- Recent Publications from the California National Primate Research Center.
- 1. Introduction.
- Good Food: 201 Perfect Cakes and Bakes.
- China Is Genetically Engineering Monkeys With Brain Disorders;
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Translating the Puzzle of Autism into Treatment
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Preview this item Preview this item. Approximately 1 in children are diagnosed as autistic, so it is also an intense growth area in behavioral and educational treatments. Financial resources have begun to be raised for more comprehensive research and an increasing number of scientists are becoming involved in autism research.
- Chapter 30, Nonhuman Primate Models for Autism Spectrum Disorders
In many respects, autism has become a model for conducting translational research on a psychiatric disorder. This text provides a comprehensive summary of all current knowledge related to the behavioral, experiential, and biomedical features of the autism spectrum disorders including major behavioral and cognitive syndromology, common co-morbid conditions, neuropathology, neuroimmunology, and other neurological correlates such as seizures, allergy and immunology, gastroenterology, infectious disease, and epidemiology.
Edited by three leading researchers, this volume contains over 80 chapters and nine shorter commentaries by thought leaders in the field, making the book a virtual "who's who" of autism research. 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.
Monogenic ASD conditions often contain a variable cluster of phenotypes which include autism as part of a syndrome [ 18 ]. More recently, our understanding of the genetic landscape of ASD has been revolutionised by several whole-exome and whole-genome sequencing studies, identifying hundreds of de novo and rare inherited variants influencing sporadic ASD risk [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].
Proteins known to cause monogenic ASD are shown in red.
Many other ASD-linked proteins also act within this synaptopathic loop, including various cell adhesion molecules e. However, in such a heterogeneous condition as ASD, it is important not to become evangelical about a single causative mechanism, especially given recent insights into the apparently critical roles of immune dysfunction and epigenetics in at least certain ASD cases [ 35 , 36 ]. Furthermore, recent phase II clinical trials which looked to regulate synaptic function via GABA and glutamate receptor modulation failed to demonstrate significant overall benefit, despite strongly positive responses in certain patients [ 37 , 38 ].
Thus, it is important to consider whether targeting the synapse using gene therapy may be most appropriate for correcting particular ASD endophenotypes in specific patient subsets, rather than seeing it as a panacea for ASD, a topic that is returned to later in this article. The field of gene therapy is littered with examples of therapies which failed to translate from their preclinical promise.
In many cases, blame can be attributed to the predictive validity of the animal model used, which is itself related to its construct validity i. Nevertheless, whilst caution should always be taken when ascribing behavioural outcomes in animals to autism, various monogenic ASD rodent models have capably demonstrated quantifiable social and communicative behavioural traits [ 42 , 43 , 44 ], laying the ground for preclinical therapeutic studies. As a caveat, it must be noted that a major limitation of ASD animal models relates to their inability to reflect heterogeneous environmental influences on the ASD phenotype, with various toxic, inflammatory and psychosocial factors difficult to incorporate in robust, reproducible animal models.
Identifying specific cells and circuits dysregulated in ASD is crucial in gene therapy design, as vectors may be targeted to specific brain regions or cell types discussed in detail later. In particular, nascent data suggest the hippocampus, cerebellum and corpus callosum contain key pathogenic circuits [ 34 , 46 , 47 , 48 ], whilst influential cell types include pyramidal cells, Purkinje cells and glial cells [ 34 , 49 ].
Recent technological advances have begun to elucidate the relationship between cell type-specific function and particular ASD endophenotypes. Meanwhile, in a TSC mouse model, chemogenetic excitation of the Right Crus I RCrusI region of the cerebellum—an area consistently noted to be altered in the ASD brain in neuroanatomical and neuroimaging studies [ 51 , 52 ]—was sufficient to specifically rescue social impairments, without rescuing repetitive or inflexible behaviours [ 53 ].
Within individual circuits, it appears that different ASD mutations may have opposing effects on synaptic function. Such data not only exemplify the heterogeneic nature of ASD but also highlight the necessity of optimal synaptic control, and are the first hint that a successful gene therapy must walk a narrow therapeutic tightrope between over- and under-stimulating synaptic transmissions. A crucial further question is whether autistic phenotypes can be reversed or are neurodevelopmentally fixed.
Remarkably, an array of studies in different monogenic ASD animal models have consistently demonstrated the potential for reversal of established neuronal dysfunction, either after pharmacological intervention or genetic reactivation of silenced alleles [ 55 , 56 , 57 , 58 , 59 , 60 ]. These findings imply that postnatally, indeed post-symptomatically, the genetic horse may not yet have bolted, and genetic correction via a delivered vector might be useful in treating cognitive dysfunction.
If the ASD phenotype is reversible rather than neurodevelopmentally fixed, as implied by studies in monogenic animal models, then it follows that continuous genetic correction will be necessary for a sustained therapeutic effect. Currently, only viral packaging systems have combined efficient transduction with long-term gene expression in vivo [ 61 ] although, as will be discussed later, certain ASD conditions may be amenable to non-virally delivered antisense nucleic acid therapies.
Find a copy in the library
Of the viruses which can transduce post-mitotic cells, rAAVs have emerged as the principal CNS delivery candidate [ 62 ]. This is based upon their relatively low immunogenicity compared to adenovirus and herpes simplex virus , limiting the likelihood of an encephalitic immune response, their ability to persist in episomal form, reducing their oncogenic potential compared to retroviruses [ 63 , 64 ] , and their high production titres [ 12 ]. There are two major ways in which the spatial dynamics of rAAV vectors can be adjusted.
Firstly, the properties of the vector itself can be modified, to include a cell type-selective capsid e. Secondly, the mode of delivery can be adjusted. Historically, rAAV vectors have been delivered intraparenchymally via stereotactic CNS injection, leading to high local concentrations with limited vector spread [ 69 ]. However, ASD appears to involve global synaptic dysregulation and thus will require global CNS gene correction to fully reverse cognitive phenotypes [ 71 , 72 ].
The latter issue may be negotiated by the use of engineered rAAV capsids, which may have lower neutralising antibody seropravalences [ 80 ]. An alternative to systemic delivery is intrathecal administration, which potentially combines relatively safe administration and global CNS transduction with fewer peripheral complications, and a higher spatial resolution limiting the dose requirements. However, there are conflicting data regarding the ability of intrathecally delivered rAAV to efficiently transduce areas outside the spinal cord [ 81 ], as well its own ability to avoid both peripheral leakage [ 82 ] and a neutralising antibody response [ 83 , 84 ].
Of note, an intrathecal AAV9 approach has been corrective in a model of giant axonal neuropathy [ 85 ] and has progressed to a clinical trial. In ASD disorders defined by loss of function mutations e. Given the limitations imposed by imperfect gene delivery strategies, a key question is whether sufficient transduction of target cell types can be attained to exert phenotypic benefit.
Encouragingly, a number of studies using monogenic animal models have demonstrated behavioural improvements after rAAV-delivered gene replacement. Finally, it was recently demonstrated that rAAV-mediated delivery of even a fragment of the MECP2 gene lacking N- and C- terminal regions along with a central domain led to phenotypic improvement in RS mice, potentially allowing extra room for construct modifications to aid target cell transduction and expression [ 89 ].
Although a cause for optimism, none of the above studies evidenced total phenotypic reversal after gene replacement. Such incomplete phenotypic reversal may be secondary to insufficient CNS transduction. However, increasing the vector dose in order to increase transduction must be balanced against the risk of dose-related toxicity. Toxicity may also occur secondary to supraphysiological expression in target cells.
Such toxicity may occur even at low transduction percentages due to uneven vector distribution within the CNS or, in the case of X-linked disorders in females, due to a mosaic pattern of CNS expression caused by random X-inactivation [ ]. Nonetheless, further studies are required to pinpoint the optimum balance between CNS transduction and on-target toxicity in various ASD syndromes.
Additionally, future gene replacement studies must better characterise the relationship between gene dose and dendritic function which was not assessed in any of the above studies. Gene expression can be silenced by sequence-specific knockdown of mRNA transcripts using techniques such as antisense oligonucleotides ASOs and short interfering RNAs siRNAs , which use the exquisite specificity conferred by Watson-Crick base pairing to bind particular mRNA transcripts and prevent their translation for a detailed mechanism see ref [ ].
These nucleic acids are typically relatively easy to manufacture, can be modified to limit degradation and inflammation, and do not require a viral vector although long-term expression of ASOs is possible using viral delivery of short hairpin RNAs [shRNAs] [ , ]. These techniques are principally useful when total or partial knockdown of a particular transcript may restore synaptic function. For example, triplication of 15q leads to a relatively common and highly penetrant type of autism linked to increased expression of UBE3A which functions as a transcription regulator in addition to its ubiquitin ligase function and subsequent downregulation of Cerebellin 1 Precursor Cbln1 , a synaptic organising protein, in the ventral tegmental area VTA [ ].
Interestingly, in the same study, whilst motor deficits were restored, other behaviours—such as anxiety and repetitive behaviours—were not. A later study, using Cre-dependent UBE3A reactivation in an AS mouse model, showed a temporal dependence for specific phenotype reversal, with anxiety and repetitive behaviours requiring gene reactivation during early development, whilst motor deficits could be restored into adulthood [ ].
Such temporal factors have not been thoroughly investigated in other monogenic ASDs but are clearly critical when considering the time point of useful intervention in humans. Finally, in a similar vein to excessive gene replacement, hyper-knockdown of target RNA may lead to rebound toxicity in both target cells and off-target cells.
Related Chapter 30, Nonhuman Primate Models for Autism Spectrum Disorders
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