ADNP Mouse Model Characterization Study
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Project Outline: New Mutated ADNP mouse model characterization Enabling studies for clinical development and drug evaluation |
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ADNP Syndrome is highly associated with autism spectrum disorder (ASD):
ASD is a neurodevelopmental disease more prevalent in males than females, and characterized by three main core symptoms; abnormal reciprocal social interactions, impaired communication and repetitive behaviors. Some medications, like risperidone and aripiprazole (antipsychotic drugs) are used to treat children with ASD suffering from severe tantrums, aggression, and self injurious behaviors. However, there is no cure for ASD to date.
In 2012, mutations were found in activity-dependent neuroprotective protein (ADNP), a gene discovered and characterized in the laboratory of Professor Illana Gozes at Tel Aviv University (TAU), in individuals with autism. This was extended in 2014. Importantly, ADNP was found to be one of the most prevalent genes mutated in ASD to date.
Previously, Professor Gozes and colleagues discovered ADNP is vital for mammalian brain formation, constituting part of an essential gene remodeling complex. ADNP regulates over 400 genes during brain development including key ASD-linked genes. The working hypothesis is that ADNP is a master gene which regulates ASD, and that ADNP replacement/enhancement therapy may be beneficial for treating related ASD. To evaluate this hypothesis, Professor Gozes and colleagues have developed a transgenic mouse line exhibiting p[partial ADNP deficiency. This is the only ADNP-deficient mouse model to date. Behavioral assays are now underway and are being validated through gene expression analysis, spanning key genes involved in ASD, with a special attention to gender differences (with ASD being several folds more prevalent in males). Furthermore, a new mouse model was generated recently in the Gozes Laboratory carrying a truncating ADNP mutation. This model was developed using the most advanced CRISPR/Cas9 genome editing techniques. This mouse will now undergo complete analysis and comparison to the human condition.
Replacement therapy to restore ADNP's activity will be addressed. ADNP regulates the formation of brain connections (synapses), which are malfunctioning in ASD. The ADNP-derived fragment NAP (drug candidate davunetide, now called CP201 discovered by Professor Gozes and colleagues), enhances the formation of brain connections and has shown positive indications of protection against cognitive impairments associated with ADNP deficiency in mice. In clinical trials, NAP increased cognitive scores in patients with Mild Cognitive Impairment (MCI), a precursor to Alzheimer's disease, with no obvious negative side effects. In schizophrenia patients, NAP protected the ability to perform activities of daily living.
Selected recent publications
Public releases: https://www.sciencedaily.com/releases/2016/02/160211142012.htm
https://www.ncbi.nlm.nih.gov/pubmed/?term=Gozes+i
https://www.jci.org/articles/view/98199
Drug development: Coronis Neurosciences (exclusively licensed from Tel Aviv University)
ASD is a neurodevelopmental disease more prevalent in males than females, and characterized by three main core symptoms; abnormal reciprocal social interactions, impaired communication and repetitive behaviors. Some medications, like risperidone and aripiprazole (antipsychotic drugs) are used to treat children with ASD suffering from severe tantrums, aggression, and self injurious behaviors. However, there is no cure for ASD to date.
In 2012, mutations were found in activity-dependent neuroprotective protein (ADNP), a gene discovered and characterized in the laboratory of Professor Illana Gozes at Tel Aviv University (TAU), in individuals with autism. This was extended in 2014. Importantly, ADNP was found to be one of the most prevalent genes mutated in ASD to date.
Previously, Professor Gozes and colleagues discovered ADNP is vital for mammalian brain formation, constituting part of an essential gene remodeling complex. ADNP regulates over 400 genes during brain development including key ASD-linked genes. The working hypothesis is that ADNP is a master gene which regulates ASD, and that ADNP replacement/enhancement therapy may be beneficial for treating related ASD. To evaluate this hypothesis, Professor Gozes and colleagues have developed a transgenic mouse line exhibiting p[partial ADNP deficiency. This is the only ADNP-deficient mouse model to date. Behavioral assays are now underway and are being validated through gene expression analysis, spanning key genes involved in ASD, with a special attention to gender differences (with ASD being several folds more prevalent in males). Furthermore, a new mouse model was generated recently in the Gozes Laboratory carrying a truncating ADNP mutation. This model was developed using the most advanced CRISPR/Cas9 genome editing techniques. This mouse will now undergo complete analysis and comparison to the human condition.
Replacement therapy to restore ADNP's activity will be addressed. ADNP regulates the formation of brain connections (synapses), which are malfunctioning in ASD. The ADNP-derived fragment NAP (drug candidate davunetide, now called CP201 discovered by Professor Gozes and colleagues), enhances the formation of brain connections and has shown positive indications of protection against cognitive impairments associated with ADNP deficiency in mice. In clinical trials, NAP increased cognitive scores in patients with Mild Cognitive Impairment (MCI), a precursor to Alzheimer's disease, with no obvious negative side effects. In schizophrenia patients, NAP protected the ability to perform activities of daily living.
Selected recent publications
Public releases: https://www.sciencedaily.com/releases/2016/02/160211142012.htm
https://www.ncbi.nlm.nih.gov/pubmed/?term=Gozes+i
https://www.jci.org/articles/view/98199
Drug development: Coronis Neurosciences (exclusively licensed from Tel Aviv University)