Gene Therapies for Autism Spectrum Disorder (ASD)

Every year, the second day of April is celebrated as Autism Day in worldwide. The day makes some consciousness about autism spectrum disorder. Unfortunately, the generality of people knows nothing about this disorder. On the other side, researchers and doctors try to find new pathways for the diagnosis and treatment of autism. Gene therapies which have rising day by day can be applied to treat autism in a few ways. But first, let’s check on autism spectrum disorder (ASD) and introduce it well.

Autism Spectrum Disorder (ASD) occurs because of early altered brain development and changes in the neural organization has been described by Kanner in 1943 for the first time by a diagnosis report of eleven children when they showed similar symptoms that had not been seen before. 23 years later, the first epidemiological study of autism has been done. DSM-5 criteria have provided that a single ASD spectrum is based on two core features: impurity for social communication and repetitive-unusual sensory motor behaviours1,3.

The reason of called a spectrum disorder is that ASD often co-occurs with other conditions. Now, Asperger’s disorder and pervasive development disorder are called a subtype of ASD. Motor abnormalities, gastrointestinal problems, epilepsy, intellectual disability, sleep disorders, and language disorders are the most common symptoms that are delivered with ASD. In addition to these conditions, some psychiatric conditions such as ADHD and anxiety can occur1,3.

For this reason of occurring ASD, environmental and genetic factors work equally. Environmental factors are mostly about pregnancy situations or familial history of some diseases. Short interpregnancy intervals, preterm birth, low birth weight, etc. are independently associated with ASD which is effective or non-effective. Non-specific and non-optimal factors during pregnancy such as metabolic conditions, hypertension, weight gain, and bacterial or viral infections; also, familial history of autoimmune diseases, and other specific situations increase the risk of ASD in the next generation1. Exposure to drugs, toxic substances, or medicines during pregnancy increases the risk of ASD in the fetus. For example, valproate which is used for the treatment of bipolar disorders, epilepsy is just one of the drugs that increase the risk. Babies in utero who has exposed to this drug have eight more times the risk of ASD4. The situation can be seen as pessimist. Fortunately, folic acid supplements before pregnancy or during pregnancy can decrease the risk of ASD and other developmental disorders1.

Genetics plays a crucial role to create risk or protection for ASD. The data of diagnosis reports of twin and family studies show that 74%-93% of the risk of ASD can be inherited. Rare genetic syndromes, especially fragile X syndrome (FXS) and tuberous sclerosis as monogenic causes were the first evidence for genetic risks factor although FXS is found in less than 2% of children who suffered ASD. Genomic copy-number variants (CNV) are more common in ASD patients. CNVs are duplicated, translocated, inversed, or deleted chromosomal subregions or loci. They can either be inherited or occur de novo (the child has them, but parents do not)1,3. In conclusion, multigenic pathogenic variants are more common in the etiology of ASD rather than monogenic causes such as FXS, tuberous sclerosis, Rett syndrome, and Schuurs-Heijmaker syndrome3.

We talked about CNVs above. Maternal 15q11-q13 duplications and chromosome 16p11.2 duplications or deletions are two examples of CNVs in autistic individuals1. A variant of only one gene in 16p11.2 can be a major driver for neuropsychiatric diseases by affecting KCTD3. However, deletions of KCTD3 may not be the only cause of a disease3. The CNVs support the multiple-hit model of autism. The interaction of genes and proteins has second other effects on autism, the disease cannot occur in polygenic ASD3

 In addition to genetic risk factors or modifiers, ASD has sex-linked modifiers. The female sex is protected from ASD and the male sex is particularly vulnerable because of differences between hormones, genetics, or specific factors. This subject has to be more searched although there are a few studies to support sex-linked modifiers. For example, a discovery provides that estrogens rescue ASD symptoms in both zebrafish and mouse models of autism3. There is a table below that summarizes the genetic susceptibility of ASD.

Figure 1: Genetic Susceptibility of ASD.

Now, we can go deep into the subject of this article. Most gene therapies focused on monogenic diseases which have a single genetic cause, and because of that, they have a more understandable and easy mechanism. Thereby, the studies for gene therapies of ASD focused on the monogenic ASD forms. Non-syndromic ASD has a multigenic mechanism and is determined as a combination of environmental and genetic factors. On the other side, syndromic ASD has rare single genetic causes which are known in other cases. So, gene therapies for monogenic ASD are rising and seen as the most promising treatment soon.

Gene therapies can be separated into two categories: transient and permanent. Transient gene technologies do not modify the genome of the host cell in contrast to permanent gene technologies. Transient gene therapies include antisense oligonucleotides (ASO), noncoding RNAs (ncRNAs), RNA editing, and gene delivery. Most noncoding RNAs act through the RNA interference pathway and reduce gene expression at the transcriptional level by binding to the host cells’ pre-mRNA and mRNA targets with numerous types of small RNAs. Some ncRNA-based drugs use this gene-silencing technique The small RNAs are small interfering RNA (siRNA), microRNA (miRNA), short hairpin RNA (shRNA), circular RNA (circRNA), small activating RNA (saRNA), and SINEUP. Another using way of RNAi is to inhibit the inhibitor. Therefore, the gene expression of the target can be increased2.

Antisense oligonucleotides (ASO) are a better therapy choice. They can be noncoding single-stranded DNA, RNA, or hybrid molecules of them. An ASO binds to an mRNA and reduces the gene expression of the target gene. The mechanism involves the RNAse H1 molecule that catalyzes the fracture of mRNA while it is binding to an ASO molecule. For example, healthy individuals have several CGG repeats in the FMR1 gene while patients have toxic level repeats in that region. With ASO, these repeats are targeted, and the disease-causing transcripts are reduced in vitro or vivo2.

  Gene delivery aims to deliver healthy genes to the host cell in the form of complementary DNA (cDNA) which has two types: extrachromosomal DNA (ecDNA), or extrachromosomal circular DNA (eccDNA). Gene delivery has already been tested and applied for FXS, Angelman syndrome (AG), Rett syndrome (RTT), and tuberous sclerosis complex (TBC). Thereby, this therapy type reduces the majority of symptoms of monogenic ASD2.

The last type of transient gene therapy is programmable RNA editing. This type has the advantage to correct disease-causing mutations at the transcriptional level by leaving the genome2.

 On the other side, permanent gene therapies aim to change the host genome and reduce the disease permanently. The current types of this kind of gene therapies for ASD are gene replacement, gene editing, and CRISPR-KO. Gene replacement recovers the LoF mutations by integrating an additional cDNA copy into the host cell genome for the right gene expression life-long. For gene editing of the host cell genome, the healthy genes are replaced by CRISPR-Cas9 instead of initial methods such as zinc-finger nucleases (ZFN), and transcription activator-like effector nucleases (TALENs). However, CRISPR-KO has a different purpose. It slices out the LoF mutations carrying region and inserts or deletes them (to indel). In vivo treatments of CRISPR-KO have been just started, in opposition to ex vivo studies of this method which use extracted patient cells. The infographic summary of the “gene therapies for monogenic ASD” is given below2.

Figure 2: Gene Therapies for Monogenic ASD.

Gene therapies for polygenic or multigenic ASD is more difficult than monogenic ones because of that polygenic ASD has a large amount of environmental element changing and directing its phenotype. Some factors, for example, combinations with the current paucity and limitations of animal models in polygenic ASD, make it a less preferable choice for gene therapy. Fortunately, there is important research on the regulation of synaptic function to diverse of ASD mutations potentially connecting a normal translation inputs or outputs6.

Despite all these theoretical and partial experimental information, is gene therapy completely ready to treat all forms of ASD? A treatment which has been studied last year provided that gene therapy could affect brain cells, a kind of adeno-associated virus called   AAV9 causes the blood-brain barrier. In addition to this information, traditional gene therapies for AG and other ASD forms are still in the pilot stages5. In spite, the future will be hopeful with developed new gene therapies for ASD patients and other developmental diseases.

References:

  1. Lord, C., Elsabbagh, M., Baird, G., & Veenstra-Vanderweele, J. (n.d.). Autism spectrum disorder. https://doi.org/10.1016/S0140-6736(18)31129-2
  2. Weuring, W., Geerligs, J., Koeleman, B. P. C., Freitag, M., Vorstman, J. A. S., & Persico, A. (2021). Gene Therapies for Monogenic Autism Spectrum Disorders. https://doi.org/10.3390/genes12111667
  3. Peça, J., Guemez-Gamboa, A., & Rylaarsdam, L. (2019). Genetic Causes and Modifiers of Autism Spectrum Disorder. https://doi.org/10.3389/fncel.2019.00385
  4. Chaste, P., & Leboyer, M. (2012). Dialogues in Clinical Neuroscience Autism risk factors: genes, environment, and gene-environment interactions. https://doi.org/10.31887/DCNS.2012.14.3/pchaste
  5. Denworth, L. (2020). Is gene therapy ready to treat some forms of autism? Science. https://doi.org/10.1126/SCIENCE.ABF2497
  6. Benger, M., Kinali M. & Mazarakis, N.D. Autism spectrum disorder: prospects for treatment using gene therapy. Molecular Autism 9,39 (2018). https://doi.org/10.1186/s13229-018-0222-8

Figure References:

  1. Peça, J., Guemez-Gamboa, A., & Rylaarsdam, L. (2019). Genetic Causes and Modifiers of Autism Spectrum Disorder. https://doi.org/10.3389/fncel.2019.00385
  2. Weuring, W., Geerligs, J., Koeleman, B. P. C., Freitag, M., Vorstman, J. A. S., & Persico, A. (2021). Gene Therapies for Monogenic Autism Spectrum Disorders. https://doi.org/10.3390/genes12111667

Isnpector: Meryem Melisa KAR

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