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Therapeutic Treatment

Preclinical Study of a FDA Approved Molecule on Mouse Models


Please see video provided by Professor Konark Mukherjee discussing the animal model and his early findings.

Therapeutic Research commenced in late 2021 and is ongoing. We provide below a timeline of Updates provided by Professor Konark Mukherjee as to the progress of the Research

Professor Mukherjee findings:

Development occurs at many levels, cells develop, organs develop and the individual develops. The brain is one of the fastest-growing organs in a child, at birth the weight of the brain is already a quarter of the adult size and by 6-7 years brain attains its adult size. According to Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), “neurodevelopmental disorders, are characterized by early-onset deficits of variable severity in personal, social, academic, or occupational functioning”. Thus, the term neurodevelopmental disorder is a descriptor for a large variety of neurological conditions that arise early in an individual’s life, and does not provide a window into the possible mechanism of the disorder. Indeed a large number of neurodevelopmental disorders occur due to insult to the developing brain in a time-limited fashion such as infection (eg.Zika virus), toxins and drugs (eg. alcohol), or trauma (cerebral palsies). These insults are more likely to cause damage to the developing nervous tissue rather than alter the specific maturation process of neurons in the brain. Despite this knowledge, within neuroscience, neurodevelopmental disorders have often been seen through the prism of neuronal development, especially when such disorders are associated with specific genetic mutations.                 

Mutations in CASK produce a neurodevelopmental disorder called microcephaly with pontine and cerebellar hypoplasia (MICPCH). It has been suggested that MICPCH may result either from improper migration of neurons to the right place during brain development or defects in synaptic neurotransmission. In the majority of MICPCH cases, however, there is no evidence of heterotopia which results from migrational defects in neurons. 

In the recently published study, we demonstrate that loss of CASK does not lead to alteration in early brain developmental trajectory. Rather, it produces loss of certain types of cells like cerebellar granule neurons. We also found that the functional loss that is seen in absence of CASK, occurs due to the loss of neurons and not due to defects in synaptic transmission. Finally, we found that in females, who have 2 CASK genes the neuronal loss is not progressive and stabilizes after early childhood. Our findings explain the clinical presentation of MICPCH in the population including the fact that microcephaly or developmental delay is often not detected for the first 3-6 months after birth and the disorder is often non-progressive. This study also indicates that an ability to stop neuronal death, especially in the first 5-6 years of life, when the brain is growing rapidly, may prove to be therapeutic.   

As referred to in my most recent Article ‘The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model published 28 March 2022’  Find out more.

Please see link here to a short video provided by Professor Konark Mukherjee discussing his recent findings which we have also outlined in detail below.

As discussed in our last update, Professor Konark Mukherjee’s key findings were:

 1. The functional loss that is seen in the absence of CASK is due to the loss of neurons;

 2. There may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss.

Since these findings, Professor Konark Mukherjee has continued his experiments on male animal models (mice) and his further indicative findings are:

  a·  The therapeutic administered significantly improved the size of the cerebellum in each of these animal models that has an absence of CASK which is indicative of the therapeutic slowing or preventing further brain cell loss.

  b·  The hope is that this therapeutic will improve the quality of life for both males and females. Whilst the therapeutic at this stage is considered to be best administered early in a child’s life ( as soon as the diagnosis is made). For males most likely the therapy is required to be lifelong, but for girls it can be stopped at the age of 5-6 years.  If administered later in childhood or even adolescence,  it is hoped that it may improve the overall brain function by reducing the biochemical stress that leads to microcephaly and cerebellar hypoplasia. Further, it may reduce any further neurodegeneration.

Moving Forward – Next Questions to be considered by way of further experiments:

1. What will be the most appropriate dosage of the therapeutic?

 2. What is the best method to deliver this therapeutic to the mice so as to improve the knowledge of the actual active amount of therapeuticthat is actually consumed by the mice models?

 3. Is there any toxicity associated with long-term treatment?

Once these questions are answered, Professor Konark Mukherjee will then consider the process involved in human trials.

Professor Mukherjee is continuing his therapeutic studies and so far he has found that there has been no adverse effect on the mice models, with a prolonged period of high dose of the therapeutic. He will continue this study to ensure that this remains the case.

Professor Mukherjee also intends to develop a Plan to be put forward to Pharmaceutical organisations in the hope that we can move forward to clinical trials (subject to his continued study of mice models). Professor Mukherjee anticipates that this Plan will be developed within 6 months. 

We will keep you updated in the new year as to this continued research project and its progress. 

Please see video update provided by Professor Konark Mukherjee outlining his recent findings and the next phase of his research.

Professor Mukherjee now based at University of Alabama (UAB) and is continuing the therapeutic funded project and  has informed us his next goal with this drug “is to see if it can prevent the most objective measure of all, lethality”. Essentially, he will test if very early delivery of this drug can prevent lethality in CASK knockout mice. (‘CASK knockout mice’ refers to mice that have been genetically modified or engineered so that they do not produce the CASK protein).

He recently published Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein dated 14 April 2024. 


“In some ways, that CASK-linked pathology is degenerative in nature provides a positive outlook. Because microcephaly in CASK-linked pathology progresses postnatally, there may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss. Regression, even in adolescence, has also been observed in some cases of MICPCH [119], again offering the tantalizing possibility that a therapeutic approach might prevent such decline under conditions when degeneration is known to progressThe potential benefits of intervention might extend even further given that non-cell-autonomous toxicity could also affect functioning of the remaining neurons; reduction of such toxicity, especially when coupled with high-intensity rehabilitative measures [120], might offer real hope for a positive impact on functional outcomes.”