Therapeutic Treatment

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.

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. 

Professor Konark Mukherjee, based at the University of Alabama, is advancing research into a potential treatment aimed at slowing or preventing cerebellar degeneration caused by CASK gene loss. This work offers new hope for improving the quality of life for children affected by CASK-related disorders.

In earlier studies, the treatment showed promising effects—supporting cerebellar growth and reducing brain cell loss in CASK-deficient mouse models. Long-term results continue to be encouraging: the drug slowed brain degeneration, preserved key brain regions, and helped prevent balance problems in treated mice.

Professor Mukherjee also explored whether the treatment could prevent early death in mice entirely lacking the CASK gene. While this outcome has not yet been achieved, efforts are ongoing to understand why. Current investigations include whether the drug can cross the placenta and whether it supports all types of brain cells.

Next Steps in the Study

1. Testing the treatment’s ability to prevent cerebellar hypoplasia in female mice with one functioning CASK gene.

2. Optimising dosage and delivery methods to rescue cask linked lethality.

Professor Mukherjee has been examining treatment effects at the molecular level in the brain and found that, even at the current dose, the drug significantly reduces gliosis in treated mice.

What is gliosis?
Gliosis is a common marker of brain stress. When neurons are under pressure or degenerating, surrounding support cells become highly activated. Increased gliosis can indicate the brain is responding to injury or ongoing stress.

In treated mice, the data indicate:
• Markers of brain stress were dramatically reduced;
• The drug clearly reached the developing brain; and
• The drug is having a measurable biological effect.

This is the most significant positive dataset since the earlier findings showing the drug could slow cerebellar degeneration.

These findings suggest the treatment may be improving the brain’s environment and reducing ongoing stress on neurons. In CASK-related disorders, slowing degeneration and protecting existing neurons can be highly meaningful.

Professor Mukherjee is now exploring two key questions:
1. Whether reducing gliosis is always beneficial, given glial activation can sometimes be neuroprotective; and
2. Whether adjusting the dosage could safely improve outcomes.

What we can say with confidence at this stage is:
• The drug is reaching the developing brain;
• It is biologically active; and
• It is changing disease-relevant markers.

That is real progress.