Pediatric Neurology 51 (2014) 595e596
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Editorial
Gene Therapy for Childhood Neurological Disease
We are going through a transformational change in child neurology. The field is moving from description of symptoms and syndromes to design of rational therapy based on identified etiology of childhood neurological diseases. Advances in genetics and genomics have enabled us to find underlying genetic defects at a dizzying pace and greatly expanded the list of potential genes responsible for neuromuscular and neurodevelopmental diseases. The challenge now is to use this knowledge to design safe and effective treatment modalities for our patients. Much of the research in pharmaceutical industry is focused on small molecules that can act on a small number of druggable targets relative to the whole genome. Viral vector-mediated gene transfer provides an alternative strategy to treat central nervous system (CNS) disorders, in particular for single gene defects. An ideal viral vector for CNS disorders would be able to get into nervous system, infect the affected cell types including nondividing cells, provide long-term and stable gene expression, and, yet, have low likelihood of integrating into the genome and generate mutations. Adeno-associated virus (AAV) has become the prominent vector for CNS gene delivery because it fulfills most of these requirements. There are more than 100 different serotypes of AAV with different cellular tropism, and the field is making considerable progress in vector technology to find the best viral vector(s) for each disease.1 This issue of Pediatric Neurology includes two articles that illustrate advances in gene therapy. These articles on muscular dystrophy and globoid cell leukodystrophy (GLD) mirror the authors’ presentations in the 2013 Child Neurology Society Presidential Symposium entitled “Gene Therapy for Childhood Neurological Diseases.” This symposium also included presentations on spinal muscular atrophy and Pompe disease. All these disorders occur due to loss of function of a single gene, making viral gene delivery approaches, which reintroduce the missing gene, a promising technique that may improve the lives of children affected with these diseases. * Communications should be addressed to: Dr. Sahin; Department of Neurology; Translational Neuroscience Center; Boston Children’s Hospital; 300 Longwood Avenue CLS14073; Boston, Massachusetts 02115. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.005
Al-Zaidy and colleagues review a number of genetic approaches aimed to ameliorate Duchenne muscular dystrophy and discuss the lessons they have learned with each of these trials.2 Duchenne muscular dystrophy is the most common childhood muscular dystrophy, and the only effective disease-modifying treatment is corticosteroids, which was discovered in 1970s.3 The mutant gene in this disease (dystrophin) is very large in size, so the investigators have focused on delivering smaller, but still functional, fragments of the gene via viral vectors. These studies have brought to attention the issue of cellular immune response affecting the efficacy of gene replacement therapy and highlighted the need for screening patients for pre-existing dystrophin immunity before enrollment in clinical trials. Gene therapy trials ongoing in other muscle diseases, such as limb-girdle muscular dystrophy type 2D, Becker muscular dystrophy, and inclusion body myositis, include both local administration and systemic vascular delivery. Li and Sands demonstrate several experimental therapies for the lysosomal disease, GLD, also known as Krabbe disease.4 Lysosomal diseases have proven well suited to viral vector-mediated gene transfer, and previous studies have demonstrated that even expressing a small amount of the missing enzymes can be therapeutic.5 Currently, the only treatment for GLD is hematopoietic cell transplantation, which can slow down the progression of disease but does not cure it. Availability of a spontaneous mouse model of GLD (twitcher mouse) that closely mimics the human disease has enabled several preclinical studies and treatment trials. Characterization of this mouse model demonstrates that there are multiple pathogenic mechanisms in this disease, and one treatment modality alone may not provide a cure. In fact, using a combination of therapeutic approaches (such as AAV-mediated gene transfer and bone marrow transplant) seems to show the most promise in terms of prolonging life of the mouse mutant. Therefore, rational combinations of therapies that address different aspects of the disease may provide the most robust efficacy of treatment not only for GLD but also for several other neurodegenerative diseases. Gene therapy for neurological diseases is experiencing a renaissance as evidenced by the advances in vector technology and ongoing clinical trials. There is still much more work to be performed before specific gene therapies will
596
Editorial / Pediatric Neurology 51 (2014) 595e596
achieve FDA approval. Together with other modalities such as RNA-based and cell-based therapies, viral vectormediated gene transfer will add significantly to the armamentarium of future child neurologists. References 1. Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5:285-297. 2. Al-Zaidy S, Rodino-Klapac L, Mendell JR. Gene therapy for muscular dystrophy: moving the field forward. Pediatr Neurol. 2014;51:607-618.
3. Drachman DB, Toyka KV, Myer E. Prednisone in Duchenne muscular dystrophy. Lancet. 1974;2:1409-1412. 4. Li Y, Sands MS. Experimental therapies in the murine model of globoid cell leukodystrophy. Pediatr Neurol. 2014;51:600-606. 5. Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Ther. 2006;13:839-849.
Mustafa Sahin, MD, PhD* Department of Neurology Translational Neuroscience Center Boston Children’s Hospital Boston, Massachusetts
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Editorial
Gene Therapy for Childhood Neurological Disease
We are going through a transformational change in child neurology. The field is moving from description of symptoms and syndromes to design of rational therapy based on identified etiology of childhood neurological diseases. Advances in genetics and genomics have enabled us to find underlying genetic defects at a dizzying pace and greatly expanded the list of potential genes responsible for neuromuscular and neurodevelopmental diseases. The challenge now is to use this knowledge to design safe and effective treatment modalities for our patients. Much of the research in pharmaceutical industry is focused on small molecules that can act on a small number of druggable targets relative to the whole genome. Viral vector-mediated gene transfer provides an alternative strategy to treat central nervous system (CNS) disorders, in particular for single gene defects. An ideal viral vector for CNS disorders would be able to get into nervous system, infect the affected cell types including nondividing cells, provide long-term and stable gene expression, and, yet, have low likelihood of integrating into the genome and generate mutations. Adeno-associated virus (AAV) has become the prominent vector for CNS gene delivery because it fulfills most of these requirements. There are more than 100 different serotypes of AAV with different cellular tropism, and the field is making considerable progress in vector technology to find the best viral vector(s) for each disease.1 This issue of Pediatric Neurology includes two articles that illustrate advances in gene therapy. These articles on muscular dystrophy and globoid cell leukodystrophy (GLD) mirror the authors’ presentations in the 2013 Child Neurology Society Presidential Symposium entitled “Gene Therapy for Childhood Neurological Diseases.” This symposium also included presentations on spinal muscular atrophy and Pompe disease. All these disorders occur due to loss of function of a single gene, making viral gene delivery approaches, which reintroduce the missing gene, a promising technique that may improve the lives of children affected with these diseases. * Communications should be addressed to: Dr. Sahin; Department of Neurology; Translational Neuroscience Center; Boston Children’s Hospital; 300 Longwood Avenue CLS14073; Boston, Massachusetts 02115. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.08.005
Al-Zaidy and colleagues review a number of genetic approaches aimed to ameliorate Duchenne muscular dystrophy and discuss the lessons they have learned with each of these trials.2 Duchenne muscular dystrophy is the most common childhood muscular dystrophy, and the only effective disease-modifying treatment is corticosteroids, which was discovered in 1970s.3 The mutant gene in this disease (dystrophin) is very large in size, so the investigators have focused on delivering smaller, but still functional, fragments of the gene via viral vectors. These studies have brought to attention the issue of cellular immune response affecting the efficacy of gene replacement therapy and highlighted the need for screening patients for pre-existing dystrophin immunity before enrollment in clinical trials. Gene therapy trials ongoing in other muscle diseases, such as limb-girdle muscular dystrophy type 2D, Becker muscular dystrophy, and inclusion body myositis, include both local administration and systemic vascular delivery. Li and Sands demonstrate several experimental therapies for the lysosomal disease, GLD, also known as Krabbe disease.4 Lysosomal diseases have proven well suited to viral vector-mediated gene transfer, and previous studies have demonstrated that even expressing a small amount of the missing enzymes can be therapeutic.5 Currently, the only treatment for GLD is hematopoietic cell transplantation, which can slow down the progression of disease but does not cure it. Availability of a spontaneous mouse model of GLD (twitcher mouse) that closely mimics the human disease has enabled several preclinical studies and treatment trials. Characterization of this mouse model demonstrates that there are multiple pathogenic mechanisms in this disease, and one treatment modality alone may not provide a cure. In fact, using a combination of therapeutic approaches (such as AAV-mediated gene transfer and bone marrow transplant) seems to show the most promise in terms of prolonging life of the mouse mutant. Therefore, rational combinations of therapies that address different aspects of the disease may provide the most robust efficacy of treatment not only for GLD but also for several other neurodegenerative diseases. Gene therapy for neurological diseases is experiencing a renaissance as evidenced by the advances in vector technology and ongoing clinical trials. There is still much more work to be performed before specific gene therapies will
596
Editorial / Pediatric Neurology 51 (2014) 595e596
achieve FDA approval. Together with other modalities such as RNA-based and cell-based therapies, viral vectormediated gene transfer will add significantly to the armamentarium of future child neurologists. References 1. Gao G, Vandenberghe LH, Wilson JM. New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005;5:285-297. 2. Al-Zaidy S, Rodino-Klapac L, Mendell JR. Gene therapy for muscular dystrophy: moving the field forward. Pediatr Neurol. 2014;51:607-618.
3. Drachman DB, Toyka KV, Myer E. Prednisone in Duchenne muscular dystrophy. Lancet. 1974;2:1409-1412. 4. Li Y, Sands MS. Experimental therapies in the murine model of globoid cell leukodystrophy. Pediatr Neurol. 2014;51:600-606. 5. Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol Ther. 2006;13:839-849.
Mustafa Sahin, MD, PhD* Department of Neurology Translational Neuroscience Center Boston Children’s Hospital Boston, Massachusetts
