Autism Spectrum Disorder (ASD) refers to a highly prevalent group of neurodevelopmental disorders showing convergent cognitive/behavioral symptoms, including impairments in language, social communication and stereotypies, often coupled to anxiety and often accompanied by intellectual disability. Thousands different causative genetic lesions have been identified for ASD, mostly represented by de novo mutations or copy number variations splitting ASD de facto into an aggregate of rare genetic diseases with phenotypic convergence.

Prof. Giuseppe Testa’s research program aims at identifying molecular mechanisms and potential therapeutic interventions for certain rare subtypes of ASD, in particular the 7Dup-Autism Spectrum Disorder (7DupASD), where the abnormal duplication of the chromosomal region 7q11.23 has been recognized as the cause. Individuals affected by 7DupASD show language impairment and hyposociality along with other characterizing aspects of ASD. The team is investigating classes of epigenetic modulators to treat ASD by tackling key mechanistic dysregulations that underlie its core symptoms.

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It is estimated that worldwide one in 160 children has an ASD. This high prevalence
appears to be increasing globally due to improved awareness, diagnostic tools and
reporting. ASD is a chronically underserved market with a clear opportunity for
companies to capitalize on this market by developing and launching an effective
drug that treats a core symptom. ASD market is expected to grow with a CAGR of
4.3% from 2018 to 2026. North America generated a revenue of $1,911.7 mln in
year 2018 and is expected to grow through 2026. Europe is anticipated to be the
second most prominent region in terms of revenue. 7Dup prevalence has been
estimated at 1:7,500-1:20,000, qualifying as a rare disease [ORPHA:96121] thus
providing the opportunity to get market exclusivity through the Orphan Drug
Designation. There are more than 6000 rare diseases affecting 30 million EU
citizens. 80% of rare diseases are of genetic origin and are often chronic and


There are currently no effective pharmacological therapies to treat
core symptoms of autistic patients, and only very partial
improvements by the extremely costly intensive behavioral therapies.
The only medications available can help with associated issues like
depression, aggressivity or seizures.

To date, the main challenges for the development of efficacious
treatments of ASD have been both the lack of reliable models to study
cognitive functions and human social interaction and the
inadequateness of high-throughput screenings for the identification of
drugs. Therefore, there is a strong unmet medical need for effective
products modulating specific neuronal pathways implicated in the
onset of such diseases.

Current technology limitations

Current ASD treatment guidelines advise the use of pharmacologic intervention
to manage disruptive behavior and to improve compliance with behavioral
interventions rather than treat core symptoms. The most common prescribed
pharmacologic classes are anti-psychotic drugs, antidepressants, stimulants, and
anticonvulsants. The only two FDA approved treatments are the atypical
antipsychotic drugs, risperidone and Abilify, for the treatment of irritability.
Several companies are developing novel first-in-class drugs by focusing on
various targets and mechanisms of action being mainly the modulation of
neurotransmission at the synapse or alteration of the levels of serotonin at the
synapse. One example is Latuda, developed by Dainippon Sumitomo Pharm, that
has an antagonistic effect on dopamine and serotonin receptors. Another
product is an enzyme replacement therapy, CM-AT, developed by Curemark, that
targets a dysfunctional digestive system in ASD children. Prof. Testa’s project
aims at developing first-in-class pharmacological agents to treat core symptoms
in rare autistic syndromes by targeting key genetic lesions and pathogenic

Killer Application

The further development of the technology will focus on the early stage
clinical development of the front-runner compound, a proprietary LSD1
inhibitor (LSD1i), for the treatment of 7DupASD patients. The effect of
LSD1i on 7DupASD core symptoms and the availability of a platform of
disease models for other rare neurodevelopmental disorders will allow
to expand the pipeline of therapeutics for 7DupASD and other rare
autistic syndromes sharing the same core symptoms and converging on
the same molecular mechanism.

The solid scientific background, the expertise and the access to
state-of-art facilities set the ground to move quickly towards the first
steps of clinical evaluation of the candidate representing a unique
opportunity for pharmaceutical companies focused on this disease area
interested in pursuing the clinical development of the candidate
towards the ASD market

Our technology and solutions

Prof. Giuseppe Testa’s group has developed a unique collection of
patient-specific neuronal models - disease avatars - including differentiated
neurons and brain organoids, starting from pluripotent stem cells reprogrammed
from skin fibroblasts of 7DupASD patients, representing uniquely relevant
models exploitable for the identification of novel druggable targets.
Dysregulation of chromatin remodelling has been identified as a new potential
target playing a critical role in the cognitive profile of 7DupASD patients. These
findings allowed to identify IEO proprietary anti-LSD1 (Lysine-specific histone
demethylase 1A) compounds as potential novel 7DupASD treatment.
Proof-of-Concept studies showed that LSD1 inhibition reverts the ASD-relevant
social deficits in 7DupASD mouse models. The effect of LSD1 inhibitors on
7DupASD core sociality symptoms and the availability of a platform of disease
models for other rare neurodevelopmental disorders allows to expand the
application of this treatment to other ASD syndromes sharing the same core
symptoms and converging on the same molecular mechanisms.


Proprietary first-in-class therapeutic molecules for 7DupASD and core
symptoms of ASD;
Preclinical Proof-of-Concept validation completed;
Reference reprogramming hub for the leading ASD mutations and largest
human iPSC cohort of 7q11.23 CNV and related ASD syndromes;
Leading expertise in brain-organoids, cell reprogramming, single-cell omics,
behavioral studies, genetic and epigenetic mechanisms in
neurodevelopmental disorders;
Invaluable patient-derived brain cortical organoid models recapitulating
early human brain development in 3D and matched mouse models
harboring disease-specific genetic lesions and displaying the core ASD


Future goals to be achieved include:
1) Regulatory preclinical studies,including full toxicology studies and GMP manufacturing of theclinical candidate;
2) Definition of regulatory approval path, includingOrphan Drug Designation;
3) Design and development of a phase I/IIclinical trial in 7DupASD patients.

Importantly, collaborations with specialized clinical centers and a worldwide 7DupASD patients’families association have already been established that will providethe clinical expertise and infrastructure, along with the patientcohorts, to design and prepare the first clinical trials of the LSD1inhibitor in 7DupASD.

Development Stage

The goals already achieved are: 1) full molecular and functional characterization of patients-derived neuronal models and brain organoids of 7DupASD and other ASD syndromes; 2) Uncovering of chromatin remodeling dysregulation as a key mechanistic layer of cognitive disruption in 7DupASD patients; 3) Identification of a lead epigenetic compound targeting the enzyme LSD1; 4) In vivo validation of efficacy of front-runner LSD1i in 7DupASD mouse models in reverting social core symptoms; 5) Set up of a protocol for a chemical High-Throughput Screening (HTS) in patients-derived differentiated neurons to identify new candidate molecules. As a therapeutic application, the current Technology Readiness Level (TRL) is 4 (technology validated in the laboratory)

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