Periodic Reporting for period 1 - TICK (Temperature InduCed K+ channel as a tool to treat neuropathic pain)
Período documentado: 2021-12-01 hasta 2023-05-31
The goal of the PoC TICK project was to move first steps towards technology transfer of a a result obtained in the frame of the ERC Adg grant noMAGIC. TICK is the name of a synthetic ion channel that conducts potassium (K+) ion only when activated by a short (30 sec) increase in local tissue temperature above 37°C (39-40°C). This range of temperature is physiological and can be easily obtained by means of an infrared lamp and/or a portable ultrasounds generator, as both stimuli penetrate superficial tissues. The idea is to use K+ channel opening to silence pain neurons (nociceptors) that become pathologically hyperactive in several diseases, including diabetes. In the frame of the TICK PoC project, we have successfully confirmed the efficacy of TICK and moved further steps towards clinical testing. What follows is s short summary of the achievements:
• Objective 1: Definition of pre-clinical protocol based on current EMA regulatory indications
Once the analgesic efficacy of TICK in vivo has been confirmed, we started a systematic verification of issues related to the preclinical protocol. These include the method of administration and the type of viral vector, the experimental model to be tested, temperature application, the duration of the analgesic effect, possible side effects, long-term virus permanence and biodistribution, dose regimen, etc. All the above issues which are inherent to gene therapy nature of the treatment, have emerged at every meeting with stake holders, investors, and mentors.
• Objective 2: Execution of ex vivo and in vivo functional tests, in line with the designed protocol for pre-clinical
A CRO (ANS Biotech) was identified to perform viral infection experiments and tests to evaluate the efficacy of TICK in vivo, following GLP (Good Laboratory Practice) practices. The neuropathic pain model we selected is the Chronic Constriction Injury Model (CCI), in the future we plan to test others, such as the diabetic and chemotherapy pain models, both available at the same CRO. The two selected viruses, AAV-PHP.S and MaCPNS2, will be injected intravenously, and one month after injection, functional tests will be started to evaluate the efficacy of the channel to reduce pain in the animal. The study will be divided into 5 experimental groups, each consisting of 5 animals: - vehicle-treated (control GFP virus without transgene) - low dose - intermediate dose - high dose - positive reference-treated group (Morphine) Different timepoints, short and long term, have been identified to also evaluate expression efficiency, toxicity and dose regimen.
Analyses of biodistribution and stability of the transgene: The tested mice will be kept in breeding and sacrificed three months after the end of the functional tests to collect the biological materials (organs, tissues, blood, etc.) necessary for the subsequent analyses of toxicity, biodistribution and stability of the transgene. The latter will consist of verifying the presence of the viral genome, mRNA expression, and TICK protein.
• Objective 3: Stakeholder analysis to validate the treatment targets and best method of administration
Contacts with stakeholders:
The team has established contacts to neuropathic pain patient associations in Italy and Europe (ISAL, IASP, PAE-EU, European Pain Federation) to better understand the real needs and get a more direct view of the problem.
The team contacted the following companies: for preclinical testing Pharmaseed (Israel) and ANS Biotech (France) were contacted and with the latter an agreement was reached after some interesting meetings to plan and carry out an initial toxicity and efficacy study of the technology.
Regarding the establishment of clinical protocols and analysis at the regulatory level, the team contacted Research Professional (RP) that is a leading Contract Research Organization (CRO) founded in 2014 and based in Hungary; for strategy, business support, analysis of risks and market analysis the team contacted Day One, a deep-tech Innovation studio based in Rome (Italy).
• Objective 4: Price and commercialization strategy by studying a cost-benefit analysis based on pre-clinical results and stakeholders’ feedback
Swot analysis: A swot analysis was conducted to identify strengths, weaknesses, opportunities, and threats related to the aim to create a startup (Fig.1). The analysis identified as a high risk factor the concern of the patients on gene therapy but that the benefits are definitively to the advantage of the technology.
The team intends to spin-off from the University creating a new group of young and skilled young people with an attitude for technology transfer. The team has already acquired as an important asset for newCO Chiara Mercurio, a student of the Industrial PhD degree.
• Objective 5: Improve the freedom to operate analysis and protect the IP
A patent (PCT WO2023042139) has been published to protect the core of the technology that is “inhibition of neuronal activity by means of potassium ion channels”. The patent covers TICK technology.
• Objective 6: Carry out a Consolidate the business model, set up the product value chain and prepare the business plan
The team reviewed the Business Model and drafted a Business Model Canvas (Fig. 2) in which the value proposition, customers, development channels, business costs and revenue stream were identified in detail.
In addition, a risk-adjusted net present value (RA-NPV) has been described (Fig.3).
• Objective 1: Definition of pre-clinical protocol based on current EMA regulatory indications
Once the analgesic efficacy of TICK in vivo has been confirmed, we started a systematic verification of issues related to the preclinical protocol. These include the method of administration and the type of viral vector, the experimental model to be tested, temperature application, the duration of the analgesic effect, possible side effects, long-term virus permanence and biodistribution, dose regimen, etc. All the above issues which are inherent to gene therapy nature of the treatment, have emerged at every meeting with stake holders, investors, and mentors.
• Objective 2: Execution of ex vivo and in vivo functional tests, in line with the designed protocol for pre-clinical
A CRO (ANS Biotech) was identified to perform viral infection experiments and tests to evaluate the efficacy of TICK in vivo, following GLP (Good Laboratory Practice) practices. The neuropathic pain model we selected is the Chronic Constriction Injury Model (CCI), in the future we plan to test others, such as the diabetic and chemotherapy pain models, both available at the same CRO. The two selected viruses, AAV-PHP.S and MaCPNS2, will be injected intravenously, and one month after injection, functional tests will be started to evaluate the efficacy of the channel to reduce pain in the animal. The study will be divided into 5 experimental groups, each consisting of 5 animals: - vehicle-treated (control GFP virus without transgene) - low dose - intermediate dose - high dose - positive reference-treated group (Morphine) Different timepoints, short and long term, have been identified to also evaluate expression efficiency, toxicity and dose regimen.
Analyses of biodistribution and stability of the transgene: The tested mice will be kept in breeding and sacrificed three months after the end of the functional tests to collect the biological materials (organs, tissues, blood, etc.) necessary for the subsequent analyses of toxicity, biodistribution and stability of the transgene. The latter will consist of verifying the presence of the viral genome, mRNA expression, and TICK protein.
• Objective 3: Stakeholder analysis to validate the treatment targets and best method of administration
Contacts with stakeholders:
The team has established contacts to neuropathic pain patient associations in Italy and Europe (ISAL, IASP, PAE-EU, European Pain Federation) to better understand the real needs and get a more direct view of the problem.
The team contacted the following companies: for preclinical testing Pharmaseed (Israel) and ANS Biotech (France) were contacted and with the latter an agreement was reached after some interesting meetings to plan and carry out an initial toxicity and efficacy study of the technology.
Regarding the establishment of clinical protocols and analysis at the regulatory level, the team contacted Research Professional (RP) that is a leading Contract Research Organization (CRO) founded in 2014 and based in Hungary; for strategy, business support, analysis of risks and market analysis the team contacted Day One, a deep-tech Innovation studio based in Rome (Italy).
• Objective 4: Price and commercialization strategy by studying a cost-benefit analysis based on pre-clinical results and stakeholders’ feedback
Swot analysis: A swot analysis was conducted to identify strengths, weaknesses, opportunities, and threats related to the aim to create a startup (Fig.1). The analysis identified as a high risk factor the concern of the patients on gene therapy but that the benefits are definitively to the advantage of the technology.
The team intends to spin-off from the University creating a new group of young and skilled young people with an attitude for technology transfer. The team has already acquired as an important asset for newCO Chiara Mercurio, a student of the Industrial PhD degree.
• Objective 5: Improve the freedom to operate analysis and protect the IP
A patent (PCT WO2023042139) has been published to protect the core of the technology that is “inhibition of neuronal activity by means of potassium ion channels”. The patent covers TICK technology.
• Objective 6: Carry out a Consolidate the business model, set up the product value chain and prepare the business plan
The team reviewed the Business Model and drafted a Business Model Canvas (Fig. 2) in which the value proposition, customers, development channels, business costs and revenue stream were identified in detail.
In addition, a risk-adjusted net present value (RA-NPV) has been described (Fig.3).