Autism spectrum disorder: prospects for treatment using gene therapy

Benger et al. Molecular Autism (2018) 9:39 https://doi.org/10.1186/s13229-018-0222-8 REVIEW Open Access Autism spectrum disorder: prospects for treatment using gene therapy Matthew Benger1, Maria Kinali2 and Nicholas D. Mazarakis1* Abstract Autism spectrum disorder (ASD) is characterised by the concomitant occurrence of impaired social interaction; restricted, perseverative and stereotypical behaviour; and abnormal communication skills. Recent epidemiological studies have reported a dramatic increase in the prevalence of ASD with as many as 1 in every 59 children being diagnosed with ASD. The fact that ASD appears to be principally genetically driven, and may be reversible postnatally, has raised the exciting possibility of using gene therapy as a disease-modifying treatment. Such therapies have already started to seriously impact on human disease and particularly monogenic disorders (e.g. metachromatic leukodystrophy, SMA type 1). In regard to ASD, technical advances in both our capacity to model the disorder in animals and also our ability to deliver genes to the central nervous system (CNS) have led to the first preclinical studies in monogenic ASD, involving both gene replacement and silencing. Furthermore, our increasing awareness and understanding of common dysregulated pathways in ASD have broadened gene therapy’s potential scope to include various polygenic ASDs. As this review highlights, despite a number of outstanding challenges, gene therapy has excellent potential to address cognitive dysfunction in ASD. Keywords: Autistic spectrum disorder, Synaptic dysfunction, ASD models, Gene therapy, Viral vector Background “Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom”—Viktor E Frankl. In autism spectrum disorder (ASD), a neurodevelopmental disorder affecting ~ 1.5% of the population [1], aetiologically diverse deficits in cognitive plasticity lead to broad impairments in communication and restricted, repetitive behaviours [2]. Comorbidities are common (~ 70% of cases) and include epilepsy; attention, mood and language disorders; sleep disturbance; gastrointestinal problems; and intellectual disability [3]. Despite the great personal and sociological cost of ASD (estimated to be $2 million/patient/year [4]), only the antipsychotics risperidone and aripiprazole are currently FDA-approved to treat ASD, indicated solely in the treatment of irritability symptoms [5]. A fundamental reason for this lack of disease-modifying therapies * Correspondence: 1 Gene Therapy, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, W12 0NN, London, UK Full list of author information is available at the end of the article may relate to ASD’s pathogenesis, which appears to be principally driven by heterogeneous genetic mutations and variants and modulated by diverse gene × environment interactions, to include pregnancy-related factors (e.g. maternal immune activation, maternal toxins) and perinatal trauma [2, 6–10]. Many of the encoded proteins implicated in ASD pathogenesis—such as cytoskeletal proteins, cell adhesion molecules and DNA-binding proteins—may be ‘undruggable’ using conventional small molecule drugs, which principally only modulate the function of receptors and enzymes [11]. In contrast, gene therapy—broadly defined as the delivery of nucleic acid polymers into cells to treat disease—may be used to repair, replace, augment or silence essentially any gene of interest in a target cell, opening up new areas of the proteome for drug targeting [12]. Other advantages of gene therapy versus small molecules include the ability to effect long-lasting clinical benefit with a single treatment and the potential to control cellular targeting via vector modifications [13]. Indeed, gene therapy is already making a clinical impact in the field of neurology, with Nusinersen, an © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Benger et al. Molecular Autism (2018) 9:39 antisense oligonucleotide therapy approved in Spinal muscular atrophy (SMA), and more recently Luxturna, a viral-based gene replacement strategy approved in Leber’s congenital amaurosis, acting as the first disease-modifying therapies in both of these diseases [14, 15]. In addition, a clinical trial in SMA by AveXis using systemic delivery of recombinant adeno-associated virus 9 (rAAV9) carrying a replacement SMN1 gene recently proved safe and efficacious in neonates [16]. On the other hand, gene therapies are clearly expensive in the short-term, with current therapies costing at least $500,000 per treatment, and thus remaining unaffordable in many healthcare systems (see ref [17] for a thorough economic analysis). This review will highlight key targets for ASD gene therapy, the utility of ASD models, and recent advances in our ability to deliver such therapies to the central nervous system (CNS). It will then move on to discuss recent gene therapy strategies in ASD, concentrating on conditions with available preclinical data, and the roadblocks facing their clinical translation. Genetic targets in ASD ASD may be divided into conditions driven by a single genetic defect (monogenic ASD) and conditions driven by multiple genetic defects (polygenic ASD). Monogenic ASD conditions often contain a variable cluster of phenotypes which include autism as part of a syndrome [18]. Whilst only accounting for ~ 5% of ASD cases [18], such disorders are prime candidates for gene therapy for two major reasons: firstly, they lend themselves to developing genetic models of ASD, which enable elucidation of the genotype to phenotype pathway, the potential for disease reversibility postnatally, and the efficacy/toxicity of novel therapeutics; secondly, Page 2 of 10 correction of a single causative protein defect has the potential to arrest and possibly reverse disease pathology. Indeed, a basis for preclinical gene therapy studies in ASD was founded by identification of the nature and function of causative genes for a number of monogenic conditions with autistic features, including Rett syndrome (RS), fragile X syndrome (FXS), Angelman syndrome (AS) and tuberous sclerosis (TSC) [19–23] (Table 1). More recently, our understanding of the genetic landscape of ASD has been revolutionised (...truncated)