Periodic Reporting for period 1 - NatProLub (NATURE-INSPIRED PROPHYLACTIC LUBRICANTS AGAINST HIV-1 AND HSV-2)
Periodo di rendicontazione: 2024-01-01 al 2024-12-31
Sexually transmitted infections (STIs) affect millions daily worldwide, disproportionately affecting women at twice the risk. Inconsistent condom use contributes to this alarming rate. Tremendous efforts are made to develop condom-free prophylaxis and to treat infected individuals, creating a significant burden on society and healthcare. Importantly, these efforts lead to antimicrobial resistance development. Currently, only two vaccines (HBV and HPV) exist. HIV and HSV are major STI epidemics. 40 million people worldwide are living with HIV. Individuals who are carriers of HSV have a fourfold increased risk of contracting HIV.
Condom-free prophylaxis against HIV have been developed, such as drug-based PrEP, which can cost EURO 28,000 per year without insurance. Therefore, people who are most at risk in low-income countries do not have access to it. In addition, levels of protection among women have been inconsistent, ranging from −49 to 76%, and side effects and drug resistance can occur. Currently, there are no products on the market with clinically validated claims for lubricants with prophylactic activity against STIs.
Nature offers valuable insights into viral protection, such as epithelial mucus coatings and dipeptides in HIV-infected Elite Controllers. The human vagina, lined with cervicovaginal mucus (CVM), scavenges HIV under acidic conditions. However, CVM pH turns neutral during the menstrual cycle and post-ejaculation, reducing its protective capacity. In addition, sialic acids on mucins of CVM are degraded in individuals infected with bacterial vaginosis (BV); here, the bacteria produce sialidases, which entail the degradation of CVM.In HIV-infected Elite Controllers, certain dipeptides enriched in blood plasma and feces, compared to HIV-1 progressors and HIV-negative individuals, act as inhibitors of HIV replication in infected cells, without antiretroviral therapy.
NatProLub aims to harness these mechanisms to develop lubricants for effective HIV and HSV prophylaxis, and even broader STIs, where natural mechanisms fall short, as an alternative or complement to condoms, and addressing gender imbalances in sexual health and avoiding the risk of developing antimicrobial resistance.
We establish protocols to extract high-quality mucins from various sources and develop innovative gels that mimic natural mucus, offering enhanced infection prophylactic efficacy when used as lubricate. These gels transition between states, liquefying during intercourse to provide lubrication and rapidly solidifying at rest to trap and immobilise viruses, facilitating their removal through natural excretion. Additionally, we enrich these gels with antiviral agents that can be released to penetrate the mucus barrier. These antivirals aim to inhibit HIV replication during the acute phase of infection, targeting any escaped virus. Safety and antiviral efficacy and antiviral mechanisms are rigorously evaluated using various models, including non-human primates.
Condom-free prophylaxis against HIV have been developed, such as drug-based PrEP, which can cost EURO 28,000 per year without insurance. Therefore, people who are most at risk in low-income countries do not have access to it. In addition, levels of protection among women have been inconsistent, ranging from −49 to 76%, and side effects and drug resistance can occur. Currently, there are no products on the market with clinically validated claims for lubricants with prophylactic activity against STIs.
Nature offers valuable insights into viral protection, such as epithelial mucus coatings and dipeptides in HIV-infected Elite Controllers. The human vagina, lined with cervicovaginal mucus (CVM), scavenges HIV under acidic conditions. However, CVM pH turns neutral during the menstrual cycle and post-ejaculation, reducing its protective capacity. In addition, sialic acids on mucins of CVM are degraded in individuals infected with bacterial vaginosis (BV); here, the bacteria produce sialidases, which entail the degradation of CVM.In HIV-infected Elite Controllers, certain dipeptides enriched in blood plasma and feces, compared to HIV-1 progressors and HIV-negative individuals, act as inhibitors of HIV replication in infected cells, without antiretroviral therapy.
NatProLub aims to harness these mechanisms to develop lubricants for effective HIV and HSV prophylaxis, and even broader STIs, where natural mechanisms fall short, as an alternative or complement to condoms, and addressing gender imbalances in sexual health and avoiding the risk of developing antimicrobial resistance.
We establish protocols to extract high-quality mucins from various sources and develop innovative gels that mimic natural mucus, offering enhanced infection prophylactic efficacy when used as lubricate. These gels transition between states, liquefying during intercourse to provide lubrication and rapidly solidifying at rest to trap and immobilise viruses, facilitating their removal through natural excretion. Additionally, we enrich these gels with antiviral agents that can be released to penetrate the mucus barrier. These antivirals aim to inhibit HIV replication during the acute phase of infection, targeting any escaped virus. Safety and antiviral efficacy and antiviral mechanisms are rigorously evaluated using various models, including non-human primates.
We have utilised a standardised laboratory purification process for porcine gastric mucin (PGM) for further purifying commercial bovine submaxillary mucin (BSM), resulting in significantly improved purity. To further improve the purity of lab-extracted PGM, we developed and tested two distinct strategies. These approaches involved introducing denaturing or reducing agents at specific stages of the purification cascade. We are currently characterising the structural integrity and functional properties of the purified mucins.
We have developed a range of gel formulations using commercial BSM and PGM, which are being characterised to assess their properties, antiviral efficacy in vitro, and mechanisms of action. These gel formulations are also being evaluated for their spreadability and retention in vaginal-mimicking environments through rheological modelling. An iterative approach is being employed to optimise the gel formulations by analysing the correlation between their properties and antiviral efficacy. Based on these assessments, crosslinking reactions will be adjusted as needed to develop the best-performing gel formulations, advancing them towards planned in vivo evaluation.
In parallel, we are generating mucin variants, characterising them using various approaches, and studying the binding mechanisms between mucin and viral particles. Additionally, we are developing droplet microfluidics to reconstruct human vaginal biopsies into multicellular microspheroids containing epithelial and tissue-resident immune cells, enabling further detailed in vitro assessments.
Comprehensive plans are underway to use in vivo models to evaluate the spreading, retention, and toxicological, immunological, and prophylactic efficacy of the most promising gel candidate.
We have been and continuously engage in communicating the NatProLub with key stakeholders, including scientists, healthcare and industry partners, policymakers, and the public through targeted outreach efforts to maximise the impact. We will exploit the translation of the research findings.
We have developed a range of gel formulations using commercial BSM and PGM, which are being characterised to assess their properties, antiviral efficacy in vitro, and mechanisms of action. These gel formulations are also being evaluated for their spreadability and retention in vaginal-mimicking environments through rheological modelling. An iterative approach is being employed to optimise the gel formulations by analysing the correlation between their properties and antiviral efficacy. Based on these assessments, crosslinking reactions will be adjusted as needed to develop the best-performing gel formulations, advancing them towards planned in vivo evaluation.
In parallel, we are generating mucin variants, characterising them using various approaches, and studying the binding mechanisms between mucin and viral particles. Additionally, we are developing droplet microfluidics to reconstruct human vaginal biopsies into multicellular microspheroids containing epithelial and tissue-resident immune cells, enabling further detailed in vitro assessments.
Comprehensive plans are underway to use in vivo models to evaluate the spreading, retention, and toxicological, immunological, and prophylactic efficacy of the most promising gel candidate.
We have been and continuously engage in communicating the NatProLub with key stakeholders, including scientists, healthcare and industry partners, policymakers, and the public through targeted outreach efforts to maximise the impact. We will exploit the translation of the research findings.
To ensure further uptake and success, the following needs are identified:
Further research and demonstration: Additional testing is required to validate safety and efficacy.
Commercialization Support: Intellectual property protection, branding, and market positioning are crucial to secure a competitive edge and build trust among consumers and healthcare providers.
Access to markets and finance: Partnerships and funding are needed for commercialisation and scalability.
Regulatory support: Collaboration with regulatory bodies to establish standards for product approval and integration into existing healthcare systems will facilitate market readiness.
Internationalisation: Expanding to global markets through collaborations can maximise impact.
Further research and demonstration: Additional testing is required to validate safety and efficacy.
Commercialization Support: Intellectual property protection, branding, and market positioning are crucial to secure a competitive edge and build trust among consumers and healthcare providers.
Access to markets and finance: Partnerships and funding are needed for commercialisation and scalability.
Regulatory support: Collaboration with regulatory bodies to establish standards for product approval and integration into existing healthcare systems will facilitate market readiness.
Internationalisation: Expanding to global markets through collaborations can maximise impact.