Periodic Reporting for period 1 - PRIME (A Personalised Living Cell Synthetic Computing Circuit for Sensing and Treating Neurodegenerative Disorders)
Période du rapport: 2021-02-01 au 2022-01-31
There remain urgent and unmet needs for the treatment of neurological diseases. Epilepsy is a serious, chronic brain disease characterized by recurrent seizures. Epilepsy is one of the most common serious neurological condition, affecting about 1% of the population, i.e. about 60 million people globally (6 million in Europe). The end result of PRIME is a software design tool for designing engineered cells that compute, diagnose, and produce therapeutic molecules capable of preventing seizures. The design tool is governed by Artificial Intelligence (AI) integrated with Molecular Communication simulations that utilize Biophysical and Statistical Mechanics modelling. This trans-disciplinary project aims to approach a serious neurological problem through a solution bringing together synthetic biology, computer science, communication engineering, nanomedicine, bioengineering and material science. This vision of implanting programmable synthetic cells that mimic electronic computing circuits is not limited to managing epileptic seizures but may extend to many other neurological diseases.
Objective 1: Developing molecular communication simulation and modeling design tool. This includes: 1. Simulating end-to-end molecular communication of molecules (e.g. tsRNA) diffusion through the device, intracellular signaling for logic computing, and release of GDNF. 2. Use of AI to design molecular logic gates using circuit theory and device structural design (optimized volume and scaffold dimensions).
Objective 2: Engineering cells to sense, perform logic computing and release GDNF. This includes: 1. Defining the molecular pathway to sense and suppress seizures. 2. Design and validation of pathway whereby tsRNA build-up in advance of a seizure competes with a GDNF-blocking miRNA, thereby prompting translation and release of GDNF. 3. Fail-safe pathway that securely triggers GDNF from a preformed releasable pool in response to seizure-induced rise in intracellular calcium concentrations.
Objective 3: Developing an encapsulated implantable device that integrates three-dimensional (3D) constructs of the cells from Objective 2 grown in hybrid biomaterial scaffolds. This includes: 1. Development of porous Polydimethylsiloxane (PDMS) membrane dimensioned and surface-treated to enable tsRNAs and GDNF diffusion. 2. Development of biocompatible hybrid microenvironment, i.e. comprised of hydrogel and electrospun non-woven porous nanofibers from brain natural polymers. 3. Create a viable environment for the development of 3D constructs of engineered cells grown in the hybrid scaffolds. 4. Integrate 1-3 into a functional biocompatible bio-computing circuit that will be tested in vitro.
Objective 4: Experimental testing and validation of device in vivo. This includes: 1. In vivo validation of the device for responsiveness to changes in tsRNA fragments. 2. In vivo evaluation of the implant performance in two rodents models of epilepsy. 3. Post-explant evaluation of implant function and tracking of epilepsy phenotype.
Objective 1: Developing molecular communication simulation and modeling design tool. This includes: 1. Simulating end-to-end molecular communication of molecules (e.g. tsRNA) diffusion through the device, intracellular signaling for logic computing, and release of GDNF. 2. Use of AI to design molecular logic gates using circuit theory and device structural design (optimized volume and scaffold dimensions).
Objective 2: Engineering cells to sense, perform logic computing and release GDNF. This includes: 1. Defining the molecular pathway to sense and suppress seizures. 2. Design and validation of pathway whereby tsRNA build-up in advance of a seizure competes with a GDNF-blocking miRNA, thereby prompting translation and release of GDNF. 3. Fail-safe pathway that securely triggers GDNF from a preformed releasable pool in response to seizure-induced rise in intracellular calcium concentrations.
Objective 3: Developing an encapsulated implantable device that integrates three-dimensional (3D) constructs of the cells from Objective 2 grown in hybrid biomaterial scaffolds. This includes: 1. Development of porous Polydimethylsiloxane (PDMS) membrane dimensioned and surface-treated to enable tsRNAs and GDNF diffusion. 2. Development of biocompatible hybrid microenvironment, i.e. comprised of hydrogel and electrospun non-woven porous nanofibers from brain natural polymers. 3. Create a viable environment for the development of 3D constructs of engineered cells grown in the hybrid scaffolds. 4. Integrate 1-3 into a functional biocompatible bio-computing circuit that will be tested in vitro.
Objective 4: Experimental testing and validation of device in vivo. This includes: 1. In vivo validation of the device for responsiveness to changes in tsRNA fragments. 2. In vivo evaluation of the implant performance in two rodents models of epilepsy. 3. Post-explant evaluation of implant function and tracking of epilepsy phenotype.
During the first year of the project, the consortium partners have worked towards the biological and technological goals of PRIME:
1. Waterford Institute of Technology (WIT) have made progress towards developing theoretical molecular communication models and simulating diffusion of molecules through the device. This will be used as part of the end-to-end channel model for molecular communications. WIT have made progress towards developing artificial intelligence models to complement bioinformatics pipelines for identifying biomarkers with Royal College of Surgeons in Ireland (RCSI).
2. Aarhus University (AU) and University of Ferrara (UniFE) have progressed well towards engineering cells to sense, perform logic computing and release GDNF.
3. Tampere University (TAU) and EPOS IASIS Research and Development Ltd. (EPOS) have made good progress towards developing an encapsulated implantable device that integrates 3D constructs of cells grown in hybrid biomaterial scaffolds.
Currently work is on-going in following deliverables.
D1.1 Project Handbook
D1.2 Data Management Plan
D1.3 Updated Data Management Plan Period 1
D1.6 Project Reports and Update Plans Year 1
D1.10 Technical/Scientific Review Meeting 1 Docs
D2.3 Repository for Simulation codes
D3.1 ARPE-19 cells that express GDNF under the regulation of miRNA
D6.1 Initial Dissemination and Exploitation Plan
D6.2 Updated Dissemination and Exploitation Plan Period 1
D7.1 HCT - Requirement No. 1
D7.2 A - Requirements No. 2
D7.3 EPQ - Requirement No. 4
1. Waterford Institute of Technology (WIT) have made progress towards developing theoretical molecular communication models and simulating diffusion of molecules through the device. This will be used as part of the end-to-end channel model for molecular communications. WIT have made progress towards developing artificial intelligence models to complement bioinformatics pipelines for identifying biomarkers with Royal College of Surgeons in Ireland (RCSI).
2. Aarhus University (AU) and University of Ferrara (UniFE) have progressed well towards engineering cells to sense, perform logic computing and release GDNF.
3. Tampere University (TAU) and EPOS IASIS Research and Development Ltd. (EPOS) have made good progress towards developing an encapsulated implantable device that integrates 3D constructs of cells grown in hybrid biomaterial scaffolds.
Currently work is on-going in following deliverables.
D1.1 Project Handbook
D1.2 Data Management Plan
D1.3 Updated Data Management Plan Period 1
D1.6 Project Reports and Update Plans Year 1
D1.10 Technical/Scientific Review Meeting 1 Docs
D2.3 Repository for Simulation codes
D3.1 ARPE-19 cells that express GDNF under the regulation of miRNA
D6.1 Initial Dissemination and Exploitation Plan
D6.2 Updated Dissemination and Exploitation Plan Period 1
D7.1 HCT - Requirement No. 1
D7.2 A - Requirements No. 2
D7.3 EPQ - Requirement No. 4
The end result of PRIME is a software design tool for designing engineered cells that compute, diagnose, and produce therapeutic molecules capable of preventing seizures. The design tool is governed by Artificial Intelligence (AI) integrated with Molecular Communication simulations that utilize Biophysical and Statistical Mechanics modelling. This trans-disciplinary project aims to approach a serious neurological problem through a solution bringing together synthetic biology, computer science, communication engineering, nanomedicine, bioengineering and material science. This vision of implanting programmable synthetic cells that mimic electronic computing circuits is not limited to managing epileptic seizures but may extend to many other neurological diseases.