Postnatal therapeutic approaches in genetic neurodevelopmental disorders

Abstract

Genetic neurodevelopmental disorders are characterized by abnormal neurophysiological and behavioral phenotypes, affecting individuals worldwide. While the subject has been heavily researched, current treatment options relate mostly to alleviating symptoms, rather than targeting the altered genome itself. In this review, we address the neurogenetic basis of neurodevelopmental disorders, genetic tools that are enabling precision research of these disorders in animal models, and postnatal gene-therapy approaches for neurodevelopmental disorders derived from preclinical studies in the laboratory.

Clinical and Neurobiological Aspects of TAO Kinase Family in Neurodevelopmental Disorders

“…Although several above-mentioned basic research discoveries may provide directions for developing potential therapies, clinical trails or even pre-clinical studies on treatment of TAO kinases related NDDs are still lacking. Current clinical training intervention and medical treatments offered for NDDs are symptomatic and behavioral based therapy (Levy and Barak, 2021), which could be applied to any possible factors caused by NDDs. In addition, nutritional supplements (Chang and Su, 2020), non-invasive brain stimulation [including transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS)] (Khaleghi et al, 2020), and deep brain stimulation in certain cases (Beszej et al, 2019;Lin et al, 2019) are being or will be applied in clinical treatments of NDDs.…”

“…Similar to all standardized drug development processes, the efficacy and toxicity in animal models should be cautiously evaluated before these candidates are applied in human clinical trials. In addition, with the significant progress of gene editing and manipulation in the last decade, gene therapy techniques are a promising direction for personalized medical treatment including CRISPR-Cas9 gene-editing for mutation replacement and antisense oligonucleotides (ASOs) for modifying protein levels (Levy and Barak, 2021). It should be noted that most of those gene therapies are still in preclinical testing stages and the number of successful clinical trials is quite limited because it is faced with critical issues when implemented in in vivo, such as limited efficiency, off-target effects, time window and delivery methods, all suggesting that much more effort is required to improve the bench-to-bedside success rate (Levy and Barak, 2021).…”

“…In addition, with the significant progress of gene editing and manipulation in the last decade, gene therapy techniques are a promising direction for personalized medical treatment including CRISPR-Cas9 gene-editing for mutation replacement and antisense oligonucleotides (ASOs) for modifying protein levels (Levy and Barak, 2021). It should be noted that most of those gene therapies are still in preclinical testing stages and the number of successful clinical trials is quite limited because it is faced with critical issues when implemented in in vivo, such as limited efficiency, off-target effects, time window and delivery methods, all suggesting that much more effort is required to improve the bench-to-bedside success rate (Levy and Barak, 2021). Theoretically, all those strategies could also be applied to the specific down-stream targets (like Septin7, myosin Va, JNK and RhoA) of TAO kinases which requires further exploration of the signaling network of TAO kinases.…”

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

“…Until recently, available treatment options for NDDs focused on managing clinical symptoms [5], as it was thought that postnatal treatment for NDDs is unlikely to provide diseasealtering effects. With more insight into the disease pathomechanisms, this common belief has been questioned [6], and there is more evidence emerging that disease-modifying therapeutic strategies for NDDs are possible. To what extent NDDs can be treated postnatally however remains to be discovered and will most likely depend on each entity individually.…”