Intranasal Delivery

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Intranasal Delivery

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Intranasal COVID-19 therapeutic shows promise in preclinical trials

5/20/21

https://www.news-medical.net/news/20210 ... rials.aspx


The coronavirus disease 2019 (COVID-19) pandemic continues to rage in many countries over a year after it first emerged in Wuhan, China. New and more infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are emerging, with concern mounting over their natural and vaccine-induced immunity evasion potential.

Rapid development and deployment of non-invasive therapeutic measures to prevent infection by all SARS-CoV-2 variants could complement the currently ongoing vaccination efforts. It will also help put an end to this unprecedented COVID-19 pandemic.

Novel intranasal therapeutic option to target SARS-CoV-2 RNA using antisense oligonucleotides

Researchers from the US and Denmark recently described a novel therapeutic option that targets the SARS-CoV-2 ribonucleic acid (RNA) using locked nucleic acid antisense oligonucleotides (LNA ASOs). They identified an LNA ASO that binds to the 5’ leader sequence of SARS-CoV-2 ORF1a/b. This disrupts a highly conserved stem-loop structure with nanomolar efficacy and inhibits viral replication in host cells. The team’s study has been released as a preprint on the bioRxiv* server.

Antisense therapy is currently used in clinical treatment for a range of different diseases, including cytomegalovirus retinitis (Fomivirsen), Duchenne muscular dystrophy (Eteplirsen), and Spinal Muscular Atrophy (Nusinersen).”

LNA ASOs inhibit SARS-CoV-2 replication and infection in mice and hamsters


The LNA ASO, when administered intranasally every day in the K18-hACE2 humanized COVID-19 mouse model, strongly (98-99%) suppressed viral replication in the lungs of the SARS-CoV-2-infected mice. This reveals potent prophylactic as well as treatment effects of LNA ASOs. The researchers found that the LNA ASO also inhibits viral infection in golden Syrian hamsters and is effective against all SARS-CoV-2 “variants of concern,” including B.1.427, B.1.1.7, and B.1.351, with high efficacy in both in vitro and in vivo studies.

LNA ASOs can override the challenge of viral mutations thanks to their ability to design sequences that are specifically targeted to highly conserved and key regulatory regions of the viral genome. In addition, LNA ASO cocktails that target multiple critical regions of the viral genome may further improve the efficacy of LNA ASOs as therapeutic candidates to overcome viral mutations.

Use of LNA ASOs may be a promising treatment approach to reduce the transmission of vaccine-resistant SARS-CoV-2 variants


The continuous evolution of SARS-CoV-2 and the emergence of new, more dangerous variants with increased morbidity and mortality poses a huge challenge to reaching “herd immunity.” Traditional methods of drug screening and vaccine development are time-consuming and may not be able to match the speed with which drug- or vaccine-resistant SARS-CoV-2 variants are emerging. Hence there is a compelling need for alternative approaches to the rapid development of drugs that effectively act against all variants of concern.

Based on the findings of the study, the authors conclude that LNA ASOs that target SARS-CoV-2 can be a promising therapeutic approach to reduce the transmission of new SARS-CoV-2 variants that are partially resistant to monoclonal antibodies and vaccines. These LNA ASOs could be administered intranasally for prophylaxis or by lung delivery using a nebulizer to decrease symptoms in severe COVID-19 patients.

LNA ASOs are chemically stable compounds that can be stored for use during future pandemics

Given the relatively small size of RNA viral genomes and the ability to rapidly sequence any genome using next-generation sequencing techniques, anti-viral LNA ASOs can be designed and screened in a fast and efficient manner that allows rapid response to all kinds of health crises.

LNA ASOs are chemically stable compounds and can be modified to target various viral RNA sequences. They can be more impactful in remote areas where vaccine distribution is challenging, and they could also be stockpiled for use during other pandemics caused by coronaviruses that may threaten humanity in the future.

" In conclusion, we have identified an intranasally delivered LNA ASO targeting the 5’ leader sequence as a viable therapeutic approach for preventing or treating SARS-CoV-2 infections, including those caused by variants of concern, indicating that LNA ASOs can be pursued as lead candidates for the treatment of COVID-19.”

*Important Notice


bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:


Chi Zhu et al. (2021). An intranasal ASO therapeutic targeting SARS-CoV-2. bioRxiv preprint server. doi: https://doi.org/10.1101/2021.05.17.444397, https://www.biorxiv.org/content/10.1101 ... 7.444397v1
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Intranasal Delivery

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Could the intranasal route be an alternate avenue of COVID-19 vaccination?

6/8/21


https://www.news-medical.net/news/20210 ... ation.aspx


The coronavirus disease 2019 (COVID-19) pandemic has exacted an enormous toll on public health and the economy in many parts of the world. The causal agent of the pandemic is the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many vaccine candidates have been developed, but the delivery of vaccines is presently limited to intramuscular vaccination (also known as ‘jabs’ or ‘shots’).

A new study has been published in the journal Vaccines that summarizes the history of vaccines, reviews the current progress in COVID-19 vaccine technology, and discusses the status of intranasal COVID-19 vaccines as a potential pathway to immunization.

Decoding the body’s immune responses to SARS-CoV-2 infection is essential to design new vaccines. SARS-CoV-2 binds to target cells through the angiotensin-converting enzyme (ACE2) receptor. Once SARS-CoV-2 enters the body, an array of pattern recognition receptors (PRRs) sense viral infection. This, subsequently, brings about phosphorylation of Interferon Regulatory Factor 3 (IRF3) and IRF7. IRF3 and IRF7 regulate type I interferon (IFN) and interferon-stimulated genes (ISGs).

SARS-CoV-2 induces low-level type I and II IFNs and also brings about the release of proinflammatory cytokines and chemokines. The activation of the immune response is crucial to fight the infection. But, the overproduction of pro-inflammatory cytokines, also known as a “cytokine storm,” has the potential to cause tissue damage and is often observed in critically ill patients.

COVID-19 patients show lymphopenia, with decreased CD4 T, CD8 T, and B cells, and the degree of lymphopenia is much more severe and persistent than other viral infections. CD8 T cells from COVID-19 patients express more inhibitory receptors (PD-1 and TIM-3), and these receptors correlate with terminal differentiation and functional cell exhaustion. CD4 T cells show similar properties as CD8 T cells.

Interestingly, some individuals unexposed to SARS-CoV-2 have SARS-CoV-2-specific CD4 T cells. The CD4 T cells cross-react with common cold viruses. This protective immunity lasts 12 months, and the potential benefits of this cross-reactivity should be examined in future research.

Currently, more than 100 vaccines have already been or are being tested in clinical trials. Traditionally, vaccines are either attenuated or inactivated pathogens or protein subunits from the pathogen. Attenuating strains can take years, and there are also safety concerns. To alleviate these concerns, pathogens inactivated by heat, radiation, or chemical treatment have been developed as vaccines. Attenuated pathogens can become more virulent, and people with comorbidities might be susceptible to the attenuated strain. Despite these limitations, in the current context, live attenuated vaccines (COVI-VAC and Codagenix) have been developed, and they have the advantage that they generally do not require adjuvants. In case adjuvants are required, aluminum hydroxide is commonly used. BBIBP-CorV and Corona Vac are two examples of such vaccines requiring the adjuvant.

Protein subunit vaccines contain viral proteins and are considered safer. However, they require adjuvants and booster shots (NVX CoV2373 and ZF2001). Viral vectors, including adenoviruses, have been used successfully to produce vaccines against pathogens such as the Ebola virus. However, some patients may have immunity against the viral vectors.

To avoid pre-existing immunity, AstraZeneca and Oxford used a chimpanzee adenovirus to deliver the gene for the S protein (ChAdOx1, AZD1222). The pandemic has led to the development of a host of DNA and RNA vaccines. Antigen-coding DNA is delivered intradermally or intramuscularly and electroporated for effective delivery into cells. RNA vaccines have been at the forefront of the current COVID-19 pandemic. mRNA-1273, which is currently in use as the “Moderna” vaccine, has shown an efficacy of 94.1%. Pfizer and BioNTech produced BNT162b2, two doses of which showed 95% protection.

Most vaccines are injected intramuscularly. The route of immunization may induce different mechanisms of protection. Also, different vaccine platforms, such as mRNA, DNA, or an adenoviral vector vaccine, bring about varied efficacy.

Recent studies have indicated that local vaccination might be more effective than other vaccination methods for mucosal infection. Mucosal vaccination does not involve needles and, hence, is safer as it eliminates the risk of blood-borne infections. There are some limitations of mucosal vaccination, though. Little is known about mucosal immunity. Antigens could be destroyed by proteolytic enzymes making their absorption difficult.

Additionally, adjuvants might be necessary, and some studies have shown that alum, which is a commonly used adjuvant, failed to IgG and IgA and recruitment of T and B cells to the mucosal area. Since SARS-CoV-2 mainly infects the upper respiratory tract, the environment of the nasal passage is important for immunity.

Many recent experiments on nasal vaccines have yielded positive preliminary results, but the results are as yet inconclusive. Although, the efficacy of intranasal vaccines may depend on the dosage or the vaccine platform; they might be an effective route to attain herd immunity because they prevent an interhuman response. Several clinical trials of intranasal vaccines, including (e.g., AdCOVID), are being conducted. More research is needed to determine the most effective route for immunization.

Journal reference:


Park, J.H. and Lee, H.K. (2021). Delivery Routes for COVID-19 Vaccines. Vaccines. 9(5). pp. 524. https://doi.org/10.3390/vaccines9050524, https://www.mdpi.com/2076-393X/9/5/524.
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Intranasal Delivery

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Researchers review the therapeutic potential of resveratrol nasal formulations in COVID-19

6/9/21


https://www.news-medical.net/news/20210 ... ID-19.aspx


In a recently published article in the journal Frontiers in Immunology, scientists have reviewed the existing literature on antiviral and anti-inflammatory efficacy of resveratrol-based inhaled formulations in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reducing coronavirus disease 2019 (COVID-19) severity.

Background

SARS-CoV-2, the causative pathogen of COVID-19, is an enveloped, positive-sense, single-stranded RNA virus with a genome size of about 30kb. Being a respiratory virus, SARS-CoV-2 primarily attacks the upper respiratory tract and causes mild respiratory complications. If this remains unresolved, the virus can spread to the lower respiratory tract and cause viral pneumonia. In severe cases, an excessively high inflammatory microenvironment (cytokine storm) together with viral pneumonia can result in respiratory failure and death.

Therapeutic benefits of resveratrol

Resveratrol is a polyphenolic compound produced in various plants. This bioactive compound possesses many health benefits, including antimicrobial, antioxidant, anti-inflammatory, and anticancer activities. There is ample evidence indicating the therapeutic benefits of resveratrol in type 2 diabetes, neurological and cardiovascular diseases, and liver, breast, colorectal, pancreatic, and prostate cancers. Moreover, studies have pointed out the antiviral efficacy of resveratrol against respiratory viruses.

Antiviral efficacy of resveratrol

Resveratrol is known to limit viral replication by inhibiting viral gene expression and protein synthesis and downregulating various signaling pathways in cells. By reducing viral replication, resveratrol subsequently prevents heightened inflammatory responses, leading to the prevention of lung injuries. The antiviral potency of resveratrol has been documented against influenza A virus, respiratory syncytial virus, human rhinovirus, and middle east respiratory syndrome coronavirus (MERS-CoV).

Anti-SARS-CoV-2 efficacy of resveratrol

Studies investigating the anti-SARS-CoV-2 activity of resveratrol reveal that the compound significantly inhibits viral replication in host cells at low micromolar concentrations. About 98% reduction in replication can be achieved by treating the cells with resveratrol after viral entry. However, pretreatment of cells with resveratrol has been found to cause a very low level of inhibition. Interestingly, some studies have shown that treatment of cells with resveratrol during viral entry can cause more than 60% reduction in viral replication, indicating that the compound has some effect on viral entry into host cells. Overall, these observations suggest that resveratrol interferes with the viral life-cycle at the early phase of infection.

Apart from direct antiviral activities, resveratrol has been found to inhibit several pathogenic pathways associated with COVID-19. These include dysregulated NLRP3 inflammasome activation, renin-angiotensin system dysfunction, and kinin−kallikrein system stimulation.

NLRP3 inflammasome and autophagy


Under physiological conditions, pathogen-induced activation of NLRP3 inflammasome leads to the production of inflammatory cytokines, which in turn facilitate the induction of adaptive immunity against the pathogen. However, an aberrant dysregulated activation of NLRP3 inflammasome can lead to the development of inflammatory disorders.

In COVID-19, SARS-CoV-2-induced inhibition of cellular autophagy and excessive production of IL-1 beta has been found to cause uncontrolled activation of NLRP3 inflammasome. Resveratrol, on the other hand, can prevent dysregulated NLRP3 inflammasome activation by inducing SIRT1 (a deacetylase) activity, promoting autophagy, and reducing inflammation.

Angiotensin converting enzyme 2 and the renin-angiotensin system

Angiotensin-converting enzyme 2 (ACE2), a component of the renin-angiotensin system, is the primary host cell protein that facilitates SARS-CoV-2 entry. However, after host cell entry, SARS-CoV-2 downregulates the expression and activity of ACE2, leading to abnormal functioning of the renin-angiotensin system and excessive production of proinflammatory and prooxidant mediators. Collectively, these events lead to the development of alveolar edema and acute lung injury. In this context, it has been hypothesized that by inhibiting SARS-CoV-2 replication, resveratrol may restore physiological functions of the renin-angiotensin system and reduce lung inflammation.

ACE2 and the Kinin−Kallikrein System


ACE2 acts on the Kinin−Kallikrein System by producing bradykinin and its metabolites. SARS-CoV-2-mediated reduction in ACE2 expression can lead to dysregulation in the Kinin−Kallikrein System and induction in the lung inflammatory microenvironment. Excessive inflammation can subsequently make the lung vasculature more susceptible to leakage and angioedema formation.

Although no direct evidence is available regarding the effect of resveratrol in inducing ACE2 expression in SARS-CoV-2-infected cells, there are studies supporting the hypothesis that resveratrol can serve as a potent adjunct anti-inflammatory agent in COVID-19 by inhibiting bradykinin-induced COX-2/PGE2 production.

Resveratrol bioavailability

Despite having potent antiviral activity, resveratrol is not a clinically suitable compound because of poor stability in aqueous solutions and low bioavailability. After oral administration, resveratrol is rapidly absorbed and extensively metabolized in the intestine and liver. As a result, only trace amounts of unaltered resveratrol remain in the plasma for biological activities.

To prevent SARS-CoV-2 infection at the early stage, a high concentration of resveratrol in the airways can be achieved by topically administering the compound through inhaled formulations. In clinical trials, a nasal spray formulation comprising carboxymethylated glycan and resveratrol has shown good efficacy in reducing the severity and recurrence of upper respiratory tract infections of viral origin. It has been suggested that the nasal spray formulation provides antiviral protection mainly by upregulating toll-like receptor 2 (TLR2) expression.

Since SARS-CoV-2 primarily transmits via respiratory droplets and attacks nasal epithelial cells, complete control over infection can be achieved by inhibiting the viral replication in the upper respiratory tract and restricting the viral propagation in the lower respiratory tract. In this context, it is highly important to conduct clinical trials to investigate the antiviral efficacy of carboxymethylated glycan and resveratrol-based nasal formulation in treating acute SARS-CoV-2 infection in COVID-19 patients.

Journal reference:

Rossi GA. 2021. Can Resveratrol-Inhaled Formulations Be Considered Potential Adjunct Treatments for COVID-19? Frontiers in Immunology. https://doi.org/10.3389/fimmu.2021.670955, https://www.frontiersin.org/articles/10 ... 70955/full.
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Intranasal Delivery

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Nose-to-brain: Nasal delivery of biopharmaceuticals to the brain

6/9/21


https://www.news-medical.net/news/20210 ... brain.aspx


Placing medications as close as possible to the site of the disease: This sounds completely believable in theory, but is unfortunately not so simple in practice. While this works well for many drugs via the bloodstream or the digestive tract, it does not apply to the brain. In this case, special protective mechanisms such as the blood-brain barrier do protect the brain and ensure that foreign substances including therapeutic agents can only reach the brain with great difficulty and to a significantly reduced extent.

However, for pathomechanisms within the central nervous system (CNS, brain and spinal cord) in particular, it is crucial that the drugs reach this organ as efficiently as possible. One example is the treatment of multiple sclerosis, a major driver of neurological disability already in young age with high socioeconomic impact.

Gentle form of administration for biopharmaceuticals through the nose

For this reason, the EU-funded joint project "N2B-patch" was launched in January 2017, in which an international consortium of eleven partners coordinated by Fraunhofer IGB set itself the task of proving a more efficient, alternative option for the therapy of multiple sclerosis. Also with the expectation that other CNS diseases may also benefit from the platform technology.

With success: the international consortium has demonstrated the proof of concept and has therefore shown that a nasal delivery system for biopharmaceuticals in the upper region of the nasal cavity via the olfactory mucosa, the regio olfactoria, is possible.

In contrast to treatment by nasal spray, which acts via the respiratory epithelium, or intravenous injection directly into the bloodstream, this innovative "nose-to-brain" approach may enable an active ingredient to bypass the path through the bloodstream and reach the brain directly. This is because the brain is separated from the nasal cavity only by the perforated ethmoid bone and a few additional cell layers, so that drugs are able to penetrate this barrier and reach the CNS directly over a short distance. Now the project ends after four and a half years.

" During our project, there were great successes to report, but also some challenges to overcome. Not least due to the Corona pandemic, which ultimately even necessitated a project extension of six months. However, all partners worked with great commitment to fulfill the work plan and achieve the project goals. At the same time, we have grown close in the consortium, and long-term partnerships have emerged that will certainly last long beyond this project - not something to be taken for granted."

- Dr. Carmen Gruber-Traub, project manager of N2B-patch at IGB

Future platform technology for a wide range of indications

The novel delivery system is so promising that a patent application is to be filed shortly. It was shown, among other things, that the formulation is stable and can thus even be stored for days and weeks at room temperature.

Since the novel system is designed to be flexible, the method may also be used in the future as a potential platform technology for other CNS diseases - for example, for the therapy of strokes and Alzheimer's disease - or even for specific cancers.

Preclinical studies convincing

"The system developed in cooperation with Beiter GmbH & Co. KG and tested by in vivo models is so gentle in its application that smelling may not be impaired in any way and no germs may enter the nose. In addition, generally no effects on the nasal microbiome were observed. Preclinical and microbiome studies have shown this," says Gruber-Traub. With the new system, it may be possible that the active ingredient could be continuously and reliably administered to the brain over a period of up to two weeks. After that, another application must be made.

However, surveys conducted by the consortium have shown that patients perceive this fact not as a burden. If repeated use also shows good tolerability by the patients, the system may also be suitable for long-term or even lifelong treatment. The system cannot be self-administered, but must be applied by a physician or trained personnel who have appropriate skill and experience. The European Multiple Sclerosis Platform (EMSP) closely accompanied the project as a partner throughout the entire duration and thus regularly involved those affected through events, campaigns or interviews.

End with symposium, but research continues

Although the new platform technology is still some time away from approval, everything is being prepared accordingly: "Work is already underway on marketing, on production in accordance with GMP (Good Manufacturing Practice) guidelines anyway, and of course the patent applications are being pushed ahead," says Gruber-Traub. "In addition, the basic research work continues even beyond this specific project, as part of the Marie Sklodowska-Curie Bio2Brain network for young scientists from around the world."

On June 17, 2021, the project will officially end with a virtual final symposium (10 a.m. to 3:30 p.m.). The event is open not only for experts from science and industry, but also patients and the interested public. During the symposium various scientific publications and short films about the novel drug delivery method that have been produced in recent years will be presented.

The program is available on the project website www.n2b-patch.eu/symposium. Interested parties can register for the free symposium via the link provided there.

Source:

Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB
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Intranasal Delivery

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New article explains the pros and cons of nasal vaccines

6/10/21


https://www.news-medical.net/news/20210 ... cines.aspx


Vaccines are mostly synonymous with needles, an efficient and effective way to provide immunity to myriad infections. As COVID-19 vaccination efforts roll out across the U.S. and the world, some experts believe that a vaccine administered through the nose could be just as effective and easier to administer. A cover story in Chemical & Engineering News, the weekly newsmagazine of the American Chemical Society, explains the pros and cons of nasal vaccines.

SARS-CoV-2, the virus that causes COVID-19, often enters the body through the nose when a person inhales. From there it encounters a network of mucosal membranes that form the body's first line of immune defense, writes Associate Editor Ryan Cross. The cells of mucus membranes create a special type of antibody, which experts say can provide both mucosal and systemic immunity when triggered by a vaccine that is sprayed into the nasal cavity. In contrast, injectable vaccines only trigger a systemic immune response. The COVID-19 vaccines currently available in the U.S. and Europe are highly effective, but there is not enough supply to inoculate the entire world. So, an intranasal version could help offset the disparity, on top of being easier to use.

However, the mucosal immune system is difficult to study, and intranasal vaccines have not generated much interest in recent years. Only one intranasal vaccine (AstraZeneca's FluMist) has come to market in the U.S., but its higher cost and mixed results compared to the typical flu shot have made it unpopular. In addition, the way the vaccine is administered means that a patient could sneeze out part of it before it's absorbed by the body, making it unclear how much of the dose a person gets.

Despite these challenges, scientists and biotech companies are still working to make intranasal vaccines for respiratory illnesses. The pandemic has provided an opportunity to run clinical trials, and at least one company hopes to manufacture and distribute nasal doses of the COVID-19 vaccine by the end of the year.


Source:

American Chemical Society
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