Periodic Reporting for period 1 - LSDiASD (Leveraging Small Demethylase inhibitors for Autism Spectrum Disorder)
Reporting period: 2016-11-01 to 2018-08-31
The main aim of this proposal was to establish proof of concept for the efficacy of novel drugs in autism spectrum disorder (ASD).
Defects occurring during development of the central nervous system give rise to neuropsychiatric disorders such as ASD. Affected individuals have often impairments in language and social communication; engage in stereotyped behaviors and display anxiety and mental retardation. ASD affects 1 in 59 children and due to this high incidence and ineffectiveness of available treatments represents a major unmet medical necessity. The similarity of symptoms between ASD and rare genetic diseases grounds the hope that some of the latter may generate insights generalizable to ASD. In this regard, the abnormal duplication of a small interval of the genome comprising 26-28 genes causes 7q microduplication syndrome (7Dup), a multisystemic disease including ASD, while the deletion of the same interval gives rise to Williams syndrome with a symmetrically opposite phenotype such as overfriendliness and preserved language abilities. Previously, we and others, found that one of the affected genes, GTF2I plays a critical role in the cognitive-behavioral profile of 7Dup individuals and in association with the enzyme lysine-specific demethylase 1 (LSD1) represses the expression of genes that are important for neuronal function.
To test the efficacy of LSD1 inhibitors as a novel treatment for the debilitating symptoms of ASD we used mouse models that have a duplication of the critical gene GTF2I (GTF2IDup).
First, we used the three-chambered sociability apparatus to determine whether GTF2IDup mice recapitulate the key symptoms of ASD. This apparatus allowed us to measure: i) the preference of GTF2IDup and wild-type (WT) mice that have no duplication of GTF2I and act as controls, to spend time with a another mouse or with an object and ii) the preference to spend time with a novel mouse or a familiar one, behaviors that are reminiscent of the social communication impairments seen in ASD patients. Indeed, as we predicted GTF2IDup mice, in contrast to WT, spent less time with another mouse and less time with the novel compared with the familiar mouse. We then identified the most effective LSD1 inhibitor and defined its administration regimen. We administered 10mg/kg of LSD1 inhibitor for 2 times/week for a total of 2 weeks and measured again mouse behavior. Remarkably, GTF2IDup mice started to spend more time with their conspecific and showed a preference for spending more time with the novel mouse. We extended the initial objectives of our proposal and found that LSD1 inhibitor not only is effective in reversing the core ASD symptoms but its effect persists even after it is eliminated from the body.
To understand the LSD1 inhibitor mode of action and molecular mechanisms we revealed the changes in gene expression and disease pathways following LSD1 inhibitor administration. Inhibition of LSD1 action affected the expression levels of genes involved in critical processes of ASD pathophysiology.
The extremely high prevalence and the ineffectiveness of available treatments increase ASD societal burden. In the course of this proposal we experimentally proved the effectiveness of LSD1 inhibitor and defined its mechanisms of action highlighting its potential as a novel ASD treatment and, overcome the prerequisites to advance the compound to the clinical trials. Furthermore, we advanced the commercialization and exploitation process through the activities performed by TTFactor. Firstly, TTF has prepared a non-confidential brochure summarizing the technology and its potential aiming to promote the visibility of the project, the brochure was freely downloadable from TTFactor website.
In parallel, the project was included in the TTF portfolio of technologies to be presented to potential partners. TTF has helped the researchers in preparing a slide deck to pitch the project.
The project was discussed with several investors and venture capital funds both during meetings organized ad hoc in our institute and during Bio Conventions, specific conventions dedicated to partnering and networking. The common feedback that TTF received from the pharma/biotech and venture capital sector was that the project is really promising and interesting but needs to be pushed towards (i) the development of a candidate molecule targeting the target GTF2I (identified during our ERC Consolidator Grant) and (ii) its validation in at least a “pilot” disease model, before considering to partner. Therefore, we feel that the results obtained during this PoC months have strongly contributed to increase the value of the project that is now ready to be presented to the previously contacted VCs to show the project advancement aiming at renewing their interest.
In addition, during these months, TTFactor has constantly monitored the progress of the scientific results from the patentability point of view to seek for strengthening our IP position with a new and more focused patent application. Indeed, we are now discussing the patentability of the PoC results with the aim of protecting the medical use of the specific compound under development and validation in the 7Dup disease.
In conclusion, thanks to LSDiASD ERC-PoC we identified, determined the mechanism of action and, experimentally demonstrated the effectiveness of a compound in reversing sociability deficits as a novel drug for autism spectrum disorder. The intensive commercialization and exploitation process advanced our compound closer to a marketable product and eventually to the patients. We have paved the way for developing a pharmaceutical product with a huge societal and financial value.
Defects occurring during development of the central nervous system give rise to neuropsychiatric disorders such as ASD. Affected individuals have often impairments in language and social communication; engage in stereotyped behaviors and display anxiety and mental retardation. ASD affects 1 in 59 children and due to this high incidence and ineffectiveness of available treatments represents a major unmet medical necessity. The similarity of symptoms between ASD and rare genetic diseases grounds the hope that some of the latter may generate insights generalizable to ASD. In this regard, the abnormal duplication of a small interval of the genome comprising 26-28 genes causes 7q microduplication syndrome (7Dup), a multisystemic disease including ASD, while the deletion of the same interval gives rise to Williams syndrome with a symmetrically opposite phenotype such as overfriendliness and preserved language abilities. Previously, we and others, found that one of the affected genes, GTF2I plays a critical role in the cognitive-behavioral profile of 7Dup individuals and in association with the enzyme lysine-specific demethylase 1 (LSD1) represses the expression of genes that are important for neuronal function.
To test the efficacy of LSD1 inhibitors as a novel treatment for the debilitating symptoms of ASD we used mouse models that have a duplication of the critical gene GTF2I (GTF2IDup).
First, we used the three-chambered sociability apparatus to determine whether GTF2IDup mice recapitulate the key symptoms of ASD. This apparatus allowed us to measure: i) the preference of GTF2IDup and wild-type (WT) mice that have no duplication of GTF2I and act as controls, to spend time with a another mouse or with an object and ii) the preference to spend time with a novel mouse or a familiar one, behaviors that are reminiscent of the social communication impairments seen in ASD patients. Indeed, as we predicted GTF2IDup mice, in contrast to WT, spent less time with another mouse and less time with the novel compared with the familiar mouse. We then identified the most effective LSD1 inhibitor and defined its administration regimen. We administered 10mg/kg of LSD1 inhibitor for 2 times/week for a total of 2 weeks and measured again mouse behavior. Remarkably, GTF2IDup mice started to spend more time with their conspecific and showed a preference for spending more time with the novel mouse. We extended the initial objectives of our proposal and found that LSD1 inhibitor not only is effective in reversing the core ASD symptoms but its effect persists even after it is eliminated from the body.
To understand the LSD1 inhibitor mode of action and molecular mechanisms we revealed the changes in gene expression and disease pathways following LSD1 inhibitor administration. Inhibition of LSD1 action affected the expression levels of genes involved in critical processes of ASD pathophysiology.
The extremely high prevalence and the ineffectiveness of available treatments increase ASD societal burden. In the course of this proposal we experimentally proved the effectiveness of LSD1 inhibitor and defined its mechanisms of action highlighting its potential as a novel ASD treatment and, overcome the prerequisites to advance the compound to the clinical trials. Furthermore, we advanced the commercialization and exploitation process through the activities performed by TTFactor. Firstly, TTF has prepared a non-confidential brochure summarizing the technology and its potential aiming to promote the visibility of the project, the brochure was freely downloadable from TTFactor website.
In parallel, the project was included in the TTF portfolio of technologies to be presented to potential partners. TTF has helped the researchers in preparing a slide deck to pitch the project.
The project was discussed with several investors and venture capital funds both during meetings organized ad hoc in our institute and during Bio Conventions, specific conventions dedicated to partnering and networking. The common feedback that TTF received from the pharma/biotech and venture capital sector was that the project is really promising and interesting but needs to be pushed towards (i) the development of a candidate molecule targeting the target GTF2I (identified during our ERC Consolidator Grant) and (ii) its validation in at least a “pilot” disease model, before considering to partner. Therefore, we feel that the results obtained during this PoC months have strongly contributed to increase the value of the project that is now ready to be presented to the previously contacted VCs to show the project advancement aiming at renewing their interest.
In addition, during these months, TTFactor has constantly monitored the progress of the scientific results from the patentability point of view to seek for strengthening our IP position with a new and more focused patent application. Indeed, we are now discussing the patentability of the PoC results with the aim of protecting the medical use of the specific compound under development and validation in the 7Dup disease.
In conclusion, thanks to LSDiASD ERC-PoC we identified, determined the mechanism of action and, experimentally demonstrated the effectiveness of a compound in reversing sociability deficits as a novel drug for autism spectrum disorder. The intensive commercialization and exploitation process advanced our compound closer to a marketable product and eventually to the patients. We have paved the way for developing a pharmaceutical product with a huge societal and financial value.