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1.
Infect Disord Drug Targets ; 2022 Apr 19.
Article in English | MEDLINE | ID: covidwho-1809167

ABSTRACT

More than 200 viruses infect humans but drugs are available for fewer than ten. To narrow the gap between 'bugs and drugs', a paradigm shift is required. The "one drug, one bug" approach should be supplemented by the "one drug, multiple bugs" strategy such that the host is targeted rather than the virus. The revolutionary viral superinfection therapy (SIT) activates the antiviral interferon gene natural defense system of host cells from within by an attenuated infectious bursal disease virus (IBDV) that releases its double-stranded RNA (dsRNA) cargo inside the cells. An attenuated IBDV vaccine strain has resolved hepatitis A virus infection (HAV) in marmoset monkeys and hepatitis B and C virus infections (HBV/HCV) in 42 patients with acute HBV or HCV. SIT was also safe and effective in four hepatically decompensated, chronically infected HBV and HCV patients. The proof-of-principle of SIT was demonstrated first in a 43-year-old male patient with COVID-19. Three doses of IBDV (3x106 IU) alleviated most of his COVID-19 symptoms, even the sense of smell returned within a week. Two additional COVID-19 patients responded similarly to oral treatment with IBDV. Furthermore, a severe herpes zoster ophthalmicus with orbital edema was healed within few days by combination of acyclovir and 7 doses IBDV (7x106 IU). IBDV is simple to manufacture and will be affordable even in resource limited settings. Acid resistant IBDV can be orally administered in an outpatient setting providing the greatest ease of dosing and the highest chance of patient compliance. Under an Emergency Use Authorization, the broad-based IBDV drug candidate could be tested immediately in clinical trials and rapidly distributed to millions of early-stage patients with COVID-19. The German Paul Ehrlich Institute supports such a phase I safety study for persons acutely infected with SARS­CoV-2. An expert team of the US National Institutes of Health-sponsored ACTIV public-private partnership came to the conclusion that the IBDV drug candidate shows merit as a potential treatment for COVID-19 and an FDA approved clinical trial is in the pipelines in Los Angeles.

2.
Topics in Antiviral Medicine ; 29(1):134-135, 2021.
Article in English | EMBASE | ID: covidwho-1250229

ABSTRACT

Background: SARS-CoV-2 is a single-stranded positive-sense RNA virus that utilizes a negative-sense subgenomic (sg)RNA intermediates for viral protein synthesis. We developed a synthetic RNA (“hijack RNA”) that is designed to be recognized by SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Upon recognition, hijack RNA is transcribed into diphtheria toxin fragment A (DT-A), to induce death specifically in infected cells, which could be a potential treatment(Fig 1A). Methods: Adeno-associated virus (AAV) was packaged with a novel vector expressing our SARS-CoV-2 hijack RNA, which contains reverse complementary strand of DT-A cDNA, flanked between secondary structures of SARS-CoV-2 sgRNA. Vero, Calu3 and HepG2 cells that were uninfected or infected with SARS-CoV-2 USA-WA1/2020 strain at 0.1 MOI, were transduced with test or GFP (control) AAVs. Uninfected jurkat, HEK and BHK-21 cells were also transduced with test AAV to assess off-target effects of hijack RNA. Cell death and viability were evaluated daily by FACS and automated cell count. The same experiments were repeated on SARS-CoV-2 RdRp expressing Vero and HepG2 cell lines to validate hijack RNA's specificity to RdRp. SCID mice were subcutaneously injected with HepG2-SARS-CoV-2-FLuc cells to establish an in vivo bioluminescent SARS-CoV-2 infection model. Mice were treated with test AAV two weeks after xenotransplantation. Infected cell killing was monitored by in vivo imaging on IVIS. Results: SARS-CoV-2 infection was eradicated from Vero, Calu3 and HepG2 cultures within 48h after test AAV transduction, confirmed by FACS analysis, cell proliferation assays and the absence of CPE in cell imagery(Fig 1B). Test AAV, or presence of hijack RNA, had no effect on uninfected cells(Fig 1C). Similar results were observed in RdRp expressing cell lines, confirming the hypothesized mechanism of action and the hijack RNA's dependence on SARS-CoV-2 RdRp. Results of ongoing in vivo studies will be presented. Conclusion: An mRNA delivered or expressed in trans to engage with SARSCoV-2 RdRp successfully hijacked the virus machinery to induce rapid death in infected cells but not in uninfected cells, resulting in total eradication of the virus within 48h. Hijack RNA's transcription into the kill molecule DT-A was dependent on viral RdRp, confirming the specificity this potential treatment. This novel approach could be used to develop an effective treatment, potentially in the form of an AAV or an aerosolized RNA drug to rapidly eradicate COVID-19 infection.

3.
ClinicalTrials.gov; 09/07/2020; TrialID: NCT04470999
Clinical Trial Register | ICTRP | ID: ictrp-NCT04470999

ABSTRACT

Condition:

Covid19;SARS-CoV-2

Intervention:

Other: Leukapheresis

Primary outcome:

Cellular immune system profiling

Criteria:


Inclusion Criteria:

- Male of female aged 18-60

- Documented current or past (max 3 months prior) diagnosis of COVID19

- Participants who has not participated in a cell or gene therapy trial for COVID19

Exclusion Criteria:

- Uncontrolled SARS symptoms

- Oxygen saturation (Pulse Ox) < 90%

- Uncontrolled diabetes

- Uncontrolled hypertension

- Active DIC, bleeding or coagulopathy which cannot be corrected with minimal
intervention

- Symptomatic, uncontrolled or severe intercurrent illness that would compromise the
ability to tolerate blood collection or leukapheresis procedure

- Systemic chemotherapy less than or equal to 2 weeks (6 weeks for clofarabine or
nitrosoureas) or radiation therapy less than or equal to 3 weeks prior to
leukapheresis

- Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test at screening

- Any patient that in the opinion of the investigator is not medically stable to undergo
the leukapheresis procedure or will not comply with the visit schedules or procedures


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