Autism's Rising Prevalence and Drug Discovery Efforts in 2016: A Review


April is ‘Autism Awareness Month’ and to draw attention to the millions of sufferers of the disorder, this a special review from Medgenera.

What is Autism?

Autism is a neurodevelopmental disorder that is characterized by impaired social interaction, communication (both, verbal and non-verbal), restricted as well as repetitive behavior. These signs are usually noticed in the first two years of the child’s life. They often develop gradually, though some children with autism proceed to develop normally, and then regress. One of the criteria for diagnosis is that the symptoms should become apparent in early childhood, typically before age three.

Autism generally falls under a range of associated diseases, known as Autism Spectrum Disorders (ASD), that are characterized by similar symptoms. Many medications are used to treat ASD symptoms that interfere with integrating a child into a standard environment when behavioral treatment fails.

Countries with Highest Autism Prevalence (per 10, 000 people)

Top countries with autism prevalence

Pharmacology (Causes)

Autism is a complex disorder which is often caused by the co-occurrence of common cause at the genetic, cognitive, and neural levels. Although, it is clear that autism has strong genetic basis but the exact mechanism is still not known. The major hypothesis relied on rare mutations with major effects or by rare multigene interactions of common genetic variants. 

genetic cause of autism

Genetic basis of autism is complex: Deletion (1), duplication (2) and inversion (3) are all chromosome abnormalities that have been implicated in autism. (Credit: Richard Wheeler /Wikimedia)

Pharmacology (Cure)

There are no medications available so far that can cure autism. However, there are some medications that provide symptomatic relief and usually they are psychoactive drugs or anticonvulsants for treating irritability, repetitive behavior, and sleeplessness that often occurs with autism, however their side effects are many, and patients may respond atypically. 

Drug Discovery Efforts in 2016 (Clinical Trials)

1. AT001 (Fluoxetine rapid dissolve)

Mechanism: SSRI

Company: Autism Therapeutics

Status: Phase III clinical trials

AT001 (Fluoxetine rapid dissolve) in clinical trials for autism treatment

The active ingredient of AT001 is fluoxetine, better known as “Prozac (trade name).” It is still in the process of development, by Autism Therapeutics (a New York pharmaceutical company) solely for the treatment of “repetitive behaviors” associated with autism. Fluoxetine functions as a selective serotonin re-uptake inhibitors (SSRI), i.e. it inhibits reuptake of the neurotransmitter serotonin and hence increases its extra-cellular concentration.

The most unique feature of AT001 is a technology called “Zydis”. It allows the fluoxetine to be absorbed as an orally disintegrating tablet (ODT). This route of administration makes it advantageous over swallowing a pill as it increases convenience and eliminates the risk of choking. Although AT001 is being tested for the treatment of repetitive behaviors associated with autism, it it also likely to improve the moods of those with depression.

Fluoxetine is also able to reverse avoidance behaviors and reduce social deficits in animal studies. The US Food and Drug Association (FDA) has granted AT001Fast Track” designation.  

2. CNDO-201 (Trichuris suis ova)

Mechanism: Immunomodulatory

Company: Coronado Biosciences (New name:  Fortress Biotech, Inc)

Status: Phase II clinical trials

CNDO-201 is in clinical trials for autism treatment

Bone theory for ASD, is that it is caused by abnormal autoimmune responses stemming from excessively hygienic environments. These autoimmune responses may contribute to excess inflammation and so, impair neurological development, possibly manifesting as autism spectrum disorders. To try and alter this effect, Fortress Biotech is developing CNDO-201, a new drug that utilities porcine whipworm eggs (Trichuris suis ova) as the active ingredient. CNDO-201 acts by reducing excessive homeostatic immune responses, this decreasing neuroinflammation and ultimately improve core and non-core symptoms.

Currently, this drug is in Phase II clinical trials and appears to be non-pathogenic and effective. While more research is required to verify safety and efficacy of CNDO-201 in larger populations, it may serve as a novel, futuristic treatment for autism.

3. Memantine

Mechanism: NMDA receptor antagonist

Company: Forest Laboratories, Inc.

Status: Phase III clinical trials

Memantine is in clinical trials for autism treatmentMemantine (brand name “Namenda”) is widely recognized as an FDA approved drug for the treatment of Alzheimer’s disease. It is currently in Phase III clinical investigation for the treatment of ASD. Out of several potential causes of ASD, theory maintains that the disorder may occur as a result of excess glutamate (a neurotransmitter) leading to excitotoxicity and neuroinflammation.

Memantine functions primarily as an NMDA (N-methyl-D-aspartate) receptor antagonist, thereby modulating neuronal passage of glutamate to improve upon symptoms of autism.  Additionally,  memantine also acts as an antagonist for 5-HT3 and nACh receptors, as well as a D2 receptor agonist. i.e. the drug also affects the neurotransmission of serotonin, acetylcholine, and dopamine neurotransmitters, respectively.

Previous research on  the effects of memantine demonstrated significant improvement in behavior, language, and self-stimulation of the affected individual. While memantine is safe and acceptable for long-term use, further research is required to clarify its usability among those with autism.

4. RG7314

Mechanism: Vasopressin-1 receptor antagonist

Company: Roche Pharmaceuticals

Status: Phase II clinical trials

RG7314 is in clinical trials for autism treatmentRG7314 is a drug under development by Roche Pharmaceuticals. It’s primary function is that of a selective vasopression-1 receptor antagonist. In other words, it specifically inhibits the transmission of vasopressin at the V1 receptor in the brain. This results in the alteration of levels of ions by modulating the movement of water across astrocyte (glial cell) plasma membranes.
Vasopressin receptors are known to promote vasoconstriction by increasing calcium ion levels in the brain, thus modulating blood flow to various regions. Researchers speculate that by antagonizing the vasopressin-1 receptor, RG7314 will prove most effective for treating emotional processing deficits and social impairment among those with autism.
As yet, however the specific mechanisms associated with V1 receptor antagonism are unclear. Further clinical trial research is necessary to better understand the drug’s side effects, safety, and efficacy among those with autism. Should the drug prove safe and effective, it may be tested for the treatment of other psychiatric and/or neurological disorders besides autism.

5. Syntocinon (Nasal Spray)

Mechanism: Synthetic oxytocin

Company: Retrophin Inc.

Status: Phase II clinical trials

retrophin is in clinical trials for autism treatmentResearch suggests that increasing the hormone oxytocin may improve social and emotional deficits associated with autism. Syntocinon is an intranasal spray developed by Retrophin that delivers a synthetic version of the hormone oxytocin to treat autism.  A study published in 2014 analysed the therapeutic effects of syntocinon in 15 children having ASD, and the results showed an effective reduction in repetitive behaviors and anxiety, and simultaneously ameliorated social deficits. It also appeared to have lasting positive effects, persisting up to 3 months post-treatment and wasn’t associated with any significant side effects or tolerability issues when administered at recommended doses.

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Featured image credit: Autism awareness hand against painted white wooden planks © Wavebreak Media Ltd (Stock Photo ID: 87481445)

Co-author: Anjali Yennemadi (Mithibai College, Mumbai)


One comment

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