WO2022269097A1

WO2022269097A1 - Sirna combinations targeting sars-cov-2 and/or host factor transcripts

Info

Publication number: WO2022269097A1
Application number: PCT/EP2022/067506
Authority: WO
Inventors: Michael Hannus; Stefan Finke
Original assignee: Alpine Antiviral Gmbh
Priority date: 2021-06-25
Filing date: 2022-06-27
Publication date: 2022-12-29

Abstract

This invention relates to siRNA combinations targeting coronavirus (SARS-CoV-2) transcripts and/or host factor transcripts. The invention further relates to siRNA combinations and pharmaceutical compositions comprising said siRNA combinations for use in the treatment and prophylaxis of coronavirus infections, particularly coronavirus disease 2019.

Description

Alpine Antiviral GmbH siRNA combinations targeting SARS-CoV-2 and/or host factor transcripts

FIELD OF THE INVENTION

This invention relates to the field of siRNA combinations targeting coronavirus (SARS-CoV-2) transcripts and/or host factor transcripts. The invention further relates to siRNA combinations and pharmaceutical compositions comprising said siRNA combinations for use in the treatment and prophylaxis of coronavirus infections, particularly coronavirus disease 2019. BACKGROUND OF THE INVENTION

The SARS-CoV-2, a newly identified b-coronavirus, (Order: Nidovirales, Family: Coronaviridae, Genus: Betacoronavirus) is the causative agent of the third large-scale pandemic in the last two decades. Coronaviruses are widely known virulent pathogens and six globally distributed species of the virus have been identified to cause illness in humans:

• human coronavirus OC43 (HCoV-OC43),

• human coronavirus HKU1 (HCoV-HKUl),

• Human coronavirus 229E (HCoV-229E), · human coronavirus NL63 (HCoV-NL63),

• Severe acute respiratory syndrome coronavirus (SARS-CoV),

• and Middle East respiratory syndrome coronavirus (MERS-CoV)

The current outbreak started in December 2019 in Wuhan City, Hubei province in China. The most common symptoms are fever, dry cough, fatigue, anosmia, and difficulty breathing. By February 2020, The World Health Organization (WHO) named the disease as Coronavirus Disease 2019 (COVID-19)

SARS CoV-2 forms spherical enveloped particles of lOOnm in diameter which contain a single (+) stranded RNA genome of 30kb. The genome encodes 16 non- structural proteins (Nspl - Nspl6) and the structural proteins M, S, N and E.

Host cell recognition and entry takes place via interaction of the angiotensin converting enzyme 2 (ACE-2) with the spike protein S. However, other routes of entry may exist. The spike protein S forms a homo trimeric structure emanating from the viral particle. The interaction between the Spike protein and the ACE-2 receptor also requires the activity of the protease TMPRSS2. Viral entry is mediated by endocytosis and release into the cytoplasm by membrane fusion. The released RNA genome is translated by the host cell thereby generating a viral encoded RNA dependent RNA polymerase, which then transcribes multiple copies of viral genomes and subgenomic RNAs. After expression of structural proteins, the newly formed single stranded RNA genomes are assembled into new viral particles, enveloped in cellular lipids in ER derived compartments and secreted from the host cell. A single infected host cell can release around 1000 viruses within 1 day.

After infection persons remain asymptomatic in average for 5 days and 99% of infected persons develop symptoms in less than 14 days (unless asymptomatic). At the same time infected persons become infectious after a latent period of 3 days in average and can spread the virus before first symptom have developed. The basic reproductive number (R0) of CoV-2 is estimated to range between 2 and 4, unless social distancing measures are taken to prevent exponential growth of infections. The experiences of the past 3 month have shown that even drastic measures with dramatic impact on social life and national economies were insufficient to efficiently control the spread of the virus.

To this point the only moderate infectiousness of SARS CoV 2 has prevented an even faster dissemination of the infectious disease but the identification of a novel Corona Variant B 1.1.7 with higher transmissibility may aggravate the current situation.

The recently initiated global vaccination campaign will require several months to show first positive results and treatments with small molecule drugs focus on anti inflammatory effects. So far repurposing strategies have not resulted in break through drugs with high curative potential.

Classical drug discovery and development strategies on the basis of small molecule inhibitors take years to develop and the difficulties in finding a drug against HIV illustrate the intrinsic challenges of viral infections. At the same time viruses with single stranded RNA genomes are optimal targets for RNAi based therapeutic strategies. Thus, there is a need for treatment options against coronavirus infections.

OBJECTIVES AND SUMMARY OF THE INVENTION The invention is based on the finding that a combination of siRNAs exhibits an antiviral effect against SARS-CoV-2. The inventors could show that the siRNA combinations of the invention reduce or eliminate SARS-CoV-2 infection. Furthermore, host factor targets were found which reduce or eliminate SARS-CoV-2 infection. Thus, coronavirus disease, preferably coronavirus 2019 disease, can be treated with the siRNA combinations of the invention.

First aspect: Combination of siRNAs

Combination of siRNAs

In a first aspect, the present invention relates to a combination of siRNAs that is targeted to one or more SARS-CoV-2 transcripts and/or host factor transcripts. It is understood, that siRNAs targeting viral transcripts also target the corresponding sequence in the viral genome, being a single (+) stranded RNA genome. Thus, the present invention relates to a combination of siRNAs which inhibits the expression of one or more SARS-CoV-2 genes and/or host factor genes in vitro , such as e.g., in a cell, or ex vivo in a cell in culture, or in vivo in a cell within a subject. The subject may be a mammal, such as, e.g., a rat, mouse, or human. In some embodiments, the subject may be a human.

In one embodiment, the invention provides a combination of siRNAs targeted to one or more SARS-CoV-2 transcripts.

In one embodiment, the invention provides a combination of siRNAs targeted to one or more host factor transcripts. In one embodiment, the combination comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 siRNAs of different sequences. Using multiple siRNAs in one siRNA combination has the advantage of reducing the danger of off-target effects and/or increasing gene silencing efficiency. In one embodiment, the combination comprises at least 8 siRNAs of different sequences. In one embodiment, the combination comprises at least 10 siRNAs of different sequences. In one embodiment, the combination comprises at least 9 siRNAs of different sequences. In one embodiment, the combination comprises at least 12 siRNAs of different sequences. In one embodiment, the combination comprises at least 13 siRNAs of different sequences. In one embodiment, the combination comprises at least 14 siRNAs of different sequences. In one embodiment, the combination comprises at least 15 siRNAs of different sequences. In one embodiment, the combination comprises at least 17 siRNAs of different sequences. In one embodiment, the combination comprises at least 18 siRNAs of different sequences. In one embodiment, the combination comprises at least 19 siRNAs of different sequences. In one embodiment, the combination comprises at least 20 siRNAs of different sequences.

In one embodiment, the combination comprises from 10 to 60 siRNAs of different sequences. In one embodiment, the combination comprises from 10 to 40 siRNAs of different sequences. In one embodiment, the combination comprises from 12 to 30 siRNAs of different sequences. In one embodiment, the combination comprises from 8 to 22 siRNAs of different sequences. In one embodiment, the combination comprises from 10 to 20 siRNAs of different sequences. In one embodiment, the combination comprises from 10 to 15 siRNAs of different sequences. In one embodiment, the combination comprises from 12 to 15 siRNAs of different sequences. In one embodiment, the combination comprises from 18 to 22 siRNAs of different sequences.

The above combinations comprising different sequences can be directed against one target transcript or more than one target transcript. The above combinations comprising different sequences can also be combined (multiple combinations of siRNAs each comprising different siRNAs of different sequences) and directed against one target transcript or more than one target transcript. E.g., a combination comprising 12 to 15 siRNAs of different sequences can be directed against one target transcript. A combination comprising 12 to 15 siRNAs of different sequences can be directed against more than one target transcript. Multiple combinations of siRNAs each comprising 12 to 15 siRNAs of different sequences can be directed against one target transcript or more than one target transcript.

In the combination of siRNAs according to the invention, each siRNA is a double- stranded siRNA comprising a sense strand and an antisense strand. The sense strand and antisense strand of the siRNA form a duplex structure. In some embodiments, the duplex region of the siRNA may have at least 11 base pairs, such as, e.g., at least 15 base pairs, at least 17 base pairs, or at least 19 base pairs. For example, the duplex region of the siRNA may have 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 base pairs. In some embodiments, the duplex region of the siRNA may have 16 base pairs. In some embodiments, the duplex region of the siRNA may have 17 base pairs. In some embodiments, the duplex region of the siRNA may have 19 base pairs. In some embodiments, the duplex region of the siRNA may have 21 base pairs. The length of the duplex region of the siRNAs in the combination according to the invention is independent of each other.

If it is referred to siRNA being a certain number of nucleotides in length, it is referred to the duplex region of the siRNA. Thus, in one embodiment, each siRNA is independently between about 10 and about 60 nucleotides in length. In one embodiment, each siRNA is independently between 10 to 30 base pairs in length. In one embodiment, each siRNA is independently between 10 to 27 base pairs in length. In one embodiment, each siRNA is independently between 15 to 27 base pairs in length. In one embodiment, each siRNA is independently between 15 to 25 base pairs in length. In one embodiment, each siRNA is independently between 17 to 23 base pairs in length. In one embodiment, each siRNA is independently between 18 to 20 base pairs in length. In one embodiment, each siRNA is 19 base pairs in length. Each strand of the siRNA may have the same length or different lengths. In some embodiments, each strand of the siRNA may be 10-29 nucleotides in length. For example, each strand may be 13-29 nucleotides in length, 16-28 nucleotides in length, 16-27 nucleotides in length, 16-25 nucleotides in length, 16-27 nucleotides in length, or 16-23 nucleotides in length, including all integers in between these ranges. In some embodiments, each strand may be 19-21 nucleotides in length, including 20 nucleotides. In some embodiments, each strand may be 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26 or 27 nucleotides in length. In some embodiments, each strand may be 16 nucleotides in length. In some embodiments, each strand may be 19 nucleotides in length. In some embodiments, each strand may be 21 nucleotides in length. In a preferred embodiment, each strand may be 19 nucleotides in length. As two or more different siRNA molecules are used in combination, the lengths of each strand of each siRNA can be identical or can be different. For the purpose of this disclosure, length calculation of any double-stranded siRNA strands shall exclude any nucleotide overhangs that may be present. In one embodiment, the combination of siRNAs is targeted to one or more SARS- CoV-2 transcripts and/or host factor transcripts, and comprises at least two siRNAs of different sequences, wherein each siRNA comprises an antisense strand and a complementary sense strand. Each siRNA of the combination according to the invention may comprise nucleotide insertions, substitutions, deletions, or mismatches. For example, disclosed are sense and antisense strands of siRNAs which may each comprise a nucleotide sequence having at least 75%, such as, e.g., at least at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or higher identity to any one of the disclosed sequences. For example, a siRNA strand (i.e. a sense or antisense strand) of 19 nucleotides with 75% identity to a disclosed sequence has 4 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 19 nucleotides with 80% identity to a disclosed sequence has 3 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 19 nucleotides with 85% identity to a disclosed sequence has 2 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 19 nucleotides with 90% identity to a disclosed sequence has 1 inserted, substituted, deleted or mismatched nucleotide.

For example, a siRNA strand (i.e. a sense or antisense strand) of 21 nucleotides with 75% identity to a disclosed sequence has 5 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 21 nucleotides with 80% identity to a disclosed sequence has 4 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 21 nucleotides with 85% identity to a disclosed sequence has 3 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 21 nucleotides with 90% identity to a disclosed sequence has 2 inserted, substituted, deleted or mismatched nucleotides. For example, a siRNA strand of 21 nucleotides with 95% identity to a disclosed sequence has 1 inserted, substituted, deleted or mismatched nucleotide.

The above described insertions, substitutions, deletions or mismatches may be independently present in the sense and/or antisense strand.

Certain embodiments of the double-stranded siRNA described herein may comprise one or more single-stranded nucleotide overhangs of one or more nucleotides at the 5’-end, 3’-end, or both ends of one or both strands. The nucleotide overhangs on each strand may be the same or different in terms of number, length, sequence, and location. For example, the nucleotide overhang may be located at the 3’ -end of the sense strand, the antisense strand, or both strands. Accordingly, the siRNA may also have a blunt end, located at the 5’-end of the antisense strand (or the 3’-end of the sense strand) or vice versa. In some embodiments, the antisense strand of the siRNA may have a nucleotide overhang at the 3’ -end and a blunt 5’ -end. The overhang may form a mismatch with the target sequence or it may be complementary to the target sequence or may be another sequence. In some embodiments, at least one end of either strand of the siRNA may comprise a nucleotide overhang of 1-5 nucleotides in length, such as, e.g., 1-5, 2-5, 1-4, 2-4, 1-3, 2-3 or 1-2 nucleotides, including all integers in between these ranges. In some embodiments, the nucleotide overhang may have 1 or 2 nucleotides in length. In various embodiments, the nucleotides in the overhang may each independently be an unmodified nucleotide or a modified nucleotide as disclosed herein or known in the art. In some embodiments, the nucleotide overhang may be 2 nucleotides. In some embodiments, the antisense strand of the siRNA may have 2 nucleotides at the 3’- end. In some embodiments, the sense strand of the siRNA may have 2 nucleotides at the 3’-end. In some embodiments, both strands of the siRNA may have 2 nucleotides at the 3’-end. In some embodiments, the nucleotide overhang may be AG. In some embodiments, the antisense strand of the siRNA may have AG at the 3’- end. In some embodiments, the sense strand of the siRNA may have AG at the 3’-end. In some embodiments, both strands of the siRNA may have AG at the 3’ -end. In one embodiment, both strands of each siRNA of the siRNA combination, wherein the strands of the single siRNAs are disclosed in Table 1 or Table 2, have an AG overhang at the 3’ -end. When two or more different siRNA molecules are used in combination, each siRNA may have the same or different overhang architectures. For example, the number, length, sequence, and location of the nucleotide overhang on each strand may be independently selected.

The siRNAs of the present invention can be chemically synthesized, expressed from a vector or enzymatically synthesized. An exemplary enzymatic synthesis is described in WO 2013/160393 using RNase Tl.

In the combination of siRNAs according to the invention, each siRNA is a double- stranded siRNA comprising a sense strand and an antisense strand. In the following the siRNAs are either defined based on the antisense or sense sequences. If the siRNAs of the invention are defined based on antisense sequences, it is to be understood, that each siRNA will contain the respective antisense sequence and a complementary sense sequence. Vice versa, if the siRNAs of the invention are defined based on sense sequences, it is to be understood, that each siRNA will contain the respective sense sequence and a complementary antisense sequence.

Sense and antisense sequences can be fully complementary or substantially complementary meaning that the siRNAs may contain a certain number of inserted, substituted, deleted and/or mismatched nucleotides, e.g. 1, 2, 3 or 4 inserted, substituted, deleted and/or mismatched nucleotides. Insertions, substitutions, deletions and/or mismatches are independently chosen and can be combined differently for each sequence. siRNA sequences targeted to SARS-CoV-2 and/or host factor transcripts siRNA sequences targeted to viral transcripts are summarized in Table 1. siRNA sequences targeted to host factor transcripts are summarized in Table 2. If it is referred to a certain SEQ ID No. in the following, the corresponding sequence is listed in Table 1 or 2. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 75% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 80% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 85% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 90% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 95% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094, wherein each sequence is independently at least about 98% identical to a sequence of SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 75% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 80% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 85% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 90% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 95% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094, wherein each sequence is independently at least about 98% identical to a sequence of SEQ ID NOs: 548 to 950 and 975 to 1094. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950 and 975 to 1094. siRNA sequences targeted to SARS-CoV-2 transcripts In one embodiment, the siRNAs of the combination according to the invention are directed to one or more SARS-CoV-2 transcripts. In one embodiment, the SARS- CoV-2 transcripts are selected from the group comprising the spike protein transcript, envelope protein transcript, nucleocapsid protein transcript, membrane protein transcript and/or Orflab polyprotein transcript. In one embodiment, the SARS-CoV-2 transcripts are selected from the group comprising the spike protein transcript, nucleocapsid protein transcript and/or membrane protein transcript. In one embodiment, the SARS-CoV-2 transcripts are selected from the group comprising the nucleocapsid protein transcript and membrane protein transcript. In one embodiment, the SARS-CoV-2 transcripts are selected from the group comprising the nucleocapsid protein transcript and Orflab polyprotein transcript. In one embodiment, the siRNAs are directed to the Orflab polyprotein transcript and/or the nucleocapsid protein transcript. In one embodiment, the siRNAs are directed to the Orflab polyprotein transcript and the nucleocapsid protein transcript. In one embodiment, the siRNAs are directed to the Orflab polyprotein transcript. In one embodiment, the siRNAs are directed to the nucleocapsid protein transcript

In one embodiment, the siRNAs of the combination according to the invention are directed to one SARS-CoV-2 transcript. In one embodiment, the siRNAs of the combination are directed to the Orflab polyprotein transcript. In one embodiment, the siRNAs of the combination are directed to the nucleocapsid protein transcript. In one embodiment, the siRNAs of the combination are directed to the membrane protein transcript. In one embodiment, the siRNAs of the combination are directed to the spike protein transcript. In one embodiment, the siRNAs of the combination according to the invention are directed to two or more SARS-CoV-2 transcripts. In one embodiment, the siRNAs of the combination are directed to SARS-CoV-2 transcripts comprising the Orflab polyprotein transcript and the nucleocapsid protein transcript. The transcripts above refer to the reference genome from NCBI (accession number NC 045512.2). The transcripts mentioned in the above embodiments are transcripts as based on the reference genome from NCBI (accession number NC_045512.2) or a sequence which is 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to it. If it is referred to the membrane protein transcript (M), nucleocapsid protein transcript (N), spike protein transcript (S) or Orfla/b polyprotein transcript (Orfla/b) herein, said transcripts can be based on the sequences SEQ ID No. 1521, 1522, 1523 or 1524 or a sequence which is 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to any one of SEQ ID Nos: 1521, 1522, 1523 or 1524. siRNA sequences targeted to viral transcripts are summarized in Table 1 below. If it is referred to a certain SEQ ID No. in the following, the corresponding sequence is listed in Table 1. siRNAs based on antisense sequences

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is independently at least about 75% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is independently at least about 80% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from 548 to 974, wherein each sequence is independently at least about 85% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is independently at least about 90% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is independently at least about 95% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is independently at least about 98% identical to a sequence of SEQ ID NOs: 548 to 974. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is independently at least about 75% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is independently at least about 80% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from 548 to 950, wherein each sequence is independently at least about 85% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is independently at least about 90% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is independently at least about 95% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is independently at least about 98% identical to a sequence of SEQ ID NOs: 548 to 950. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950.

In a preferred embodiment, the siRNAs are directed to the Orflab polyprotein transcript. Thus, in a preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869; wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 720 to 869. In another preferred embodiment, the siRNAs are directed to the nucleocapsid protein transcript. Thus, in a preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 590 to 634.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634 (siRNA combination SARS-CoV-2-N-p3 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 620 to 634.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 765 to 779 (siRNA combination SARS-CoV-2-orflab-p3 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 765 to 779, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 765 to 779, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequence SEQ ID Nos: 765 to 779, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequence SEQ ID Nos: 765 to 779, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequence SEQ ID Nos: 765 to 779, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 765 to 779.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824 (siRNA combination SARS-CoV-2-orflab-p6 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 810 to 824.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 750 to 764 (siRNA combination SARS-CoV-2-orflab-p2 according to Table 1), wherein each siRNA is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 750 to 764, wherein each siRNA is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 750 to 764, wherein each siRNA is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 750 to 764, wherein each siRNA is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 750 to 764, wherein each siRNA is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 750 to 764, wherein each siRNA is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 750 to 764.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 840 to 854 (siRNA combination SARS-CoV-2-orflab-p8 according to Table 1). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619 (siRNA combination SARS-CoV-2-N-p2 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 605 to 619. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734 (siRNA combination SARS-CoV-2-orflab-pl according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 720 to 734. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839 (siRNA combination SARS-CoV-2-orflab-p7 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 825 to 839. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 855 to 869 (siRNA combination SARS-CoV-2-orflab-p9 according to Table 1).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719 (siRNA combination SARS-CoV-2-orflO according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 710 to 719.

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749 (siRNA combination SARS-CoV-2-orflab-plO according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 735 to 749.

In one embodiment, the combination of siRNAs comprises SEQ ID NOs: 548 to 1094 and 1320 to 1520 (all siRNA combinations targeted to viral transcripts according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1320 to 1331 (siRNA combination SARS-CoV-2-N-rgnl-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1332 to 1343 (siRNA combination SARS-CoV-2-N-rgn2-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1344 to 1355 (siRNA combination SARS-CoV-2-orflab-rgnl-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1356 to 1367 (siRNA combination SARS-CoV-2-orflab-rgnl-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1368 to 1379 (siRNA combination SARS-CoV-2-orflab-rgn2-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1380 to 1390 (siRNA combination SARS-CoV-2-orflab-rgn3-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1391 to 1402 (siRNA combination SARS-CoV-2-orflab-rgn4-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1403 to 1413 (siRNA combination SARS-CoV-2-orflab-rgn4-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1414 to 1424 (siRNA combination SARS-CoV-2-orflab-rgn5-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1425 to 1436 (siRNA combination SARS-CoV-2-orflab-rgn6-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1437 to 1448 (siRNA combination SARS-CoV-2-orflab-rgn6-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1449 to 1460 (siRNA combination SARS-CoV-2-orflab-rgn6-p3 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1461 to 1472 (siRNA combination SARS-CoV-2-orflab-rgn7-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1473 to 1484 (siRNA combination SARS-CoV-2-orflab-rgn7-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1485 to 1496 (siRNA combination SARS-CoV-2-orflab-rgn7-p3 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1497 to 1508 (siRNA combination SARS-CoV-2-orflab-rgn7-p4 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1509 to 1520 (siRNA combination SARS-CoV-2-orflab-rgn7-p5 according to Table 1).

In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847 (siRNA combination Cov-best-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (siRNA combination Cov-best-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823 (siRNA combination Cov-best-p3 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (siRNA combination Cov-best-pl +Cov-best-p2, also termed Cov-best- pl +p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, 854, 840, 810, 728, 633, 850, 822, 634, 827, 823 (siRNA combination Cov-best-pl +Cov-best-p2+Cov-best-p3, also termed Cov-best-pl +p2+p3, according to Table 1).

In one embodiment, each antisense sequence of the above described combinations, e.g. SARS-CoV-2-N-rgnl-p2, SARS-CoV-2-N-rgn2-pl, SARS-CoV-2-orflab-rgnl- pl, S ARS-CoV-2-orf 1 ab-rgn 1 -p2, SARS-CoV-2-orflab-rgn2-pl, SARS-CoV-2- orflab-rgn3-pl, SARS-CoV-2-orflab-rgn4-pl, SARS-CoV-2-orflab-rgn4-p2 SARS- CoV-2-orflab-rgn5-pl SARS-CoV-2-orflab-rgn6-pl SARS-CoV-2-orflab-rgn6-p2 SARS-CoV-2-orflab-rgn6-p3, SARS-CoV-2-orflab-rgn7-pl, SARS-CoV-2-orflab- rgn7-p2, SARS-CoV-2-orflab-rgn7-p3, SARS-CoV-2-orflab-rgn7-p4, SARS-CoV- 2-orflab-rgn7-p5, cov-best-pl, cov-best-p2, cov-best-p3, Cov-best-pl +Cov-best-p2, Cov-best-pl +Cov-best-p2+Cov-best-p3, is independently at least about 75% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (siRNA combination Cov-best-pl+p2 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729.

Each of the the above described combination of siRNAs may comprise less than the described sequences (i.e. less siRNAs). Thus, in one embodiment, each of the above described combination of siRNAs comprises at least 5 siRNAs comprising 5 different antisense sequences out of the SEQ ID Nos as mentioned for the respective combination (i.e. at least 5 siRNAs). In one embodiment, the combination of siRNAs comprises at least 8 siRNAs comprising at least 8 different antisense sequences of the above SEQ ID Nos (i.e. at least 8 siRNAs). This especially applies to the siRNA combinations comprising 10 antisense sequences, but can also apply to siRNA combinations comprising 12, 15 or 20 antisense sequences. In one embodiment, the combination of siRNAs comprises at least 10 siRNAs comprising at least 10 different antisense sequences of the above SEQ ID Nos (i.e. at least 10 siRNAs). This especially applies to the siRNA combinations comprising 12 antisense sequences, but can also apply to siRNA combinations comprising 15 or 20 antisense sequences. In one embodiment, the combination of siRNAs comprises at least 13 siRNAs comprising at least 13 different antisense sequences of the above SEQ ID Nos. This especially applies to the siRNA combinations comprising 15 antisense sequences, but can also apply to siRNA combinations comprising 20 antisense sequences. In one embodiment, the combination of siRNAs comprises at least 15 siRNAs comprising at least 15 different antisense sequences of the above SEQ ID Nos. In one embodiment, the combination of siRNAs comprises at least 17 siRNAs comprising at least 17 different antisense sequences of the above SEQ ID Nos. In one embodiment, the combination of siRNAs comprises at least 18 siRNAs comprising at least 18 different antisense sequences of the above SEQ ID Nos. In one embodiment, the combination of siRNAs comprises at least 19 siRNAs comprising at least 19 different antisense sequences of the above SEQ ID Nos. This applies to the siRNA combinations comprising 20 antisense sequences, such as, e.g. cov-best-pl+p2.

In one embodiment, the siRNA combination comprises at least 10 or 11 siRNAs of different sequences, wherein the antisense strand of each of the 10 or 11 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 590 to 604 (SARS-CoV-2-N-pl); or

(b) SEQ ID Nos: 605 to 619 (SARS-CoV-2-N-p2); or

(c) SEQ ID Nos: 620 to 634 (SARS-CoV-2-N-p3); or (d) SEQ ID Nos: 1320 to 1331 (SARS-CoV-2-N-rgnl-p2);

(e) SEQ ID Nos: 1332 to 1343 (SARS-CoV-2-N-rgn2-pl).

Preferably, each of the antisense strand sequences is selected from the same group.

In one embodiment, the siRNA combination comprises at least 10, 11, 12, 13, 14 or 15 siRNAs of different sequences, wherein the antisense strand of each of the 10, 11,

12, 13, 14 or 15 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 590 to 604 (SARS-CoV-2-N-pl); or

(b) SEQ ID Nos: 605 to 619 (SARS-CoV-2-N-p2); or

(c) SEQ ID Nos: 620 to 634 (SARS-CoV-2-N-p3). Preferably, each of the antisense strand sequences is selected from the same group.

In one embodiment, the siRNA combination consists of 10, 11, 12, 13, 14 or 15 siRNAs of different sequences, wherein the antisense strand of each of the 10, 11, 12, 13, 14 or 15 siRNAs has a sequence selected from the following groups: (a) SEQ ID Nos: 590 to 604 (SARS-CoV-2-N-pl); or

(b) SEQ ID Nos: 605 to 619 (SARS-CoV-2-N-p2); or

(c) SEQ ID Nos: 620 to 634 (SARS-CoV-2-N-p3);

Preferably, each of the antisense strand sequences is selected from the same group. In one embodiment, the siRNA combination comprises at least 10 or 11 siRNAs of different sequences, wherein the antisense strand of each of the 10 or 11 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 1320 to 1331 (SARS-CoV-2-N-rgnl-p2); or

(b) SEQ ID Nos: 1332 to 1343 (SARS-CoV-2-N-rgn2-pl). Preferably, each of the antisense strand sequences is selected from the same group.

In one embodiment, the siRNA combination consists of 10, 11 or 12 siRNAs of different sequences, wherein the antisense strand of each of the 10, 11 or 12 siRNAs has a sequence selected from the following groups: (a) SEQ ID Nos: 1320 to 1331 (SARS-CoV-2-N-rgnl-p2); or

(b) SEQ ID Nos: 1332 to 1343 (SARS-CoV-2-N-rgn2-pl).

12, 13, 14 or 15 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 720 to 734 (SARS-CoV-2-orflab-pl); or

(b) SEQ ID Nos: 750 to 764 (SARS-CoV-2-orflab-p2); or

(c) SEQ ID Nos: 765 to 779 (SARS-CoV-2-orflab-p3); or (d) SEQ ID Nos: 780 to 794 (SARS-CoV-2-orflab-p4); or

(e) SEQ ID Nos: 795 to 809 (SARS-CoV-2-orflab-p5); or

(f) SEQ ID Nos: 810 to 824 (SARS-CoV-2-orflab-p6); or

(g) SEQ ID Nos: 825 to 839 (SARS-CoV-2-orflab-p7); or

(h) SEQ ID Nos: 735 to 749 (SARS-CoV-2-orflab-plO). Preferably, each of the antisense strand sequences is selected from the same group.

In one embodiment, the siRNA combination comprises at least 9 or 10 siRNAs of different sequences, wherein the antisense strand of each of the 9 or 10 siRNAs has a sequence selected from the following groups: (a) SEQ ID Nos: 1344 to 1355 (SARS-CoV-2-orflab-rgnl-pl); or (b) SEQ ID Nos: 1356 to 1367 (SARS-CoV-2-orflab-rgnl-p2); or

(c) SEQ ID Nos: 1368 to 1379 (SARS-CoV-2-orflab-rgn2-pl); or

(d) SEQ ID Nos: 1380 to 1390 (SARS-CoV-2-orflab-rgn3-pl); or

(e) SEQ ID Nos: 1391 to 1402 (SARS-CoV-2-orflab-rgn4-pl); or (f) SEQ ID Nos: 1403 to 1413 (SARS-CoV-2-orflab-rgn4-p2); or

(g) SEQ ID Nos: 1414 to 1424 (SARS-CoV-2-orflab-rgn5-pl); or

(h) SEQ ID Nos: 1425 to 1436 (SARS-CoV-2-orflab-rgn6-pl); or

(i) SEQ ID Nos: 1437 to 1448 (SARS-CoV-2-orflab-rgn6-p2); or

(j) SEQ ID Nos: 1449 to 1460 (SARS-CoV-2-orflab-rgn6-p3); or (k) SEQ ID Nos: 1461 to 1472 (SARS-CoV-2-orflab-rgn7-pl); or

(l) SEQ ID Nos: 1473 to 1484 (SARS-CoV-2-orflab-rgn7-p2); or

(m) SEQ ID Nos: 1485 to 1496 (SARS-CoV-2-orflab-rgn7-p3); or

(n) SEQ ID Nos: 1497 to 1508 (SARS-CoV-2-orflab-rgn7-p4); or

(o) SEQ ID Nos: 1509 to 1520 (SARS-CoV-2-orflab-rgn7-p5); or (p) SEQ ID Nos: 720 to 734 (SARS-CoV-2-orflab-pl); or

(q) SEQ ID Nos: 750 to 764 (SARS-CoV-2-orflab-p2); or

(r) SEQ ID Nos: 765 to 779 (SARS-CoV-2-orflab-p3); or

(s) SEQ ID Nos: 780 to 794 (SARS-CoV-2-orflab-p4); or

(t) SEQ ID Nos: 795 to 809 (SARS-CoV-2-orflab-p5); or (u) SEQ ID Nos: 810 to 824 (SARS-CoV-2-orflab-p6); or

(v) SEQ ID Nos: 825 to 839 (SARS-CoV-2-orflab-p7); or

(w) SEQ ID Nos: 735 to 749 (SARS-CoV-2-orflab-plO).

Preferably, each of the antisense strand sequences is selected from the same group. In one embodiment, the siRNA combination comprises at least 10, 11, 12, 13 or 14 siRNAs of different sequences, wherein the antisense strand of each of the 10, 11, 12, 13 or 14 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 720 to 734 (SARS-CoV-2-orflab-pl); or

(b) SEQ ID Nos: 750 to 764 (SARS-CoV-2-orflab-p2); or (c) SEQ ID Nos: 765 to 779 (SARS-CoV-2-orflab-p3); or (d) SEQ ID Nos: 780 to 794 (SARS-CoV-2-orflab-p4); or

(e) SEQ ID Nos: 795 to 809 (SARS-CoV-2-orflab-p5); or

(f) SEQ ID Nos: 810 to 824 (SARS-CoV-2-orflab-p6); or

(g) SEQ ID Nos: 825 to 839 (SARS-CoV-2-orflab-p7); or (h) SEQ ID Nos: 735 to 749 (SARS-CoV-2-orflab-plO).

In one embodiment, the siRNA combination consists of 10, 11, 12, 13, 14 or 15 siRNAs of different sequences, wherein the antisense strand of each of the 10, 11, 12, 13, 14 or 15 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 720 to 734 (SARS-CoV-2-orflab-pl); or

(b) SEQ ID Nos: 750 to 764 (SARS-CoV-2-orflab-p2); or

(c) SEQ ID Nos: 765 to 779 (SARS-CoV-2-orflab-p3); or

(d) SEQ ID Nos: 780 to 794 (SARS-CoV-2-orflab-p4); or (e) SEQ ID Nos: 795 to 809 (SARS-CoV-2-orflab-p5); or

(f) SEQ ID Nos: 810 to 824 (SARS-CoV-2-orflab-p6); or

(g) SEQ ID Nos: 825 to 839 (SARS-CoV-2-orflab-p7); or

(h) SEQ ID Nos: 735 to 749 (SARS-CoV-2-orflab-plO).

In one embodiment, the siRNA combination comprises at least 9 or 10 siRNAs of different sequences, wherein the antisense strand of each of the 9 or 10 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 1344 to 1355 (SARS-CoV-2-orflab-rgnl-pl); or (b) SEQ ID Nos: 1356 to 1367 (SARS-CoV-2-orflab-rgnl-p2); or

(c) SEQ ID Nos: 1368 to 1379 (SARS-CoV-2-orflab-rgn2-pl); or

(d) SEQ ID Nos: 1380 to 1390 (SARS-CoV-2-orflab-rgn3-pl); or

(e) SEQ ID Nos: 1391 to 1402 (SARS-CoV-2-orflab-rgn4-pl); or

(f) SEQ ID Nos: 1403 to 1413 (SARS-CoV-2-orflab-rgn4-p2); or (g) SEQ ID Nos: 1414 to 1424 (SARS-CoV-2-orflab-rgn5-pl); or (h) SEQ ID Nos: 1425 to 1436 (SARS-CoV-2-orflab-rgn6-pl); or

(i) SEQ ID Nos: 1437 to 1448 (SARS-CoV-2-orflab-rgn6-p2); or

(j) SEQ ID Nos: 1449 to 1460 (SARS-CoV-2-orflab-rgn6-p3); or

(k) SEQ ID Nos: 1461 to 1472 (SARS-CoV-2-orflab-rgn7-pl); or (1) SEQ ID Nos: 1473 to 1484 (SARS-CoV-2-orflab-rgn7-p2); or

(m) SEQ ID Nos: 1485 to 1496 (SARS-CoV-2-orflab-rgn7-p3); or

(n) SEQ ID Nos: 1497 to 1508 (SARS-CoV-2-orflab-rgn7-p4); or

(o) SEQ ID Nos: 1509 to 1520 (SARS-CoV-2-orflab-rgn7-p5).

In one embodiment, the siRNA combination consists of 10 or 11 siRNAs of different sequences, wherein the antisense strand of each of the 10 or 11 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 1380 to 1390 (SARS-CoV-2-orflab-rgn3-pl); or (b) SEQ ID Nos: 1403 to 1413 (SARS-CoV-2-orflab-rgn4-p2); or

(c) SEQ ID Nos: 1414 to 1424 (SARS-CoV-2-orflab-rgn5-pl).

In one embodiment, the siRNA combination consists of 11 or 12 siRNAs of different sequences, wherein the antisense strand of each of the 11 or 12 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 1344 to 1355 (SARS-CoV-2-orflab-rgnl-pl); or

(b) SEQ ID Nos: 1356 to 1367 (SARS-CoV-2-orflab-rgnl-p2); or

(c) SEQ ID Nos: 1368 to 1379 (SARS-CoV-2-orflab-rgn2-pl); or (d) SEQ ID Nos: 1391 to 1402 (SARS-CoV-2-orflab-rgn4-pl); or

(e) SEQ ID Nos: 1425 to 1436 (SARS-CoV-2-orflab-rgn6-pl); or

(f) SEQ ID Nos: 1437 to 1448 (SARS-CoV-2-orflab-rgn6-p2); or

(g) SEQ ID Nos: 1449 to 1460 (SARS-CoV-2-orflab-rgn6-p3); or

(h) SEQ ID Nos: 1461 to 1472 (SARS-CoV-2-orflab-rgn7-pl); or (i) SEQ ID Nos: 1473 to 1484 (SARS-CoV-2-orflab-rgn7-p2); or (j) SEQ ID Nos: 1485 to 1496 (SARS-CoV-2-orflab-rgn7-p3); or

(k) SEQ ID Nos: 1497 to 1508 (SARS-CoV-2-orflab-rgn7-p4); or

(l) SEQ ID Nos: 1509 to 1520 (SARS-CoV-2-orflab-rgn7-p5).

In one embodiment, the siRNA combination comprises at least 8, 9 or 10 siRNAs of different sequences, wherein the antisense strand of each of the 8, 9 or 10 siRNAs has a sequence selected from the following groups:

(a) SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847 (Cov-best-pl); (b) SEQ ID Nos: 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (Cov-best-p2);

(c) SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823 (Cov-best-p3).

Preferably, each of the antisense strand sequences is selected from the same group. Preferably, the siRNA combination comprises 9 siRNAs of different sequences. Preferably, the siRNA combination comprises 10 siRNAs of different sequences.

In one embodiment, the siRNA combination comprises at least 12, 14, 16 or 18 siRNAs of different sequences, wherein the antisense strand of each of the 12, 14, 16 or 18 siRNAs has a sequence selected from the following groups:

(c) SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823 (Cov-best-p3).

Preferably, each of the antisense strand sequences is selected from the same group. Preferably, the siRNA combination comprises at least 12 siRNAs of different sequences. Preferably, the siRNA combination comprises at least 16 siRNAs of different sequences. Preferably, the siRNA combination comprises at least 18 siRNAs of different sequences.

In one embodiment, the siRNA combination consists of 8, 9 or 10 siRNAs of different sequences, wherein the antisense strand of each of the 8, 9 or 10 siRNAs has a sequence selected from the following groups: (a) SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847 (Cov-best-pl);

(b) SEQ ID Nos: 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (Cov-best-p2);

(c) SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823 (Cov-best-p3).

Preferably, each of the antisense strand sequences is selected from the same group. Preferably, the siRNA combination consists of 10 siRNAs of different sequences.

In one embodiment, the siRNA combination comprises at least 17, 18, 19 or 20 siRNAs of different sequences, wherein the antisense strand of each of the 17, 18, 19 or 20 siRNAs has a sequence selected from SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (Cov-best- pl+p2). Preferably, the siRNA combination comprises 19 siRNAs of different sequences. Preferably, the siRNA combination comprises 20 siRNAs of different sequences.

In one embodiment, the siRNA combination consists of 17, 18, 19 or 20 siRNAs of different sequences, wherein the antisense strand of each of the 17, 18, 19 or 20 siRNAs has a sequence selected from SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (Cov-best- pl+p2). Preferably, the siRNA combination consists of 20 siRNAs of different sequences.

For each of the above embodiments, the antisense strand sequences are independently at least about 75% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 98% identical to the corresponding sequence. It needs to be understood that each siRNA of the combination contains an antisense sequence as described above and a sense sequence that is chosen to be complementary to the antisense sequence. However, the sense sequence must not be perfectly complementary but can contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides. In one embodiment, the sense strand of the siRNA contains 1 or 2 inserted, substituted, deleted and/or mismatched nucleotides. In one embodiment, the sense strand of the siRNA contains 1 inserted, substituted, deleted and/or mismatched nucleotide. Furthermore, each antisense sequence which is complementary to a sequence within the target mRNA must not be perfectly complementary to the target mRNA but can, independently from the other antisense sequences within the combination of siRNAs, contain a certain number of inserted, substituted, deleted and/or mismatched nucleotides, e.g. up to 3, up to 2, or 1 inserted, substituted, deleted and/or mismatched nucleotide(s). siRNAs based on sense sequences

In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 75% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 80% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 85% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 90% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 95% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427, wherein each sequence is at least about 98% identical to a sequence of SEQ ID NOs: 1 to 427. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 1 to 427.

In a preferred embodiment, the siRNAs are directed to the Orflab polyprotein transcript. Thus, in a preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322; wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 173 to 322.

In another preferred embodiment, the siRNAs are directed to the nucleocapsid protein transcript. Thus, in a preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 43 to 87.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87 (siRNA combination SARS-CoV-2-N-p3 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 73 to 87.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 218 to 232 (siRNA combination SARS-CoV-2-orflab-p3 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 218 to 232, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 218 to 232, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequence SEQ ID Nos: 218 to 232, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequence SEQ ID Nos: 218 to 232, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequence SEQ ID Nos: 218 to 232, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequence SEQ ID Nos: 218 to 232. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277 (siRNA combination SARS-CoV-2-orflab-p6 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 263 to 277.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 203 to 217 (siRNA combination SARS-CoV-2-orflab-p2 according to Table 1), wherein each siRNA is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217, wherein each siRNA is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217, wherein each siRNA is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217, wherein each siRNA is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217, wherein each siRNA is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217, wherein each siRNA is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 203 to 217.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 293 to 307 (siRNA combination SARS-CoV-2-orflab-p8 according to Table 1). In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72 (siRNA combination SARS-CoV-2-N-p2 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 58 to 72.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187 (siRNA combination SARS-CoV-2-orflab-pl according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 173 to 187.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292 (siRNA combination SARS-CoV-2-orflab-p7 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 278 to 292.

In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 308 to 322 (siRNA combination SARS-CoV-2-orflab-p9 according to Table 1). In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172 (siRNA combination SARS-CoV-2-orflO according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 163 to 172.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202 (siRNA combination SARS-CoV-2-orflab-plO according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 188 to 202.

In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1107 to 1118 (siRNA combination SARS-CoV-2-N-rgnl-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1119 to 1130 (siRNA combination SARS-CoV-2-N-rgn2-pl according to Table 1).

In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1131 to 1142 (siRNA combination SARS-CoV-2-orflab-rgnl-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1143 to 1154 (siRNA combination SARS-CoV-2-orflab-rgnl-p2 according to Table

1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1155 to 1166 (siRNA combination SARS-CoV-2-orflab-rgn2-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1167 to 1177 (siRNA combination SARS-CoV-2-orflab-rgn3-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1178 to 1189 (siRNA combination SARS-CoV-2-orflab-rgn4-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1190 to 1200 (siRNA combination SARS-CoV-2-orflab-rgn4-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1201 to 1211 (siRNA combination SARS-CoV-2-orflab-rgn5-pl according to Table

1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1212 to 1223 (siRNA combination SARS-CoV-2-orflab-rgn6-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1224 to 1235 (siRNA combination SARS-CoV-2-orflab-rgn6-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos:

1236 to 1247 (siRNA combination SARS-CoV-2-orflab-rgn6-p3 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1248 to 1259 (siRNA combination SARS-CoV-2-orflab-rgn7-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1260 to 1271 (siRNA combination SARS-CoV-2-orflab-rgn7-p2 according to Table

1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1272 to 1283 (siRNA combination SARS-CoV-2-orflab-rgn7-p3 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 1284 to 1295 (siRNA combination SARS-CoV-2-orflab-rgn7-p4 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos:

1296 to 1307 (siRNA combination SARS-CoV-2-orflab-rgn7-p5 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300 (siRNA combination Cov-best-pl according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 177, 290, 271, 185, 76, 187, 81, 65, 301, 182 (siRNA combination Cov-best-p2 according to Table 1). In one embodiment, the combination of siRNAs comprises at least SEQ ID Nos: 307, 293, 263, 181, 86, 303, 275, 87, 280, 276 (siRNA combination Cov-best-p3 according to Table 1). In one embodiment, each sequence of the above described pools SARS-CoV-2-N- rgnl-p2, SARS-CoV-2-N-rgn2-pl, SARS-CoV-2-orflab-rgnl-pl, SARS-CoV-2- orf 1 ab-rgn 1 -p2, S ARS-CoV-2-orf 1 ab-rgn2-p 1 , SARS-CoV-2-orf 1 ab-rgn3 -p 1 ,

SARS-CoV-2-orf 1 ab-rgn4-p 1 , S ARS-CoV-2-orf 1 ab-rgn4-p2 S ARS-CoV-2-orf 1 ab- rgn5-pl SARS-CoV-2-orflab-rgn6-pl SARS-CoV-2-orflab-rgn6-p2 SARS-CoV-2- orflab-rgn6-p3, SARS-CoV-2-orflab-rgn7-pl, SARS-CoV-2-orflab-rgn7-p2, SARS-CoV-2-orflab-rgn7-p3, SARS-CoV-2-orflab-rgn7-p4, SARS-CoV-2-orflab- rgn7-p5, cov-best-pl, cov-best-p2, cov-best-p3, cov-best-pl+p2+p3, as mentioned in Table 1, is independently at least about 75% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, each sequence is independently at least about 98% identical to the corresponding sequence.

In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182 (siRNA combination Cov-best-pl +p2 according to Table 1), wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the combination of siRNAs comprises at least sense sequences SEQ ID Nos: 63, 299, 272, 302, 295, 179, 298, 268, 82, 300, 177, 290, 271, 185, 76, 187, 81, 65, 301, 182. siRNAs based on antisense and sense sequences In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 974, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 962, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 962, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 962, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 548 to 950, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869 (orflab polyprotein transcript being the target), wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 720 to 869, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634 (nucleocapsid protein transcript being the target), wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences.

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 2 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can independently contain up to 1 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 590 to 634, wherein each sequence is at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences. In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634 (siRNA combination SARS-CoV-2-N-p3), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 620 to 634, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779 (siRNA combination SARS-CoV-2-orflab-p3), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 765 to 779, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824 (siRNA combination SARS-CoV-2-orflab-p6), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 810 to 824, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764 (siRNA combination SARS-CoV-2-orflab-p2), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 750 to 764, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854 (siRNA combination SARS-CoV-2-orflab-p8), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 840 to 854, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619 (siRNA combination SARS-CoV-2-N-p2), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 605 to 619, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734 (siRNA combination SAR.S-CoV-2-orflab-pl), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 720 to 734, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839 (siRNA combination SARS-CoV-2-orflab-p7), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 825 to 839, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869 (siRNA combination SARS-CoV-2-orflab-p9), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 855 to 869, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719 (siRNA combination SARS-CoV-2-orflO), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 710 to 719, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749 (siRNA combination SARS-CoV-2-orflab-plO), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 735 to 749, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

In one embodiment, the siRNA combination comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729 (siRNA combination Cov-best-pl+p2), wherein each sequence is independently at least about 75% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 80% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 85% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 90% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 95% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence). In one embodiment, the combination of siRNAs comprises at least antisense sequences SEQ ID NOs: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729, wherein each sequence is independently at least about 98% identical to the corresponding sequence; and wherein the sense sequences are complementary to said antisense sequences, and wherein each sense sequence can optionally and independently contain up to 3 inserted, substituted, deleted and/or mismatched nucleotides (relative to the antisense sequence).

Table 1: siRNA sequences targeted to viral transcripts, sense and antisense sequences are given 5’ to 3’

siRNA sequences targeted to host factor transcripts

In one embodiment, the siRNAs of the combination according to the invention are directed to one or more host factor transcripts. In one embodiment, the host factor transcripts are selected from host factor transcripts associated with lipid metabolism. siRNA sequences targeted to host factor transcripts are summarized in Table 2 below. If it is referred to a certain SEQ ID No. in the following, the corresponding sequence is listed in Table 2. siRNAs based on antisense sequences

In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 75% identical to the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 85% identical the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In one embodiment, the antisense sequences of the siRNAs are independently selected from SEQ ID NOs: 975 to 1094. In one embodiment, the siRNAs are directed to the CERS6 transcript. Thus, in a preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1065 to 1094.

In one embodiment, the siRNAs are directed to the SMPD2 transcript. Thus, in a preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 75% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 80% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 85% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 90% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 95% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064, wherein each sequence is independently at least about 98% identical to the corresponding sequence. In another preferred embodiment, the antisense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 1035 to 1064. siRNAs based on sense sequences

In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 75% identical to the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 80% identical to the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 85% identical the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 90% identical to the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 95% identical to the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547, wherein each sequence is at least about 98% identical to the corresponding sequence. In one embodiment, the sense sequences of the siRNAs are independently selected from SEQ ID NOs: 428 to 547. In a preferred embodiment, the siRNAs are directed to the CERS6 transcript transcript. Thus, in a preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 518 to 547.

In another preferred embodiment, the siRNAs are directed to the SMPD2 transcript. Thus, in a preferred embodiment, the sense sequences of the siRNAs are independently selected from the group comprising SEQ ID NOs: 488 to 517.

Table 2: siRNA sequences targeted to host factor transcripts, sense and antisense sequences are given 5’ to 3’

- Ill -

siRNA delivery

Hereinafter, the drug delivery system for delivering the siRNAs will be described. A nucleic acid delivery system may be used to increase an intracellular delivery efficiency of siRNA. The nucleic acid delivery system for delivering nucleic acid material into cells may include a viral vector, a non-viral vector, liposome, cationic polymer, a micelle, an emulsion, albumin, and solid lipid nanoparticles. The non- viral vector may have high delivery efficiency and long retention time. The viral vector may include a retroviral vector, an adenoviral vector, a vaccinia virus vector, an adeno-associated viral vector, and an oncolytic adenovirus vector. The nonviral vector may include a plasmid. In addition, various forms such as a liposome, a cationic polymer, a micelle, an emulsion, an albumin and solid lipid nanoparticles may be used. The cationic polymer for delivering nucleic acid may include natural polymer such as chitosan, atelocollagen, cationic polypeptide, and synthetic polymer such as poly(L-lysine), linear or branched poly-ethylene imine (PEI), spermine modified, cyclodextrin-based polycation, and dendrimer. A particularly preferred delivery system for delivering the siRNA combinations is albumin. Exemplary albumin siRNA delivery has been described in Joshi et al., 2020 “Albumin nanocarriers for pulmonary drug delivery: An attractive approach” and Mehta et al., 2019 “Targeting KRAS Mutant Lung Cancer Cells with siRNA-Loaded Bovine Serum Albumin Nanoparticles”.

The lipid nanoparticles form nucleic acid-lipid particles with the siRNA. The nucleic acid-lipid particles generally include a cationic lipid, a non-cationic lipid, a sterol, and a lipid for preventing coagulation of particles (for example, a PEG-lipid conjugate). The nucleic acid-lipid particles have an extended cycle lifespan after they are i.v. injected and are accumulated at a remote position (for example, a position physically remote from an administration site) and thus are extremely beneficial for a systemic application. Also, when nucleic acids are present in the nucleic acid-lipid particles according to one embodiment of the present invention, the nucleic acids are resistant to destruction by nucleases in an aqueous solution. The nucleic acid-lipid particles and a method of preparing the same are, for example, disclosed in US Patent Nos. 5,976,567; 5,981,501; 6,534,484; 6,586,410; and 6,815,432; and WO 96/40964. The nucleic acid-lipid particles may also include one or more additional lipids and/or other components, for example, cholesterol. The other lipids may be included in a liposome composition for various purposes, for example, a purpose of preventing oxidation of lipids or attaching a ligand onto a surface of a liposome. Any number of lipids may exist since the liposome composition may include amphipathic, neutral, cationic, and anionic lipids. Such lipids may be used alone or in combination.

The additional components that may be present in the nucleic acid-lipid particles include a bilayer stabilizing component, for example, a polyamide oligomer (for example, see US Patent No. 6,320,017), a peptide, a protein, a detergent, and lipid derivatives, for example, PEG conjugated to phosphatidylethanolamine, and PEG conjugated to ceramide (see US Patent No. 5,885,613). The nucleic acid-lipid particles may include at least one second aminolipid or cationic lipid, a neutral lipid, a sterol, and a lipid selected to reduce aggregation of lipid particles during formation in order to contribute to structural stabilization of particles which prevent charge- induced aggregation during the formation. The nucleic acid-lipid particles may be prepared using an extrusion method or an in line mixing method. The extrusion method (also referred to as a batch process) is a method of preparing a void liposome (e.g., having no nucleic acids) in advance and adding nucleic acids to the void liposome, which is disclosed in US Patent Nos. 5,008,050; 4,927,637; and 4,737,323; and Biochim Biophys Acta. 1979 Oct 19; 557(l):9-23; Biochim Biophys Acta. 1980 Oct 2; 601(3):559-7; Biochim Biophys Acta. 1986 Jun 13; 858(1): 161-8; and Biochim. Biophys. Acta 1985 812, 55-65. The in-line mixing method is a method of adding lipids and nucleic acids to a mixing chamber side by side. The mixing chamber may be simply a T-connector, or any of other mixing chambers known in the related art. Such methods are disclosed in US Patent Nos. 6,534,018 and 6,855,277; US Patent Publication No 2007-0042031, and Pharmaceuticals Research, Vol. 22, No. 3, Mar. 2005, pp. 362-372. A formulation may be prepared using any methods known in the related art.

Generally, the lipid-siRNA nanoparticles may be spontaneously formed during mixing. Depending on a desired particles size distribution, the resulting nanoparticles mixture may be extruded through a polycarbonate membrane (for example, having a cut-off size of 200 nm or 100 nm).

For efficient delivery to target tissue, the combination of siRNAs (or siRNA pools) according to the invention may be incorporated into nanoparticles, which can enter cells by endocytosis and reach the cytoplasm by endosome escape. Nanoparticles can be formed by a broad range of natural or synthetic molecules as lipids, proteins (e.g. albumin) or polymers. In order to deliver these nanoparticles to the lung, incorporation into microparticles with aerodynamic diameters between 1 and 5 pm is performed. The matrices of these microparticles comprise excipients such as mannitol and trehalose which readily dissolve upon impact on lung lining fluid to release their nano-sized cargo. A method to produce such nano-in-microparticles is spray drying, a method well established in chemical and pharmaceutical industry, see also Keil et al., “Impact of Crystalline and Amorphous Matrices on Successful Spray Drying of siRNA Polyplexes for Inhalation of Nano-in-Microparticles”, 2021. Chemical modifications

In various embodiments, the siRNA may be chemically modified to enhance activity (e.g., stability, efficacy, and specificity), cellular distribution or cellular uptake, or other properties of the siRNA. The siRNAs disclosed herein may be synthesized and/or modified by methods well established in the art. Various embodiments of the siRNA may comprise at least one modified nucleotide (such as, e.g., by chemically modification, conjugation, or substitution) with any suitable group for improving the properties of the siRNA. It is unnecessary for all positions in a given siRNA to be uniformly modified. In some embodiment, more than one modifications may be incorporated in a single siRNA or at a single nucleoside within a siRNA. Exemplary modifications include, e.g., end modifications, e.g., 5’-end modifications (e.g., phosphorylation, conjugation, inverted linkages, etc.) or 3’ -end modifications (e.g., conjugation, DNA nucleotides, inverted linkages, etc.); base modifications, e.g., replacement with stabilizing bases, destabilizing bases, or bases that base pair with an expanded repertoire of partners, removal of bases (abasic nucleotides), or conjugated bases; sugar modifications (e.g., at the T -position or 4’ -position) or replacement of the sugar; and/or backbone modifications, including modification or replacement of the phosphodiester linkages.

Embodiments of siRNAs having modified backbones may include those that retain a phosphorus atom in the backbone and those do not. Exemplary modifications on the phosphate backbones of the siRNA include, e.g., phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, alkyl phosphonates, and those having inverted polarity wherein the adjacent pairs of nucleotides are linked 3’-5’ to 5’-3’ or 2’-5’ to 5’-2\ In some embodiments, the sugar backbone of the siRNA may be replaced by, e.g., amide, morpholine, cyclobutyl, etc. In certain embodiments, at least one strand of the siRNA may comprise a phosphorothioate modified phosphate backbone. The phosphorothioate may comprise a P-S bond replacing a P-OH bond in the phosphate backbone.

In various embodiments, any of the modified siRNAs described herein may also comprise one or more modified sugar moieties. The modified sugar moiety may be a ribose or a deoxyribose. For example, the siRNA may comprise at least one modified nucleotide chosen from: e.g., a 2’-deoxy-2’-fluoro modified nucleotide, 2’-0-methyl modified nucleotide, 2’-deoxy-modified nucleotide, 2’ -0-(2-m ethoxy ethyl) nucleotide (2’-MOE-nucleotide), 2’-amino-modified nucleotide, 2’ -alkyl-modified nucleotide, and 2-SH-modified nucleotide. Exemplary modified sugar moieties also include, e.g., a locked nucleic acid (LNA), an open-loop or unlocked nucleic acid (UNA), and a peptide nucleic acid (PNA). Similar modifications may also be made at other positions on the siRNA, such as, e.g., at the 3’ position of the sugar on the 3’- terminal nucleotide, or at the 5’ position of the sugar on the 5’ -terminal nucleotide. In some embodiments, at least one strand of the siRNA may comprise a T -O-methyl modified nucleotide, i.e., a 2’-0-methyl modification on a ribose or a deoxyribose. In some embodiments, at least one strand of the siRNA may comprise a 2’-deoxy-2’- fluoro modified nucleotide, i.e., a 2’-deoxy-2’-fluoro modification on a ribose or a deoxyribose. In some embodiments, at least one strand of the siRNA may comprise an LNA. The LNA may comprise a cyclic structure formed between 2’-0 and 4’-C in a ribose or deoxyribose. In some embodiments, at least one strand of the siRNA may comprise an open-loop nucleic acid or UNA. The open-loop nucleic acid or UNA may comprise a breakage between 2’-C and 3’-C of a ribose or deoxyribose. In some embodiments, at least one strand of the siRNA may comprise a PNA. The PNA may comprise an amide containing backbone replacing the sugar backbone of a nucleotide.

In various embodiments, siRNAs described herein may comprise a nucleobase (or base) modification. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases, such as, e.g., 5-methylcytosine (5-me-C), 5 -hydroxymethyl cytosine, 5- acetylenyl uracil, 5-ethynyluracil, 5-propynyl uracil, xanthine, hypoxanthine, 2- aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2- thiouracil, 5-halouracil, 5-propynyl uracil, 6-azo cytosine, 5-uracil (pseudouracil), indole, 8-halo, 8-amino and other 8-modified adenines and guanines. In some embodiments, at least one strand of the siRNA may comprise an indole modification. In some embodiments, at least one strand of the siRNA may comprise a 5- methylcytosine modification. In some embodiments, at least one strand of the siRNA may comprise a 5-ethynyluracil modification.

Exemplary modifications of the siRNAs described herein also include linking the siRNA to one or more moieties or conjugates, which may enhance the activity of cellular uptake or targeting, or improve the half-life of the siRNA. Such moieties may include but are not limited to lipid moieties (such as, e.g., cholesteryl derivative, phospholipid, aliphatic chain), peptides, nanoparticle, markers (such as, e.g. cyanine fluorescent dye (e.g., Cy3 or Cy5)), polymers (such as, e.g., polyamine or polyethylene glycol chain), sugars (such as, e.g., galactosyl derivative), antibodies, biotin, cholic acid, ligand, thiol, vitamin (such as, e.g., vitamin E), NH₂, phosphate, and folate. The conjugates may be linked to the siRNA at the 5’ -end, 3’ -end, or both ends, or internally. In some embodiments, at least one strand of the siRNA may comprise a terminal nucleotide linked to a cholesteryl derivative. In some embodiments, the cholesteryl derivative is cholesterol. In some embodiments, at least one strand of the siRNA may comprise a terminal nucleotide linked to a galactosyl derivative. In some embodiments, the galactosyl derivative is galactose. In some embodiments, at least one strand of the siRNA may comprise one or more N-acetylgalactosamine (GalNAc) moieties. In some embodiments, the GalNac moiety is a monovalent GalNAc moiety, a bivalent GalNAc moiety, a trivalent GalNAc moiety, or a tetravalent GalNAc moiety. In some embodiments, at least one strand of the siRNA may comprise a terminal nucleotide linked to a peptide. In some embodiments, the peptide comprises the amino acid sequence N’-Arg-Gly-Asp-C’, i.e., an RGD peptide. In some embodiments, at least one strand of the siRNA may comprise a terminal nucleotide linked to a fluorescent marker. In some embodiments, the fluorescent marker is cyanine marker. In some embodiments, at least one strand of the siRNA may comprise a terminal nucleotide linked to a biotin molecule. In some embodiments, at least one strand of the siRNA may comprise a phosphorylated terminal nucleotide. Various embodiments of the siRNA may comprise any combination of one or more modifications disclosed herein or known in the art. In some embodiments, at least one strand of the siRNA may comprise at least one chemical modification chosen from: (a) a phosphorothioate modified phosphate backbone; (b) a 2’-0-methyl modification in a ribose or deoxyribose; (c) a 2’-deoxy-2’-fluoro modification in a ribose or deoxyribose; (d) an LNA; (e) an open-loop nucleic acid or (UNA); (f) an indole modification; (g) a 5-methylcytosine; (h) a 5’-ethynyluracil; (i) a terminal nucleotide linked to a cholesteryl derivative (such as, e.g., cholesterol); (j) a terminal nucleotide linked to a galactosyl derivative (such as, e.g., GalNAc); (k) a terminal nucleotide linked to a peptide (such as, e.g., an RGD peptide); (1) a phosphorylated terminal nucleotide (such as, e.g., 5’ -phosphorylation); (m) a GalNAc moiety; (n) a terminal nucleotide linked to a fluorescent marker (such as, e.g., a cyanine marker); and (o) a terminal nucleotide linked to a biotin molecule. For example, at least one strand of the siRNA may comprise a combination of one or more modifications chosen from the above. Finally, the siRNAs of the invention can also be modified based on click chemistry. Click chemistry describes pairs of functional groups that rapidly and selectively react (click) with each other in mild, aqueous conditions. The method is routinely used in bioconjugation reactions, for instance to selectively substitute nucleotides at specific positions with suitable side groups as for instance lipids or sugars as GlcNAc. In this approach, nucleosides with reactive click groups as for instance uridine with alkyne and azides click groups may be enzymatically incorporated in RNA molecules using RNA polymerase T7. In a second reaction, RNA molecules containing click- modified nucleotides may selectively react with a second click partner containing for instance strained cyclooctynes groups.

Preferred click modified nucleosides reported to work with RNA polymerase T7 by Jena bioscience are 5-azido-C3-UTP and 5-ethynyl-UTP. Further click modified nucleosides include 5-azidomethyl-UTP, 5-azido-PEG4-UTP, DBCO-PEG4-UTP, DBCO-PEG4-UTP, DBCO-PEG4-UTP, DBCO-PEG4-UTP and DBCO-PEG4-UTP. Click chemistry is described inter alia in https://www.jenabioscience.com/images/741d0cd7d0/20140306_Click_Chemistry_B ackground_information_pdf_creator.pdf.

Second aspect: Pharmaceutical composition comprising the siRNA combinations

The present invention also relates to a pharmaceutical composition comprising a siRNA combination as described above in the first aspect. In one embodiment, the pharmaceutical composition optionally comprises a pharmaceutically acceptable carrier, diluent, or excipient. When two or more different siRNAs are used in combination, the siRNAs may be present, for example, in an equimolar ratio. Two or more combined siRNAs may be used together or sequentially.

"Pharmaceutically acceptable carrier, diluent or excipient" refers to any of the standard pharmaceutical carriers, diluents, buffers, and excipients, such as, e.g., a phosphate buffered saline (PBS) solution, 5% aqueous solution of dextrose, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents and/or adjuvants. Suitable pharmaceutical carriers, diluents or excipients and formulations are known in the art. Proper pharmaceutical carriers, diluents, or excipients may be selected depending upon the intended mode of administration of the active agent.

The pharmaceutical compositions may be administered by methods known in the art or disclosed herein. For example, the pharmaceutical compositions may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer, intratracheal, intranasal), epidermal, and transdermal, spinal, oral, or parenteral. The preferred administration is inhalative, i.e. by inhalation.

In some embodiments, the pharmaceutical composition may be delivered to cells by a carrier chosen from a cationic liposome, chitosan nanoparticle, peptide, and polymer. In contrast to a delivery carrier compound, a "pharmaceutical acceptable carrier" or "excipient" refers to a pharmaceutically acceptable solvent, suspending agent, or any other pharmacologically inert vehicle for delivering one or more nucleic acids to a subject. The excipient can be liquid or solid and can be selected, according to the planned manner of administration, to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Exemplary pharmaceutical carriers include, e.g., binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, com starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.). Suitable pharmaceutically acceptable carriers include, e.g., water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. The pharmaceutical compositions may be formulated into any of many possible dosage forms, such as, e.g., tablets, capsules, gel capsules, powders, or granules. The pharmaceutical compositions may also be formulated as solutions, suspensions, emulsions, or mixed media. In some embodiments, the pharmaceutical compositions may be formulated as a solution. For example, the siRNA may be administered in an unbuffered solution, such as, e.g., in saline or in water. In some embodiments, the siRNA may also be administered in a suitable buffer solution. For example, the buffer solution may comprise acetate, citrate, prolamine, carbonate, or phosphate, or any combination thereof. In some embodiments, the buffer solution may be phosphate buffered saline (PBS). The pH and osmolality of the buffer solution containing the siRNA can be adjusted to be suitable for administering to a subject.

In some embodiments, the pharmaceutical compositions may also be formulated as suspensions in aqueous, non-aqueous, or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

In some embodiments, the pharmaceutical compositions may also be formulated as emulsions. Exemplary emulsions include heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 mm in diameter. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, the oily phase, or itself as a separate phase. Microemulsions are also included as an embodiment of the present disclosure. In some embodiments, the pharmaceutical compositions may also be formulated as liposomal formulations. As used herein, the term "liposome" refers to a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior that contains the composition to be delivered. Cationic liposomes are positively charged lipo- somes which are believed to interact with negatively charged nucleic acid molecules, e.g., DNA molecules, to form a stable complex. Liposomes that are pH-sensitive or negatively-charged are believed to entrap DNA rather than complex with it. Both cationic and non-cationic liposomes can be used to deliver the nucleic acid molecules described herein to cells. Liposomes also include "sterically stabilized" liposomes, which may one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes include those in which part of the vesicle-forming lipid portion of the liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic oligomers, such as a polyethylene glycol (PEG) moiety.

The pharmaceutical compositions described herein may also include surfactants. In some embodiments, the pharmaceutical compositions may also employ various penetration enhancers to effect the efficient delivery of nucleic acids. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers may also enhance the permeability of lipophilic drugs. Exemplary penetration enhancers include surfactants, fatty acids, bile salts, chelating agents, and non-chelating non- surfactants.

Third aspect: Treatment of coronavirus disease using the siRNA combinations

According to one embodiment, the silencing of coronavirus genes and/or host factor genes by the siRNA combination of the present invention may remarkably reduce or eliminate SARS-CoV-2 infection, and therefore treat coronavirus disease, preferably coronavirus 2019 disease. Accordingly, the siRNA combination according to one embodiment of the present invention may be used as a coronavirus disease, preferably coronavirus 2019 disease, therapeutic agent, and thus the present invention provides a composition for use in the treatment of coronavirus disease, preferably coronavirus 2019 disease, comprising the siRNA combination.

Further is described herein a method of treating coronavirus disease, preferably coronavirus 2019 disease, which includes administering a pharmaceutically effective amount of the siRNA combination to a subject in need thereof. Here, the administration of the siRNA combination may inhibit, stop, delay or prevent the occurrence or progression of the disease conditions. Fourth aspect: Kit comprising the siRNA combinations

In a fourth aspect, the present invention relates to a kit comprising the siRNA combination as described in the first aspect. FIGURE LEGENDS

Figure la Average effect of antiviral siPOOLs on SARS-CoV-2 infection rate in tissue culture. 30 siPOOLs covering all transcripts of SARS-CoV-2, were tested in multiple independent experiments. siPOOLs targeting human ACE2 and TMPRSS2 were used as positive controls. A siPOOL consisting of non-targting siRNAs (negl), transfection reagent only (mock), absence of any treatment (untreated) and a siPOOL targeting human KIF11 (KIF11) were used as negative controls. Non-infected (uninfected) cells were used to monitor the background of the assay. Human Caco2 cells (2 experiments) and

African Green Monkey Kidney Vero cells (5 experiments) were infected with multiple titers of SARS-CoV-2 24h after siPOOL transfection and incubated for 24h or 48h. Viral infection was determined with a microscopy based assay, quantifying the total cells number by Hoechst stained cell nuclei and SARS-CoV-2 infected cells with a specific antibody detecting the viral N-protein. Infection rate is indicated as percentage of infected cells, normalized to the negative control siPOOL (negl). Each bar end error represents the average and standard deviation of triplicate mean values from 3 to 7 independent experiments. siPOOLs targeting different regions of the vims show large differences in antiviral activity.

Figure lb Average effect of siPOOLs targeting human host factors on SARS- CoV-2 infection rate in tissue culture. 4 siPOOLs targeting selected genes involved in human lipid metabolism, were tested in 2 experiments. siPOOLs targeting human ACE2 and TMPRSS2 were used as positive controls. A siPOOL consisting of non-targting siRNAs (negl), transfection reagent only (mock) and a siPOOL targeting human KIF11 (KIF11) were used as negative controls. Human Caco2 cells were infected with SARS-CoV-2 48h after siPOOL transfection and incubated for 24h or 48h. Viral infection was determined with a microscopy-based assay, quantifying the total cell number by Hoechst stained cell nuclei and SARS-CoV-2 infected cells with a specific antibody detecting the viral N-protein. Infection rate is indicated as percentage of infected cells, normalized to the negative control siPOOL (negl). Each bar represents the normalized average and standard deviation of triplicate mean values from 2 experiments.

Figure 2 Screening results from all SARS-CoV-2 siPOOLs in list format, indicating numerical values for infection rate and cell count. The same experimental data was used as in figure la. Normalized mean and standard deviation are indicated for infection rate (% infected, SD% infected) and cell count (% cell count, SD % cell count). siPOOLs are ranked by the strength of the antiviral effect showing the strongest siPOOL (SARS-CoV-2-N-p3) on top. siPOOLs reducing infection rate below 15% are marked with a light grey star. siPOOLs reducing cell number by more than 20% are marked with a dark grey star. The column “bullet graph” gives a graphical representation of antiviral activity (vertical line) and cell toxicity (horizontal bar).

Figure 3 (a-e) Detailed visualization of screening results arranged by siPOOLs and controls. The figures are based on the same experimental data as Figure la and 2. Each panel shows the results of one single SARS- CoV-2 siPOOl or control in up to 7 experiments as indicated below the bars: Experiment 1 and 2 in human Caco2 cells with 24h and 48h incubation post infection (24h, 48h), experiment 3 to 7 in African Green Monkey Kidney Vero cells (CoVir l to CoVir_5). Gaps indicate experiments where siPOOLs were omitted. Bars indicate the normalized mean infection rate of experimental triplicates in %. Normalized mean cell count is indicated as line. Y-axis indicates % normalized readout with the negative control siPOOL set to 100. Figure 4 (a-e) Screening results of antiviral siPOOLs and controls indicated as box plots. The figures are based on the same experimental data as figure la, 2 and 3a-e using individual replicate data points. Each box plot represents data of up to 7 experiments. Light grey box plots indicate normalized mean infection rate. Dark grey boxes indicate normalized mean cell count. X-axis labels show the siPOOL or control used (top), the readout (center) and the number of data points (bottom).

Figure 5 Representative fluorescence microscopy images of human Caco2 cells infected with SARS-CoV-2. Cells were transfected with a siPOOL targeting the viral N-gen (left) and the negative control siPOOL (right). 24h post transfection cells were infected with SARS-CoV-2 and fixed 48h later. Cell nuclei were stained with Hoechst (blue). SARS-CoV-2 infection was detected with a monoclonal antibody recognizing the viral N-gene (orange). Infected cells appear as blue cell nuclei with orange surrounding cytoplasma. Images were acquired with an automated epifluorescence microscope using a 20x lense.

Multiple adjacent imaged fields were stitched to a large, high- resolution image. The square field to the lower right shows a fraction of the images in higher magnification.

Figure 6A-F Deconvolution of highly active antiviral siPOOLs in individual siRNAs Figure 7 New antiviral siPOOLs targeting sensitive regions of the viral genome Figure 8 Optimized antiviral siPOOLs consisting of most active single siRNAs from deconvolution of best siPOOLs

Figure 9 Validation of optimized siPOOLs in alpha, delta and omicron strain of SARS-CoV-2

Figure 10 Time course of planned in vivo study in hamsters, delivering an antiviral lead siPOOL to nose and lung.

DETAILED DESCRIPTION

These and other objectives as they may become apparent from the ensuing disclosure can be attained by the subject matter of the independent claims. Some of the specific embodiments considered by the present disclosure form the subject matter of the dependent claims.

The present disclosure will be described with respect to particular aspects and embodiments thereof and with reference to certain figures and examples but the invention is not limited thereto but only by the claims. The present invention illustratively described in the following may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein.

For the purposes of the present disclosure it should be understood that phrases like “Combination of siRNAs for use in prophylactic and/or therapeutic treatment of.

“Use of a combination of siRNAs in the manufacture of a composition for prophylactic and/or therapeutic treatment of ...”, or “Method of prophylactic and/or therapeutic treatment of... by applying a combination of siRNAs to...” all circumscribe that a combination of siRNAs is used for a specific prophylactic and/or therapeutic purpose (such as in the present case the prophylactic and/or therapeutic treatment of coronavirus 19 disease).

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. A suitable source for the understanding of such technical terms may be Giinter Kahl, The Dictionary of Gene Technology, 2nd edition, 2001, Wiley VCH. For the purposes of the present disclosure, the following terms are defined below.

The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

The term "or" means, and is used interchangeably with, the term "and/or," unless context clearly indicates otherwise.

To the extent that the term "contain," "include," "have," or grammatical variants of such term are used in either the disclosure or the claims, such term can be inclusive in a manner similar to the term "comprising" as "comprising" is interpreted when employed as a transitional word in a claim. The term "including" or its grammatical variants mean, and are used interchangeably with, the phrase "including but not limited to". Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. For the purposes of the present invention, the term "consisting of is considered to be a preferred embodiment of the term "comprising of. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also to be understood to disclose a group which preferably consists only of these embodiments. E.g., if hereinafter a group is defined to comprise at least a certain number of sequences, this is also to be understood to disclose a group which preferably consists only of these sequences.

The term "about" means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. The term "about" in the context of the present invention denotes an interval of accuracy that the person skilled in the art will understand to still ensure the technical effect of the feature in question. In general, the term "about" is intended to modify a numerical value above and below the stated value by a variance of ± 10%.

The term "target sequence" refers to a contiguous portion of the nucleotide sequence of an RNA molecule formed during the transcription of a target gene, including mRNA produced by RNA processing of a primary transcription product. In various embodiments, the target sequence may comprise 10-30 contiguous nucleotides of a SARS-CoV-2 and/or host factor mRNA, such as, e.g., 10-25 or 15-20 contiguous nucleotides of the mRNA. In some embodiments, the target sequence may comprise 11, 13, 15, 17, 19, 21, 23, 25, or 27 contiguous nucleotides of the mRNA. In some embodiments, the target sequence may comprise 19 contiguous nucleotides of the mRNA.

The term “host factor” describes a gene of the host (e.g. a mammal, preferably a human), which when silenced via RNAi, leads to reduced or eliminated viral infection (e.g. SARS-CoV-2 infection) and therefore, reduced or eliminated symptoms of coronavirus disease, preferably, coronavirus 2019 disease.

The term "complementary" means that a nucleic acid can hybridize via hydrogen bond and form a duplex structure with another nucleic acid sequence under certain conditions. Such conditions may include, e.g., stringent conditions. The term "stringent conditions" for hybridization refers to conditions under which a nucleic acid having complementarity to a target sequence predominantly hybridizes with the target sequence, and substantially does not hybridize to non-target sequences. Stringent conditions are sequence-dependent and vary depending on a number of factors. For example, the longer the sequence, the higher the temperature at which the sequence may hybridize to its target sequence. The skilled person will be able to determine the set of conditions most appropriate for a test of complementarity of two sequences in accordance with the ultimate application of the hybridized nucleotides. The hybridization may be mediated by Watson-Crick base pairing or non-Watson- Crick base pairing, or base pairing formed with non-natural or modified nucleotides, as long as the above requirements with respect to their ability to hybridize are fulfilled. Examples of non-Watson-Crick base pairing include G:U wobble or Hoogstein base pairing. In certain embodiments, the hybridization between a nucleic acid molecule and its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity. In some embodiments, the two nucleotide sequences are "fully complementary" with each other when all the contiguous nucleotides of the first nucleotide sequence base pairs with the same number of contiguous nucleotides of the second nucleotide sequence, e.g. with the first nucleotide sequence being the sense sequence and the second nucleotide sequence being the antisense sequence of the siRNA. "Substantially complementary" means that the two sequences may be fully complementary, or they may form one or more mismatched base pairs upon hybridization, while retaining the ability to hybridize under the conditions most relevant to their ultimate application. In some embodiments, the two sequences form no more than 6 mismatches upon hybridization. For example, the two sequences may form no more than 4, 3, 2 or 1 mismatch. Where two sequences are designed to form one or more single-stranded nucleotide overhangs upon hybridization, such overhangs shall not be regarded as mismatches for determining complementarity. For example, one oligonucleotide having 19 nucleotides in length and another oligonucleotide having 23 nucleotides in length, wherein the longer oligonucleotide comprises a sequence of 19 nucleotides that is fully complementary to the shorter oligonucleotide, may yet be referred to as "fully complementary" for the purposes of this disclosure.

The term "sequence identity" (e.g. a "sequence having 50% identity to") refers to the extent that a sequence is identical on a nucleotide-by-nucleotide basis over a window of comparison (i.e., the entire sequence of a reference sequence). A "percentage identity" (or "% identity") may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the full length of the reference sequence), and multiplying the result by 100 to yield the percentage of sequence identity. Optimal alignment of sequences for aligning a comparison window may be conducted by computerized implementations of algorithms available in the art, such as, e.g., the BLAST® family of programs, or by inspection and the best alignment (i.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Thus, the term "sequence identity" refers to the ratio of the number of identical nucleotides to the reference sequence when those identical sequences are compared with the entire sequence of the reference sequence. Sequence identity between chemically modified siRNA sequences is calculated by comparing the corresponding unmodified nucleotide sequences. For example, if a single-stranded RNA has 15 nucleotides in length, including 14 contiguous or non-conti guous nucleotides identical to a reference RNA sequence having 19 nucleotides, the identity between the two RNA sequences is 74% (14nt/19nt). By way of another example, if a single-stranded RNA has 17 nucleotides in length, which are identical to a reference RNA sequence having 19 nucleotides, the identity between the two RNA sequences is 89% (17nt/19nt). By way of another example, if a single-stranded RNA has 23 nucleotides in length and the reference RNA sequence has 19 nucleotides in length, and the longer RNA comprises 19 contiguous or non-contiguous nucleotides identical to the shorter reference RNA sequence, the longer RNA sequence may be said to "contain" the short reference RNA sequence. In other words, a reference sequence may be interrupted by insertions or deletions as well as with substitutions in calculating percentage identity.

"G," "C," "A," and "U" each stand for guanine, cytosine, adenine and uracil nucleotide bases, respectively. "T" and "dT" are used interchangeably and refer to a deoxyribonucleotide of which the nucleobase contains thymine, such as, e.g., deoxyribothymine, 2’-deoxythymidine or thymidine. The term "nucleotide "or "ribonucleotide" or "deoxyribonucleotide"refers to a natural nucleotide comprising a nucleobase, a sugar and at least one phosphate group (e.g., a phosphodiester linking group). These terms can also refer to a modified nucleotide, e.g., a chemically- modified nucleotide, or a surrogate replacement moiety. Guanine, cytosine, adenine, and uracil may be replaced by other moieties without substantially altering the base pairing properties of an oligonucleotide comprising a nucleotide bearing such replacement moiety. For example, a nucleotide comprising inosine as its base may base pair with nucleotides containing adenine, cytosine or uracil. Hence, nucleotides containing uracil, guanine or adenine in the nucleotide sequences described herein may be replaced by a nucleotide containing, e.g., inosine. And cytosine anywhere in the nucleotide sequences described herein may be replaced with guanine or uracil.

The term "nucleobase" or "base" are used interchangeably to refer to a purine or pyrimidine base found in natural DNA or RNA (e.g., uracil, thymine, adenine, cytosine and guanine). The terms also include analogs or modified counterparts of these natural purines and pyrimidines, which may confer improved properties to the nucleic acid molecule.

The term "short interfering RNA" or "siRNA" refers to any nucleic acid molecule capable of inhibiting or down-regulating gene expression, e.g., by mediating sequence-specific degradation of an RNA transcript, e.g., an mRNA, through RNAi or gene silencing. In some embodiments, the siRNA can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions. The antisense region comprises a nucleotide sequence that is complementary to the nucleotide sequence in a target nucleic acid molecule (e.g., an Orflab polyprotein transcript and/or the nucleocapsid protein transcript) or a portion thereof (e.g., a target sequence or a portion thereof), and the sense region comprises a nucleotide sequence corresponding to the target sequence or a portion thereof. In some embodiments, the siRNA can be assembled from two separate oligonucleotides and comprises a sense strand and an antisense strand, wherein the antisense and sense strands are complementary, i.e. each strand comprises a nucleotide sequence that is complementary to a nucleotide sequence in the other strand such that the antisense strand and sense strand form a duplex or double-stranded structure. The antisense strand comprises a nucleotide sequence that is complementary to a nucleotide sequence in a target nucleic acid molecule (e.g., an Orflab polyprotein transcript and/or the nucleocapsid protein transcript) or a portion thereof (e.g., a target sequence or a portion thereof), and the sense strand comprises a nucleotide sequence corresponding to the target sequence or a portion thereof. In some embodiments, the siRNA can also be assembled from a single oligonucleotide, wherein the self-complementary sense and antisense regions of the siRNA are linked by a nucleotide based or non-nucleotide based linker(s). In some embodiments, the siRNA can be a polynucleotide having a duplex, asymmetric duplex, hairpin, or asymmetric hairpin secondary structure. In some embodiments, the siRNA can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions. The circular polynucleotide can be processed either in vivo or in vitro to generate an active siRNA molecule capable of mediating RNAi. In some embodiments, the siRNA can also comprise a single-stranded polynucleotide having nucleotide sequence complementary to a nucleotide sequence in a target nucleic acid molecule or a portion thereof (e.g., an Orflab polyprotein transcript and/or the nucleocapsid protein transcript), where such siRNA molecule does not require the presence within the siRNA molecule of a nucleotide sequence corresponding to the target sequence or a portion thereof.

In certain embodiments, the siRNA molecules need not be limited to those molecules containing only natural nucleotides, but further encompasses modified nucleotides and non-nucleotides. For example, the majority of nucleotides of each strand of an siRNA molecule are ribonucleotides, but as described in detail below and in the section “Chemical modifications”, each or both strands can also include one or more non-ribonucleotides, e.g., a deoxyribonucleotide, and/or a modified nucleotide, e.g., a chemically modified nucleotide. In some embodiments, the siRNA molecules may include chemical modifications at multiple nucleotides or multiple chemical modifications on a single nucleotide. Such modifications may include all types of modifications disclosed herein or known in the art. The term modified nucleotide generally refers to a nucleotide, which contains a modification in the chemical structure of the base, sugar and/or phosphate of the unmodified (or natural) nucleotide as is generally known in the art.

The term "siRNA" can also include other terms used to describe nucleic acid molecules capable of mediating sequence-specific RNAi, e.g., double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically-modified siRNA, and post-transcriptional gene silencing RNA (ptgsRNA). In addition, the term "RNAf'can include other terms used to describe sequence-specific RNAi, such as post-transcriptional gene silencing, gene silencing, translational inhibition, or epigenetics. In some embodiments, the siRNA may modulate, e.g., inhibit, the expression of Orflab polyprotein transcript and/or the nucleocapsid protein transcript in a cell, e.g. a cell in a culture or a cell within a subject, such as, e.g., a mammalian subject, e.g., a human.

A "nucleotide overhang" refers to the unpaired nucleotide or nucleotides that protrude from the duplex structure of a double-stranded siRNA molecule when a 3’- end of one strand of the siRNA extends beyond the 5’ -end of the other strand, or vice versa. "Blunt" or "blunt end" means that no unpaired nucleotides exist at that end of a double-stranded siRNA molecule, i.e., no nucleotide overhang. The siRNAs described herein include double-stranded siRNAs with nucleotide overhangs at one end, i.e., siRNAs with one overhang and one blunt end, or with nucleotide overhangs at both ends. The siRNAs described herein also include siRNA that is double- stranded over its entire length, i.e., no nucleotide overhang at either end of the molecule.

The term "inhibit", "down-regulate", "reduce", "silence", "block" or "suppress" all used interchangeably, means that the expression of the gene, or level of the mRNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or level or activity of one or more proteins or protein subunits, is reduced below that observed in the absence of the nucleic acid molecules (e.g., siRNA) described herein. In certain embodiments, inhibition, down- regulation, reduction, silencing, blocking, or suppression with an siRNA molecule is below that level observed in the presence of an inactive or attenuated molecule. In another embodiment, inhibition, down-regulation, reduction, silencing, blocking, or suppression with an siRNA molecule is below that level observed in the presence of, for example, an siRNA molecule with a scrambled sequence or with mismatches (e.g., an siRNA molecule with a random non-specific sequence). The term a "subject" or a "subject in need thereof includes a mammalian subject such as a human subject.

The term a "therapeutically effective amount" or "effective amount" of a compound or composition refers to an amount effective in the prevention or treatment of a disorder for the treatment of which the compound or composition is effective. The term includes the amount of an siRNA molecule that, when administered to a subject for treating coronavirus disease, preferably coronavirus 2019 disease, is sufficient to effect treatment of the disease, e.g., by diminishing, ameliorating, or maintaining the existing disease or one or more symptoms of the disease, or by inhibiting the progression of the disease. The "therapeutically effective amounfor "effective amount" may vary depending on the combination of siRNAs, the route of administration, the disease and its severity, and the health, age, weight, family history, genetic makeup, stage of pathological processes, the types of preceding or concomitant treatments, if any, and other individual characteristics of the subject to be treated. In various embodiments, the term "treatment" includes treatment of a subject (e.g. a mammal, such as a human) or a cell to alter the current course of the subject or cell. Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may be performed either prophylactically or subsequent to the initiation of a pathologic event or contact with an etiologic agent. Also included are "prophylactic" treatments, which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset. "Treatment" or "prophylaxis" does not necessarily indicate complete eradication, cure, or prevention of the disease or condition or the associated symptoms. In various embodiments, the term "treatment" may include relieving, slowing, or reversing the pathological processes or symptoms. “Corona disease 2019” or COVID-19 is a contagious disease caused by SARS-CoV- 2. In particular COVID-19 refers to a disease as defined in the current international classification of diseases (ICD-11, World Health Organisation, Version: 09/2020). More particularly, COVID-19 is used to denote the disease, diagnosed clinically, epidemiologically or otherwise, irrespective of whether laboratory testing is conclusive, inconclusive or not available.

Treating or preventing of COVID-19 may include treating or preventing at least one of lung fibrosis, interstitial pneumonia, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), aveolar damage, kidney injury, vasculopathy, cardiac injury, acute myocardial injury, chronic damage to the cardiovascular system, thrombosis and venous thromboembolism, in a patient with COVID-19. In a specific embodiment lung fibrosis, interstitial pneumonia, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), kidney injury, such as proteinuria and acute kidney injury, and vasculopathy are triggered by COVID-19. COVID19 is caused by SARS-CoV-2, also termed 2019-nCoV, which refers to severe acute respiratory syndrome coronavirus-2 firstly described by Zhu et ah, 2019 and variants thereof, e.g. without limitation variant B.l.1.7 (also known as 201/501 Y. VI, VOC 202012/01), B.1.351 (20H/501Y.V2) and PI, as defined by the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses (ICTV-CSG). Accordingly, SARS-CoV-2 is used to denote all variants of a virus, according to ICTV belonging to realm Riboviria, kingdom Orthomavirae, phylum Pisuviricota, class Pisoniviricetes, order Nidovirales, family Coronaviridae, genus Betacoronavirus, subgenus Sarbecovirus, species Severe acute respiratory syndrome- related coronavirus, strain Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). EXAMPLES

Example 1: siRNA transfection in different cell lines using siRNA combinations targeting SARS-CoV-2 or host factor transcripts

Materials and methods

For siRNA transfection of Vero E6 cells (Cercopithecus aethiops; CCLV-RIE 0929, Collection of Cell Lines in Veterinary Medicine [CCLV], Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany) and CaCo2 cells (Homo sapiens, colon; CCLV- RIE No. 0789), siRNA transfection mix was prepared with RNAiMax transfection reagent (Thermo Fisher) according to the supplier’s instructions and transferred to 96 well tissue culture plates (20 mΐ [3 nM siRNA] per well). siRNA sequences correspond to the sequences as listed in tables 1 and 2 with the corresponding names and SEQ ID Nos. Then, cells were seeded (10⁴ cells in 80m1 cell culture medium/well) and incubated at 37 °C and 5% C0_2. 48 hrs after transfection, the cells were infected by adding SARS-CoV-2 isolate 2019_nCoV Muc-IMB-1 (5xl0³ plaque forming units in 100 mΐ cell culture medium / well). At 24 or 48h hrs post infection, the cells were fixed with 4% paraformaldehyde (30 min incubation at room temperature) and immunostained with a monoclonal antibody recognizing the viral nucleoprotein N (4E10A3A1 (RRID:AB_2833160) by standard indirect immunofluorescence protocols). Cell nuclei were stained with Hoechst 33342 (Sigma-Aldrich).

For quantitative analysis of inhibitory effects, the stained cells were imaged with a Leica Thunder imaging system (lOx objective, 6 fields of view per well). Acquired image data sets were quantitatively analyzed with the image analysis software packages arivis Vision4D or CellProfiler. In both cases, cell nuclei were segmented and counted using the Hoechst DNA staining. As cells normally have one single cell nucleus, the number of cell nuclei was considered to be the number of cells. Staining intensity of the viral nucleoprotein in the vicinity of cell nuclei was used to determine viral infection of individual cells. Infection rate in the cell population was defined as the percentage of cells with perinuclear nucleoprotein staining above a given threshold.

Results In Caco2 cells, all viral and host factor siRNA combinations (siPOOLs) were screened once with two different infection time points, 24 h and 48h post transfection. In Caco2 cells, general infection rate was low with approximately 3% of untreated cells showing viral infection. 5 independent screening experiments with different subsets of viral siPOOls and one single infection timepoint, 24h post transfection, were performed in Vero E6 cells. Here infection rate was close to 100% in untreated cells. All experiments were performed in triplicates. Triplicate means and standard deviations were normalized to the negative control siPOOL (negl) plate mean. For each viral and host factor siPOOL, data from all experiments was aggregated to one mean value, shown in figure la and figure lb. For clarity, the negative control siPOOL “negl” used for normalization is indicated in black and set to 100%. The following additional controls were used in the screening experiments: “untreated”: cells without siPOOL or transfection reagent (light grey); “mock”: transfection reagent only (dark grey); “KIFll”: transfection control with siPOOL targeting human KIFll (grey), “unifected”: untreated cells that were not infected with the virus. siPOOLs targeting human ACE2 and human TMPRSS2 were used as positive controls. As ACE2 and TMPRSS2 are not perfectly conserved between human and green monkey (Cercopithecus aethiops), silencing of Ace2 and Tmprss2 is expected to be less efficient. Viral and host factor siPOOLs correspond to the remaining bars. Infection rates in negative control, KIFll and mock transfected cells as well as untreated cells were similar demonstrating the reproducibility of the assay. The infection rate calculated for uninfected controls indicates the background of the assay.

Several viral siPOOLs show an almost complete inhibition (Figure la). Strongest anti -viral effects are achieved with two of the three siPOOLs targeting the N-gene and a subset of the 10 siPOOLs targeting the large orflab gene. The 5 siPOOLs targeting the S-gene showed intermediate anti-viral effects.

The inhibition of viral infection by silencing host factors was generally weaker than for the direct silencing of viral targets (Figure lb). All host factor data was performed in human Caco2 cells, where the human ACE2 control siPOOLs allows efficient target silencing (<10% remaining mRNA, data not shown) and a 70% reduction in infection. Of all tested host factor siPOOLs, CERS6 and SMPD2 silencing showed the strongest anti-viral effect of approximately 50%. In the literature, both genes were shown to cooperate not only in sphingolipid metabolism but also in the control of inflammation and apoptosis (Int J Mol Med. 2017 Feb;39(2):453-462. doi: 10.3892/ijmm.2016.2835. Epub 2016 Dec 22).

Example 2: Deconvolution of siRNA pools of 15 siRNAs into individual siRNAs and functional testing of antiviral activity in cell culture Materials and methods

For siRNA transfection of Vero E6 cells (Cercopithecus aethiops; CCLV-RIE 0929, Collection of Cell Lines in Veterinary Medicine [CCLV], Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany) siRNA transfection mix was prepared with RNAiMax transfection reagent (Thermo Fisher) according to the supplier’s instructions and transferred to 96 well tissue culture plates (20 mΐ per well). siRNA sequences correspond to the sequences as listed in tables 1 and 2 with the corresponding names and SEQ ID Nos. Then, cells were seeded (10⁴ cells/well in 80m1 cell culture medium/well) and incubated at 37 °C and 5% C02. Final siRNA concentration after cell seeding was 3nM. 20 hrs after transfection, the cells were infected by adding SARS-CoV-2 isolate 2019_nCoV Muc-IMB-1, which had been passaged on vero cells (5x103 plaque forming units in 100 mΐ cell culture medium / well). At 48h hours post infection, the cells were fixed with 4% paraformaldehyde (30 min incubation at room temperature) and immune-stained with a monoclonal antibody recognizing the viral nucleoprotein N (4E10A3A1 (RRID:AB_2833160) by standard indirect immunofluorescence protocols. Cell nuclei were stained with Hoechst 33342 (Sigma-Aldrich).

A negative control siPOOL (“Neg”) with 30 non-targeting 30 siRNAs and mock transfected cells, treated with transfection reagent without siRNAs were present in 2 replicates on each 96well plate. The antiviral siPOOL SAR.S-CoV-2-ORFlab-pl was used as positive control (“pos”). Single siRNAs and positive controls were tested in two replicates, present on two identical experimental plates. Mean cell count and % infected cells of samples and controls were normalized to the mean of all 4 Neg replicates on the two replicate plates and indicated as percentage of the negative control.

Results

6 antiviral siPOOLs, SARS-CoV-2-N-pl, SARS-CoV-2-N-p2, SARS-CoV-2- ORFlab-pl, SARS-CoV-2-ORFlab-p6, SARS-CoV-2-ORFlab-p7 and -p8, were deconvoluted in their 15 individual siRNAs and assayed for antiviral activity and cell toxicity as described. No cell toxicity, obvious in strongly reduced cell count was observed for the controls or any of the individual siRNAs. Antiviral activity of the positive control siPOOL was strong with 14% and 6% remaining infection on the two experimental plate duplicates (pi -2 amd p3-4) as compared to the negative control. In contrast, the antiviral activity of the individual siRNAs varied strongly with the strongest siRNA, orflab-p6-si06, reducing viral infection to 1% and some siRNAs showing no significant antiviral activity. 30 siRNAs with strongest antiviral activity ranging from 1% to 25% % infected cells were selected to compose 3 optimized siPOOls with 10 siRNAs each. The functional validation of these 3 siPOOLs cov-best-pl, cov-best-p2 and cov-best-p3 are described in examples 4 and 5. Figures 6A to 6F show the data of each deconvoluted siPOOL in a separate figure.

Each bar represents the mean of 2 to 4 replicates, normalized to the plate mean of all Neg control samples. Names of single siRNAs or controls are indicated below each bar. The negative control siPOOL “Neg” used for normalization is shown as 100, Two mean values are shown for the transfection reagent only control mock (“mock pi -2” and mock p3-4” )and the positive control pos (“pos pi -2” and pos p3-4”) representing the antiviral siPOOL SARS-CoV-2-ORFlab-pl. Blue bars indicate normalized cell count, representing cell viability. Orange bars indicate normalized percentage of infected cells. Figure 6A shows 15 individual siRNAs, N-p2-si01 to N- p2-sil5 of siPOOL SARS-CoV-2_N-p2. Figure 6B shows 15 individual siRNAs, N- p3-si01 to N-p3-sil5 of siPOOL SARS-CoV-2_N-p3. Figure 6C shows 15 individual siRNAs, ORFlab-pl-siOl to ORFlab-pl-sil5 of siPOOL SARS-CoV-2-ORFlab - pi. Figure 6D shows 15 individual siRNAs, ORFlab-p6-si01 to ORFlab-p6-sil5 of siPOOL SARS-CoV-2-ORFlab-p6. Figure 6E shows 15 individual siRNAs, ORFlab-p7-si01 to ORFlab-p7-sil5 of siPOOL SARS-CoV-2-ORFlab -p7. Figure 6F shows 15 individual siRNAs, ORFlab-p8-si01 to ORFlab-p8-sil5 of siPOOL SARS-CoV-2-ORFlab -p8.

Example 3: Testing of 17 new antiviral siPOOLs targeting sensitive regions of the viral genome Materials and methods

Based on the screening dataset of 30 siRNA pools covering the entire SARS-CoV-2 genome, 2 regions in the N-gene and 7 regions in the ORF- lab-gene were identified as highly sensitive to inhibition with siRNA molecules. A total of 17 siPOOLs, each consisting of 10 to 12 siRNAs with new target sequence not covered in the initial screen were designed, synthesized and tested in the established cell based infection assay, described in materials and methods of example 2.

Results:

All siPOOLs showed high to very high antiviral activity. 4 of the new 17 siPOOLs were more active than ORF-lab-pl, representing one of the most active pools of the first set of 30 antiviral siPOOLs used as positive control in this experiment.

None of the new siPOOLs show stronger anti-proliferative activity than the mock control, indicating a very low cell toxicity of the new siPOOLs.

The exceptionally high rate of strongly active, new siPOOLs designed for specific regions of the viral genome validates the finding that certain regions of the viral genome, namely the N-gene and ORFlab gene (or preferably, sections of the N-gene and certain parts of the ORFlab gene) are especially suitable for the silencing with siRNAs.

Figure 7 shows the data of the new antiviral siPOOLs and controls each bar representing the mean of 2 to 4 replicates, normalized to the plate mean of all Neg control samples. Names of new antiviral siPOOLs or controls are indicated below each bar. The negative control siPOOL “Neg” used for normalization is shown as 100, The transfection reagent only control is termed “mock”. The positive control “pos” represents the antiviral siPOOL SAR.S-CoV-2-ORF lab-pl. Blue bars indicate normalized cell count, representing cell viability. Orange bars indicate normalized percentage of infected cells.

Example 4: Testing of optimized siPOOLs, consisting of selected, highly active siRNAs.

Materials and methods

30 siRNAs with strongest antiviral activity reducing viral infection to 1% to 25% infection were recombined to 3 new siPOOLs termed cov-best-pl, cov-best-p2 and cov-best-p3. Cov-best -pi containing the 10 strongest siRNAs reducing viral infection to 1% to 8%, cov-best-p2 containing the second best set of siRNAs reducing viral infection to a range of 9% to 15% and cov-best-p3 containing the third best set of siRNAs, reducing viral infection to a range of 16% to 25%. The new siPOOLs were tested individually as well as in combinations. For comparison, a set of other antiviral siPOOLs with varying antiviral activity was tested. Each siPOOL or siPOOL combination was tested in 4 replicates. The infection assay was identical to the protocol described in example 2. For data processing, single replicate values were first normalized to the plate mean of all Neg control samples. Next medians and standard deviations were calculated for each sample and control. Results

Cov-best-pl and cov-best-p2 siPOOLs show a similar, strong antiviral activity as the positive control Orf-lab-pl with a slight tendency to even higher efficiency. Cov- best-p3 containing the weakest of the top 30 selected siRNAs shows a significantly lower antiviral activity. Combinations of the siPOOls show intermediate phenotypes. With the positive control siPOOL (“pos”) Orflab-pl reducing viral infection only to an average of 30%, the experiment shows an overall lower efficiency and higher variability of the RNAi reagents which can be attributed to differences within the technical variability of the cell based assay.

Even with the limitations of higher variability and overall lower activity, the results generally demonstrate the reproducible impact of the siRNA composition on the activity of siRNA pools: Cov-best-pl and Cov-best-p2 being reassembled from the strongest siRNAs of different siRNA pools indeed show the same level of antiviral activity as the positive control Orflab. Cov-best-p3 lacking the strongest siRNAs shows consistent but somewhat weaker antiviral activity. The experiment further supports the use of the reassembled cov-best-pl and cov-best p2 siPOOLs as lead siPOOLs for follow up studies.

Figure 8 shows the data of the new optimized antiviral siPOOLs and controls each bar representing the median of 4 replicates, normalized to the plate mean of all Neg control samples. Names of antiviral siPOOLs or controls are indicated below each bar. The negative control siPOOL “Neg” used for normalization is shown as 100, The transfection reagent only control is termed “mock”. The positive control “pos” represents the antiviral siPOOL SARS-CoV-2-ORFlab-pl. Blue bars indicate normalized cell count, representing cell viability. Orange bars indicate normalized percentage of infected cells. For comparison, 7 other antiviral siPOOLs SARS-CoV- 2-N-p3 (sown as “N-p3”), SARS-CoV-2-ORFlab-p2 (sown as “orflab-p2”), siPOOLs SARS-CoV-2-S-p3 (sown as “S-p3”), SARS-CoV-2-ORFlab-rgnl-p2 (sown as “orfl-rgnl-p2”), SARS-CoV-2-ORFlab-rgn7-p4 (sown as “orfl-rgn7-p4”), SARS-CoV-2-ORFlab-rgn6-p3 (sown as “orfl-rgn6-p3”) and SARS-CoV-2-ORF3a- p3 (sown as “orfia-pS”) are shown as comparison.

Example 5: Validation of lead siPOOLs for the in vivo testing in a hamster model and preclinical development

Materials and methods

The optimized siPOOLs cov-best pi, cov-best p2 and cov-best p3 were combined and validated in two compositions to serve as lead siPOOLs for animal testing and preclinical development: cov-best pi and cov-best p2 (cov-best pl+p2) and cov-best pi, cov-best p2 and cov-best p3 (cov-best pl+p2+p3). Vero cells were transfected and infected in 96well plate format generally following the protocol described in example 2. Different to the original conditions, cells were infected with a 10 fold higher dose of SARS-CoV-2 isolate 2019_nCoV Muc-IMB-1 (5xl0⁴ plaque forming units in 100 mΐ cell culture medium / well) and fixed 24h post infection. (Staining, imaging and data analysis was performed as described for example 2.

Results As already observed in example 4, the two lead siPOOLs cov-best-pl+p2 and cov- best-pl+p2+p3 show a stronger antiviral activity than the positive control “pos” identical to SARS-CoV-2-ORF lab-pl. With the cell count being even slightly above the negative and mock control, both lead siPOOLs show no apparent cell toxicity, supporting their use for in vivo testing. Figure 9 shows the data of the optimized and combined antiviral lead siPOOLs. and controls. Each bar representing the mean of 3 replicates, normalized to the plate mean of all Neg control samples. Names of antiviral siPOOLs or controls are indicated below each bar. The negative control siPOOL “Neg” used for normalization is shown as 100, The transfection reagent only control is termed “mock”. The positive control “pos” represents the antiviral siPOOL SARS-CoV-2- ORFlab-pl. Blue bars indicate normalized cell count, representing cell viability. Orange bars indicate normalized percentage of infected cells.

Example 6 Materials and methods

The lead siPOOL cov-best-pl+p2 consistig of the twenty single siRNAs with the strongest antiviral effect shown in example 2 and validated in examples 4 and 5 was produced in lpmol scale for testing in an animal model. 400nmol of the negative control “Neg” were produced as reference. Both siPOOLs were tested for interferon response, assessing the expression of the interferon response gene IFIT1. Both siPOOLs showed no increased expression as compared to mock transfected and non transfected samples indicating the absence of cell toxicity by interferon response.

The antiviral lead siPOOL and the negative control siPOOL will be formulated in lipid nanoparticle using 3 different lipid compositions, representing the current gold standard LNP formulation and two novel formulations with optimized properties for the delivery to airway epithelia in nose, trachea and lung. The gold standard LNP formulation is considered to be the lipid composition of the LNPs used for the approached siRNA drug Onpattro /Patisiran and the currently used mRNA based SARS-CoV-2 vaccines developed by BionTech/Pfizer. Generally, lipid nanoparticles entrapping siPOOLs are prepared by established rapid mixing protocols (https://onlinelibrary.wiley.com/doi/full/10.1002/smtd.201700375). In brief, lipid mixtures in ethanol are mixed rapidly with siPOOLs dissolved in sodium acetate or sodium citrate buffer (pH 4). Resulting LNP-siPOOLs formulations are dialyzed against physiological buffer (pH 7.4), sterile filtered, and concentrated. LNP-siPOOLs size and polydispersity are determined by dynamic light scattering (DLS) measurement. siPOOLs entrapment efficiency is assessed by Quant-iT Ribogreen RNA assay. Total lipid concentration is assessed by cholesterol quantification assay.

Syrian hamsters (Mesocricetus auratus) will be infected with SARS-CoV-2 by oral instillation of virus suspension to the tongue ground, which results in inhalation of the virus in infection of the lung. At 1 day post infection (dpi), siPools are applied by instillation to the tongue ground and nose. siPool treatment is repeated at 2 and 3 dpi. Oral swabs for qRT-PCR detection of the virus are taken daily. At 4 dpi, the animals will be euthanized and lung tissues will be analysed for the level of SARS-CoV-2 infection by qRT-PCR, conventional histochemistry and 3D-Imaging of virus distribution in lung lobes.

4 groups of six hamsters will be tested for the antiviral siPool in three LNP formulations and the negative control in the gold standard LNP formulation. In addition, one group of three hamsters without any siRNA application will be included as negative controls.

Figure 10 shows the time course of the ongoing in vivo study with 3 siRNA treatements 24h, 48h and 72h after infection applied to nose and lung.

The invention further relates to the following embodiments:

1. A combination of siRNAs targeted to one or more severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transcripts and/or host factor transcripts, wherein said combination of siRNAs comprises at least two siRNAs of different sequences and wherein each siRNA comprises an antisense strand and a sense strand.

2. The combination according to 1, wherein the combination comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 siRNAs of different sequences.

3. The combination according to 1 or 2, wherein each siRNA is independently 10 to 27 base pairs in length, preferably 15 to 27 base pairs in length and most preferably 17 to 23 base pairs in length. 4. The combination according to any of the preceding items, wherein the antisense strand of each siRNA is independently selected from SEQ ID NOs: 548 to 1094 and is independently at least 75% identical to the selected sequence.

5. The combination according to any of the preceding items, wherein the siRNAs are directed to one or more SARS-CoV-2 transcripts selected from the group comprising the spike protein transcript, envelope protein transcript, nucleocapsid protein transcript, membrane protein transcript and/or Orflab polyprotein transcript; wherein preferably the siRNAs are directed to the Orflab polyprotein transcript and/or the nucleocapsid protein transcript.

6. The combination according to any of the preceding items, wherein the antisense strand of each siRNA is independently selected from SEQ ID NOs: 548 to 974 and is independently at least 75% identical to the selected sequence.

7. The combination according to any of the preceding items, wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 720 to 869 or wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 590 to 634.

8. The combination according to any of 1 to 4, wherein the siRNAs are directed to the CERS6 transcript and/or SMPD2 transcript.

9. The combination according to any of 1 to 4, wherein the antisense strand of each siRNA is independently selected from SEQ ID NOs: 975 to 1094 and is independently at least 75% identical to the selected sequence.

10. The combination according to any of 1 to 4, wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 1035 to 1064 or wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 1065 to 1094.

11. The combination according to any of the preceding items, wherein each siRNA optionally comprises 1-5 single-stranded nucleotides at its 3’ terminus, preferably 2 single-stranded nucleotides.

12. The combination according to any of the preceding items, wherein each siRNA optionally comprises a modification selected from (a) a phosphorothioate modification in the phosphate backbone;

(b) T -O-methyl modification in a ribose;

(c) 2^,-deoxy-2’-fluoro modification in a ribose;

(d) a locked nucleic acid (LNA) modification;

(e) an open-loop nucleic acid modification; (f) an indole modification;

(g) a 5’-methylcytosine modification in a base;

(h) a 5’-ethynyluracil modification in a base;

(i) a terminal nucleotide linked to a cholesteryl derivative;

(j) a terminal nucleotide linked to a galactose; (k) a terminal nucleotide linked to a polypeptide;

(l) a phosphorylation modification;

(m) a GalNAc moiety;

(n) a terminal nucleotide linked to a fluorescent marker; and

(o) a terminal nucleotide linked to a biotin molecule. 13. A pharmaceutical composition comprising the combination of siRNAs according to any of 1 to 12.

14. A combination of siRNAs according to any one of 1 to 12 for use in the treatment of coronavirus disease, preferably coronavirus 2019 disease (Covid-19). 15. A kit comprising the combination of siRNAs according to any one of 1 to 12.

Claims

2. The combination according to claim 1, wherein the combination comprises at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 siRNAs of different sequences.

3. The combination according to claim 1 or 2, wherein each siRNA is independently 10 to 27 base pairs in length, preferably 15 to 27 base pairs in length and most preferably 17 to 23 base pairs in length.

4. The combination according to any of the preceding claims, wherein the sequence of the antisense strand of each siRNA is independently selected from SEQ ID NOs: 548 to 1094 and 1320 to 1520 and is independently at least 75% identical to the selected sequence.

5. The combination according to any of the preceding claims, wherein the siRNAs are directed to one or more SARS-CoV-2 transcripts selected from the group comprising the spike protein transcript, envelope protein transcript, nucleocapsid protein transcript, membrane protein transcript and/or Orflab polyprotein transcript.

6. The combination according to any of the preceding claims, wherein the siRNAs are directed to the Orflab polyprotein transcript and/or the nucleocapsid protein transcript.

7. The combination according to any of the preceding claims, wherein the sequence of the antisense strand of each siRNA is independently selected from SEQ ID NOs: 548 to 950 and is independently at least 75% identical to the selected sequence.

8. The combination according to any of the preceding claims, wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 720 to 869 or wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 590 to 634.

9. The combination according to any of claims 1 to 4, wherein the siRNAs are directed to the CERS6 transcript and/or SMPD2 transcript.

10. The combination according to any of claims 1 to 4, wherein the sequence of the antisense strand of each siRNA is independently selected from SEQ ID NOs: 975 to 1094 and is independently at least 75% identical to the selected sequence.

11. The combination according to any of claims 1 to 4, wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 1035 to 1064 or wherein the antisense strand of each siRNA is independently selected from the group comprising SEQ ID NOs: 1065 to 1094.

12. The combination according to any of claims 1 to 6, wherein the combination comprises at least 8 or 9 siRNAs of different sequences, wherein the antisense strand of each of the 8 or 9 siRNAs has a sequence selected from one of the following groups: (a) SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847; or

(b) SEQ ID Nos: 724, 837, 818, 732, 623, 734, 628, 612, 848, 729; or

(c) SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823; wherein each of the antisense strand sequences is selected from the same group.

13. The combination according to claim 12, wherein the combination consists of

8, 9 or 10 siRNAs of different sequences, wherein the antisense strand of each of the 8, 9 or 10 siRNAs has a sequence selected from one of the following groups:

(a) SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847; or

(b) SEQ ID Nos: 724, 837, 818, 732, 623, 734, 628, 612, 848, 729; or (c) SEQ ID Nos: 854, 840, 810, 728, 633, 850, 822, 634, 827, 823; wherein each of the antisense strand sequences is selected from the same group.

14. The combination according to any of claims 1 to 6, wherein the combination comprises at least 17, 18 or 19 siRNAs of different sequences, wherein the antisense strand of each of the 17, 18 or 19 siRNAs has a sequence selected from SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729.

15. The combination according to claim 14, wherein the combination consists of 17, 18, 19 or 20 siRNAs of different sequences, wherein the antisense strand of each of the 17, 18, 19 or 20 siRNAs has a sequence selected from SEQ ID Nos: 610, 846, 819, 849, 842, 726, 845, 815, 629, 847, 724, 837, 818, 732, 623, 734, 628, 612, 848, 729.

16. The combination according to any of the preceding claims, wherein each siRNA optionally comprises 1-5 single-stranded nucleotides at its 3’ terminus, preferably 2 single-stranded nucleotides.

17. The combination according to any of the preceding claims, wherein each siRNA optionally comprises a modification selected from

(a) a phosphorothioate modification in the phosphate backbone; (b) T -O-methyl modification in a ribose;

(c) 2’-deoxy-2’-fluoro modification in a ribose;

(d) a locked nucleic acid (LNA) modification;

(e) an open-loop nucleic acid modification;

(f) an indole modification; (g) a 5’-methylcytosine modification in a base;

(h) a 5’-ethynyluracil modification in a base;

(i) a terminal nucleotide linked to a cholesteryl derivative;

(j) a terminal nucleotide linked to a galactose;

(k) a terminal nucleotide linked to a polypeptide; (1) a phosphorylation modification; (m) a GalNAc moiety;

(n) a terminal nucleotide linked to a fluorescent marker; and

(o) a terminal nucleotide linked to a biotin molecule.

18. A pharmaceutical composition comprising the combination of siRNAs according to any of claims 1 to 16.

19. A combination of siRNAs according to any one of claims 1 to 16 for use in the treatment of coronavirus disease, preferably coronavirus 2019 disease (Covid-19).

20. A kit comprising the combination of siRNAs according to any one of claims 1 to 16.