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MultIscale precision therapies for NeuroDEvelopmental Disorders

Periodic Reporting for period 1 - MINDED (MultIscale precision therapies for NeuroDEvelopmental Disorders)

Reporting period: 2018-01-01 to 2019-12-31

Neurodevelopmental disorders (NDDs) are characterized by brain function deficits that usually show up early in children and can run throughout the lifetime of individuals. These deficits can affect memory as well as the ability to learn, socialize and maintain self-control. As such, NDDs represent an enormous burden for the affected patients, their families and society. Multiple studies predict a steady growth in the incidence of NDDs over the coming years. Within the EU, the incidence of autism spectrum disorders (ASD), a subtype of NDDs, is estimated at present to range between 45 and 70 per 10,000 children, and is expected to increase to over 100 per 10,000. Moreover, the requirement for lifelong care of NDD patients has a dramatic impact on healthcare costs, given that the average lifetime cost per ASD patient is estimated to be ~ 3.0 MEuro. To date, remedies available to clinicians are limited to interventional therapies and medications, mostly antipsychotic drugs.
The societal and economic impact, the growing incidence, and the lack of any cure call for radical changes in the way NDDs are studied and treated. Synergistic and highly interdisciplinary approaches combining the development of novel molecular therapies with innovative rehabilitation strategies hold potential for revolutionizing the life of NDD patients.
MINDED will develop and integrate across three major disciplines:
• nanomedicine, for the precise delivery of therapeutic and imaging agents to diseased sites by rationally designing multifunctional nanoconstructs;
• molecular neuroscience, for the identification/study of genes involved in NDDs and synthesis of RNAs for restoring their physiological expression;
• cognitive neuroscience robotics, for the development of novel diagnostic and therapeutic sensorimotor approaches to NDDs by assistive robotics.
The integration of nanomedicine, neuroscience and robotic technologies – the MINDED technologies – requires to establish a new class of scientists and entrepreneurs trained to stretch their knowledge over multiple disciplines, work in highly interdisciplinary teams, and think outside conventional silos. The main objective of MINDED is to bridge together diverse vertical silos building common foundations for future, highly interdisciplinary careers. As such MINDED aims at:
• develop a highly interdisciplinary post-doctoral training program by integrating notions pertaining to the fields of nanomedicine, molecular neuroscience and cognitive neuroscience robotics;
• involve post-doctoral scientists in highly interdisciplinary research activities aiming at developing advanced technologies for the assessment, stratification, treatment of NDD patients and at their business exploitations
In the first period of the MINDED project, the focus has mostly been on the haploinsufficient gene Euchromatine histone methyl transferase 1 (Ehmt1), which is associated with developmental delay and intellectual disability, severely limited or absent speech, weak muscle tone. This gene is associated with a NND called the Kleffstra syndrome. In collaboration with the group of Prof. Hans van Bokhoven at Radboud University Medical Center, biodegradable polymeric microparticles are being developed for the sustained long term delivery of antipsychotic drugs, such as Olanzapine (OLN), Risperidone, and Clemastine. These nanomedicines will allow to delivery in a sustained manner for several months therapeutic molecules to treat Kleffstra and other NDD syndromes, avoiding taking multiple pills daily and thus help with patient compliance. Also, in collaboration with Prof. Thomas Sudhof at Stanford University, nanoparticles are being developed for the delivery of compounds to restore the function of BK channels in neurons. This technology is supposed to recover the expression of specific synaptic molecules and thus ameliorate the overall behavior and learning ability of patients.
Other on-going activities at the interface between neuroscience and nanotechnology involve the design, fabrication and testing of different nanoparticles for crossing the blood brain barrier and ‘infect’ the brain with RNA-based molecules; microfluidic chips for assessing ex-vivo the performance of nanoparticles while reproducing an artificial brain/vascular compartment; and the development of multiscale, hierarchical computational models to predict the biophysical behavior of polymeric nanomedicines.
At a the macroscopic scale, the Cognitive Neuroscience Robotics MINDED fellows are developing new diagnostic and therapeutic sensorimotor approaches against NDDs. In particular, functional Magnetic Resonance Imaging (fMRI) and visual analyses are being used to study the neural basis of acquired limb loss, congenital limb loss and supernumerary limb in collaboration with the CHUV in Lausanne and to assess body representation. This activity will improve our understanding of how body portions, such us limbs, are perceived by children and adults. Another group of MINDED fellows is looking at movement kinematics of autistic children and adults to infer on the stage of the diseases as well as develop novel tools for assessing the efficacy of therapeutic interventions. A third group of MINDED fellows is using humanoid robots, such as iCub, to investigate the effect of sensory sensitivity on training protocols for healthy and patients with Autistic Spectrum Disorders
In the second portion of the MINDED project, the activities will focus also on additional genes of interest to NDD, specifically Forkhead box G1 (Foxg1), which is associated with impaired development, structural brain abnormalities, abnormal and involuntary movements; and Frataxin (FXN), which is associated with impaired muscle coordination, loss of strength and sensation in the arms and legs; muscle stiffness; and impaired speech, hearing, and vision. Lipid Nanoparticles will be optimized for the delivery of different and multiple RNA molecules across the blood brain barrier to modulate the expression of genes involved in NDD. Systematic studies will be completed on identifying the most effective ways to delivery therapeutic molecules to the brain, including systemic, intracranial, intranasal and intraspinal delivery. At the macroscale, cognitive neuroscience robotics will continue to be employed to develop and establish new diagnostic and therapeutic sensorimotor approaches for NDDs. Finally, in the second portion of the project, the MINDED fellows will acquire specific skills in the area of management, technology and entrepreneurship. Many of the core challenges encountered in the business world today are situated at the intersection of technology and management, and require fast and innovative, entrepreneurial solutions. To successfully meet those challenges, professionals must be able to bridge the worlds of technology and management, understand the functioning of modern business organizations in a holistic manner, be able to think out of the box in order to develop new approaches, manage a variety of firm-internal processes and engage with external stakeholders. Furthermore, in the case of biomedical technologies, successful entrepreneurs should also be aware of marketing authorization processes for novel therapeutic agents and devices which are established by regulatory agencies. All this will fall Within the business development area of the MINDED project.
Project MINDED Flyer