Overview
Although we have only conducted preliminary verification of the NanoDisguiser concept in the laboratory, our ultimate goal is to develop related products. Through extensive consultations and literature review, we envisioned a drug to assist in the treatment of viral infections, taking HIV infection as an example. We have considered issues that need attention, such as preclinical validation, and hope to promote the introduction of this innovative drug.
Figure 1: Our 5 stages to taking our venture from its current stage to our desired end goal.
Product Introduction
Based on our designed NanoDisguiser, a platform technology that can help combat multiple viral infections, we have taken HIV as an example to develop a drug that can help treat HIV infection, due to the fact that the membrane fusion mechanism of HIV infecting human cells is typical and representative.
The product is primarily composed of antiviral nanodiscs and uses PBS as the buffer component. Before use, the product should be diluted with PBS buffer to the required concentration[1].
Since HIV spreads through the bodily fluids of infected individuals, with the highest viral load in the blood after infection, we adopted intravenous injection as the drug delivery method to ensure direct and efficient action at the lesion site. During the acute phase of HIV infection, the concentration of circulating CD4+T cells in patients significantly decreases, and the level of free virus increases exponentially[2]. Therefore, we hope that our designed product can effectively reduce the amount of free virus in the blood during the acute infection phase, protecting T cells from further damage.
Our product is expected to show synergistic potential when used in combination with existing drugs. For example, by loading the HIV-1 Env V3 tip region-neutralizing antibody KD-247 into the nanodiscs, the interaction between the CD4 receptor on the immunonanodiscs and gp120 exposes the antibody binding site on gp120, allowing the antibody to easily approach gp120[3], potentially providing better therapeutic effects. Nanodiscs can also be used to carry gp41 immunotoxins (such as 7B2-dgA), where interactions between the nanodiscs and the virus induce conformational changes in gp120, potentially increasing the virus's sensitivity to gp41 toxins[4]. Studies have also shown that nanodiscs can significantly enhance the delivery efficiency and targeting of antiretroviral drugs, including tenofovir[5]. When used in combination with immunonanodiscs, this system is expected to protect uninfected cells in circulation while inhibiting HIV replication in already infected cells, providing dual protection. Additionally, we envision using immunonanodiscs to stabilize the hydrophobic interleukin-2 (IL-2) and achieve sustained release in vivo, promoting T cell proliferation and activation[6], thereby enhancing anti-HIV efficacy.
Figure 2: Nanodisc-based Drug
Nanodiscs create a highly stable environment for membrane proteins, maintaining their biological activity and significantly improving their solubility in aqueous solutions. Since HIV surface Env receptors are numerous, neutralizing antibodies need to block a large number of Envs to exhibit antiviral activity. In contrast, the antiviral activity of immunonanodiscs does not decrease with the number of Env[1], highlighting their efficient antiviral capability. In summary, our product opens up new pathways in HIV treatment, showing extremely broad application prospects.
Pre-Clinical Testing
Although we have validated the effectiveness of NanoDisguiser in vitro, there is still a significant distance before it can be used as a clinical drug. Firstly, we need to conduct a series of preclinical experiments to test the efficacy of NanoDisguiser in vivo. At this stage, we mainly consider two major issues: whether the drug is therapeutically safe and whether the therapeutic effect meets expectations.
Currently, the most commonly used animal model for preclinical testing of AIDS drugs is the humanized mouse model with an immune system. This type of mouse model somewhat simulates a person with an intact immune system and can be used in studies on the pathogenesis and drug evaluation of AIDS. The preparation of the humanized AIDS mouse model requires tail vein injection of CD34+ hematopoietic stem cells, followed by infection with the HIV virus. By detecting indicators such as the proportion of human cells in peripheral blood, spleen, and bone marrow, as well as the HIV content in mesenteric lymph nodes and peripheral blood, the success of the mouse model construction can be verified[7].
To evaluate the therapeutic effect of the drug, we will conduct a series of control experiments, including blank control, comparison with commonly used clinical drugs, and comparisons before and after the treatment period. To assess the therapeutic safety of NanoDisguiser, we will track and record various physical indicators of three groups of mice during the treatment period, such as body weight, behavioral characteristics, cognitive function, liver function, etc. Additionally, we will collect blood samples from each group of mice during the treatment process to monitor inflammation levels and HIV markers.
Furthermore, the preclinical mouse experiments we conduct can also be used to test various key indicators required for NanoDisguiser to further become a drug: usage dosage, frequency of administration, treatment period, etc.
Clinical Trials
After our NanoDisguiser drug passes preclinical testing, we will continue to focus on clinical trials to promote its eventual market release.
Our country has a series of requirements for clinical trials of AIDS drugs. To this end, we consulted the "Technical Guidelines for Clinical Trials of Anti-HIV Infection Drugs" issued by the National Medical Products Administration, hoping to obtain more guidance. First, we need to strictly follow the standards to prepare a clinical trial protocol. Then we need to sequentially conduct pharmacokinetic tests in healthy individuals, drug interaction studies, pharmacodynamic studies in HIV-infected individuals, dose studies, and confirmatory studies. Among them, good randomized controlled trials and patient recruitment standards are very important. For treatment-naive or non-resistant patients, it is necessary to design randomized, blinded, standard treatment-controlled non-inferiority trials; for patients with multiple drug resistance, new drugs or placebos need to be added to the background treatment for randomized, placebo-controlled superiority trials. In addition, there are certain rules for the selection of control drugs.
At the same time, we will complete these rigorous and systematic designs through extensive communication and cooperation with hospitals and pharmaceutical companies. The cost of bringing a drug to market is undoubtedly huge, and our team will also strive to obtain support from all sectors of society, including government agencies.
Phase I-III Clinical Trial
Figure 3: Steps and purposes of phase 1, phase 2 and phase 3 clinical trials.
Our Target Audience
1. The Current Target Audience
As a broad-spectrum antiviral therapy devoid of drug resistance and minimal side effects, NanoDisguiser theoretically offers a therapeutic solution for all enveloped viral infections. However, in light of the actual market demands, we have strategically decided to initially target severe influenza patients and HIV-positive individuals. Given the annual surge of 3 to 5 million severe influenza cases and 1.3 million new HIV infections globally, we anticipate serving a population of approximately 6 million worldwide.
2. The Future Target Audience
At the end of 2019, COVID-19 swept across the globe, infecting over 760 million people. The rapid mutation of viral strains and their heightened infectiousness pose formidable challenges to current antiviral treatments. Thanks to its relatively straightforward development principle, NanoDisguiser can swiftly adapt to future pandemic outbreaks caused by enveloped viruses, leveraging the understanding of how these viruses infiltrate cells. Furthermore, NanoDisguiser boasts the capability to combat multiple viral subtypes, positioning it as a potential frontrunner among antiviral medications in the face of the next global health crisis. We are confident that NanoDisguiser will serve as the first line of defense for humanity, fortifying our resilience against viral threats.
NDA & Approval and Launch
Prepare NDA documents:
Organize all clinical trial data and study reports.
Prepare Chemistry, Manufacturing and Controls (CMC) information for the drug.
Prepare drug inserts including indications, dosage, side effects, warnings and precautions.
Prepare other supporting documents such as non-clinical pharmacology and toxicology studies, clinical study reports, statistical analysis reports, etc.
Submission of NDA:
Submit the NDA to the drug regulatory agency (e.g., U.S. Food and Drug Administration FDA).
Pay the application fee.
Provide all necessary documents and data.
Regulatory Agency Review:
The regulatory agency reviews the NDA to assess the safety, efficacy, and quality of the drug.
The regulatory agency may request additional information or conduct additional studies.
On-site inspection:
The regulatory agency may conduct an on-site inspection of the manufacturing facility to ensure that the manufacturing process is in compliance with Good Manufacturing Practices (GMP).
Approval Process:
If the review is satisfactory, the regulatory agency will approve the NDA.
If there are problems, the regulator may deny approval, request additional studies or provide additional information.
Post-market monitoring:
Even if a drug is approved, post-marketing surveillance (Phase IV clinical trials) is required to continuously assess the long-term safety and efficacy of the drug.
Pharmaceutical companies are required to report any adverse events to regulators and regularly update safety information about the drug.
Regulatory and Compliance & IP Protection
Ongoing Compliance:
Pharma companies must ensure that the manufacturing and distribution of the drug is continuously compliant with regulatory requirements.
Market Access:
Once approval has been granted, a pharmaceutical company can begin to market the drug.
IP Protection:
Please view Entrepreneurship page to learn more.
Our Features
The nanodisc technology that directly mediates viral uncoating offers an innovative approach to viral therapy. By directly acting on the virus, the nanodisc induces the shedding of the viral envelope, thus disrupting the virus's structure and rendering it incapable of continuing to infect host cells. The uncoated virus loses its protective shell and becomes easily degradable by the host's defense mechanisms, thereby completely losing its infectivity. The pores formed by the fusion of the virus and the nanodisc may play a crucial role in reducing infectivity by providing a direct passage into the viral envelope from the environment.
1. Reduction of Drug Resistance
Antiviral drugs targeting the viral envelope not only exhibit broad-spectrum antiviral activity but also are less likely to induce resistance since the envelope originates from the host cell membrane, which is not under the direct control of the virus. Any potential mutations that might reduce receptor-mediated membrane fusion to confer resistance to the nanodisc would also eliminate the virus's virulence.
2. Non-Dependence Mechanism
This approach does not rely on specific stages of the viral lifecycle and can act at various stages of viral infection.
3. Stability
Nanodiscs are made of biocompatible materials such as phospholipids and cholesterol, reducing toxicity and immune reactions during long-term use. The structure of the nanodisc also protects the stability and activity of receptor proteins, extending their effective period in the body.
4. High Specificity Recognition
The surface of the nanodisc is loaded with specific receptor proteins that can efficiently recognize and bind to the envelope proteins on the virus surface, avoiding interference with the normal metabolic activities of cells in the body.
5. Broad Spectrum
On one hand, by targeting the process of viral entry into cells, nanodiscs can combat various viral subtypes; on the other hand, by loading different receptor proteins, nanodiscs can also be applied to the treatment of various enveloped viruses (such as HIV, HBV, HCV, influenza virus, etc.).
References
[1] Kong B, Moon S, Kim Y, Heo P, Jung Y, Yu S-H, Chung J, Ban C, Kim YH, Kim P, Hwang BJ, Chung W-J, Shin Y-K, Seong BL, Kweon D-H. Virucidal nano-perforator of viral membrane trapping viral RNAs in the endosome. Nature Communications. 2019;10(1):185. doi: 10.1038/s41467-018-08138-1.
[2] Clarke C, Pankavich S. Three-stage modeling of HIV infection and implications for antiretroviral therapy. Journal of Mathematical Biology. 2024;88(3):34. doi: 10.1007/s00285-024-02056-1.
[3] Kobayakawa T, Konno K, Ohashi N, Takahashi K, Masuda A, Yoshimura K, Harada S, Tamamura H. Soluble-type small-molecule CD4 mimics as HIV entry inhibitors. Bioorg Med Chem Lett. 2019;29(5):719-23. Epub 2019/01/23. doi: 10.1016/j.bmcl.2019.01.011; PMID: 30665681.
[4] Pincus SH, Stackhouse M, Watt C, Ober K, Cole FM, Chen HC, Smith Iii AB, Peters T. Soluble CD4 and low molecular weight CD4-mimetic compounds sensitize cells to be killed by anti-HIV cytotoxic immunoconjugates. J Virol. 2023;97(10):e0115423. Epub 2023/09/29. doi: 10.1128/jvi.01154-23; PMID: 37772823; PMCID: PMC10617435.
[5] Garcia CR, Rad AT, Saeedinejad F, Manojkumar A, Roy D, Rodrigo H, Chew SA, Rahman Z, Nieh MP, Roy U. Effect of drug-to-lipid ratio on nanodisc-based tenofovir drug delivery to the brain for HIV-1 infection. Nanomedicine (Lond). 2022;17(13):959-78. Epub 2022/06/02. doi: 10.2217/nnm-2022-0043; PMID: 35642549; PMCID: PMC9583757.
[6] Mitsuyasu RT. The potential role of interleukin-2 in HIV. Aids. 2001;15 Suppl 2:S22-7. Epub 2001/06/27. doi: 10.1097/00002030-200102002-00005; PMID: 11424973.
[7] Cheng L, Yu H, Li G, Li F, Ma J, Li J, Chi L, Zhang L, Su L. Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection. JCI Insight. 2017;2(12). Epub 2017/06/15. doi: 10.1172/jci.insight.94366; PMID: 28614789; PMCID: PMC5470878.
