

Keyword(s):

Gene Therapy ◽

Future Prospects ◽

Cns Diseases

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

Bioimpacts ◽

10.34172/bi.2021.21 ◽

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.

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585. Gene Therapy for Mouse Model of Krabbe Disease

Molecular Therapy ◽

10.1016/s1525-0016(16)34920-6 ◽

2013 ◽

Vol 21 ◽

pp. S224

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Krabbe Disease

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

Frontiers in Medicine ◽

10.3389/fmed.2021.760236 ◽

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.

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