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US-20260125672-A1 - NUCLEIC ACID CONSTRUCT COMPRISING UTR AND USE THEREOF

US20260125672A1US 20260125672 A1US20260125672 A1US 20260125672A1US-20260125672-A1

Abstract

The present invention relates to a nucleic acid construct comprising a UTR and use thereof. Specifically, the UTR can significantly improve the expression efficiency of a target gene in the nucleic acid construct. The nucleic acid construct may comprise a nucleic acid sequence expressing, for example, a human hepatocyte growth factor (hHGF), and can be used in a gene therapy for serious lower limb ischemia, diabetic foot, and other diseases.

Inventors

  • Jun Jiang
  • Linfeng Yang
  • Qinjun CHEN
  • Xiaoyu SONG
  • Wei Ning
  • Cheng Liao

Assignees

  • Shanghai Regenelead Therapies Co., Ltd.

Dates

Publication Date
20260507
Application Date
20230512
Priority Date
20220513

Claims (20)

  1. 1 . A nucleic acid construct, comprising: (a) an open reading frame (ORF), and (b) an untranslated region (UTR), the UTR comprising the following sequence: any one of SEQ ID NOs: 12 and 26 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 1 and 15 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 4-5 and 18-19 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 6-8 and 20-22 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 9-11 and 23-25 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 13 and 27 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 14 and 28 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 29 and 30 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 35-37 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 42 and 43 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 46 and 47 or a sequence having at least 90% identity thereto, or any one of SEQ ID NOs: 31-34, 38-41, and 44-45 or a sequence having at least 90% identity thereto.
  2. 2 . The nucleic acid construct according to claim 1 , wherein the nucleic acid construct comprises a 3′ untranslated region (3′UTR) and a 5′ untranslated region (5′UTR) selected from the group consisting of any one of the following: 1) the 3′UTR comprises the sequence set forth in SEQ ID NO: 1 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 2) the 3′UTR comprises the sequence set forth in SEQ ID NO: 2 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 3) the 3′UTR comprises the sequence set forth in SEQ ID NO: 3 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 4) the 3′UTR comprises the sequence set forth in SEQ ID NO: 4 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 5) the 3′UTR comprises the sequence set forth in SEQ ID NO: 5 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 6) the 3′UTR comprises the sequence set forth in SEQ ID NO: 6 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 7) the 3′UTR comprises the sequence set forth in SEQ ID NO: 7 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 8) the 3′UTR comprises the sequence set forth in SEQ ID NO: 8 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 9) the 3′UTR comprises the sequence set forth in SEQ ID NO: 9 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 10) the 3′UTR comprises the sequence set forth in SEQ ID NO: 10 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 11) the 3′UTR comprises the sequence set forth in SEQ ID NO: 11 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 12) the 3′UTR comprises the sequence set forth in SEQ ID NO: 12 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 13) the 3′UTR comprises the sequence set forth in SEQ ID NO: 13 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 14) the 3′UTR comprises the sequence set forth in SEQ ID NO: 14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15-47 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15-47; 15) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 15 or a sequence having at least 90% identity thereto; 16) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 16 or a sequence having at least 90% identity thereto; 17) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 17 or a sequence having at least 90% identity thereto; 18) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 18 or a sequence having at least 90% identity thereto; 19) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 19 or a sequence having at least 90% identity thereto; 20) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 20 or a sequence having at least 90% identity thereto; 21) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 21 or a sequence having at least 90% identity thereto; 22) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 22 or a sequence having at least 90% identity thereto; 23) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 23 or a sequence having at least 90% identity thereto; 24) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 24 or a sequence having at least 90% identity thereto; 25) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 25 or a sequence having at least 90% identity thereto; 26) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 26 or a sequence having at least 90% identity thereto; 27) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 27 or a sequence having at least 90% identity thereto; 28) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 28 or a sequence having at least 90% identity thereto; 29) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 29 or a sequence having at least 90% identity thereto; 30) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 30 or a sequence having at least 90% identity thereto; 31) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 31 or a sequence having at least 90% identity thereto; 32) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 32 or a sequence having at least 90% identity thereto; 33) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 33 or a sequence having at least 90% identity thereto; 34) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 34 or a sequence having at least 90% or 95% identity thereto; 35) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 35 or a sequence having at least 90% identity thereto; 36) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 36 or a sequence having at least 90% identity thereto; 37) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 37 or a sequence having at least 90% identity thereto; 38) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 38 or a sequence having at least 90% identity thereto; 39) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 39 or a sequence having at least 90% identity thereto; 40) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 40 or a sequence having at least 90% identity thereto; 41) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 41 or a sequence having at least 90% identity thereto; 42) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 42 or a sequence having at least 90% identity thereto; 43) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 43 or a sequence having at least 90% identity thereto; 44) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 44 or a sequence having at least 90% identity thereto; 45) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 45 or a sequence having at least 90% identity thereto; 46) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 46 or a sequence having at least 90% identity thereto; or 47) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 1-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 1-14, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 47 or a sequence having at least 90% identity thereto; 48) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 12-14 or a sequence having at least 90% identity to any one of SEQ ID NOs: 12-14, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15, 29, 30, and 32 or a sequence having at least 90% identity to any one of SEQ ID NOs: 15, 29, 30, and 32; 49) the 3′UTR comprises the sequence set forth in SEQ ID NO: 12 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15, 29, 30, and 32 or a sequence having at least 90% identity thereto; 50) the 3′UTR comprises the sequence set forth in SEQ ID NO: 13 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15, 29, 30, and 32 or a sequence having at least 90% identity thereto; 51) the 3′UTR comprises the sequence set forth in SEQ ID NO: 14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 15, 29, 30, and 32 or a sequence having at least 90% identity thereto; 52) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 12-14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 15 or a sequence having at least 90% identity thereto; 53) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 12-14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 29 or a sequence having at least 90% identity thereto; 54) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 12-14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 30 or a sequence having at least 90% identity thereto; or 55) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 12-14 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 32 or a sequence having at least 90% identity thereto.
  3. 3 . (canceled)
  4. 4 . The nucleic acid construct according to claim 1 , further comprising: (c) a polyadenylic acid (poly-A) tail, wherein optionally, the poly-A tail is selected from the group consisting of A120, A30L70, HGH polyA, SV40 polyA, BGH polyA, rbGlob polyA, and SV40late polyA; wherein the A120 comprises 120 adenine nucleotides, and the A30L70 comprises the sequence set forth in SEQ ID NO: 52 or a sequence having at least 90% identity thereto.
  5. 5 . The nucleic acid construct according to claim 1 , wherein the ORF encodes hepatocyte growth factor (HGF), an antibody or an antigen-binding fragment thereof, preferably human hepatocyte growth factor (hHGF), an anti-PD-1 antibody or an antigen-binding fragment thereof optionally, wherein the ORF comprises any one selected from the group consisting of the following 1)-2): 1) a polynucleotide sequence encoding the amino acid sequence set forth in SEQ ID NO: 109; and 2) the polynucleotide sequence set forth in any one of SEQ ID NOs: 110-113 or a polynucleotide sequence having at least 90% identity thereto; or, the ORF comprises any one selected from the group consisting of the following 1)-3): 1) a polynucleotide sequence encoding a heavy chain amino acid sequence set forth in SEQ ID NO: 117, and/or a polynucleotide sequence encoding a light chain amino acid sequence set forth in SEQ ID NO: 118; 2) a polynucleotide sequence encoding a HCDR1, a HCDR2, and a HCDR3 in the heavy chain amino acid sequence set forth in SEQ ID NO: 117, and a polynucleotide sequence encoding a LCDR1, a LCDR2, and a LCDR3 in the light chain amino acid sequence set forth in SEQ ID NO: 118, the CDRs being defined according to the Kabat, IMGT, Chothia, AbM, or Contact numbering scheme, preferably the Kabat numbering scheme; and 3) the polynucleotide sequence set forth in SEQ ID NO: 119 or a polynucleotide sequence having at least 90% identity thereto, and/or the polynucleotide sequence set forth in SEQ ID NO: 120 or a polynucleotide sequence having at least 90% identity thereto; optionally, the nucleic acid construct comprises the sequence set forth in any one of SEQ ID NOs: 115, 116, and 127 or a sequence having at least 90% identity thereto, or comprises the sequence set forth in SEQ ID NO: 124 or a sequence having at least 90% identity thereto and/or the sequence set forth in SEQ ID NO: 125 or a sequence having at least 90% identity thereto.
  6. 6 . (canceled)
  7. 7 . (canceled)
  8. 8 . An RNA molecule, comprising: (a) an open reading frame (ORF), and (b) an untranslated region (UTR), the UTR comprising the following sequence: any one of SEQ ID NOs: 69 and 83 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 58 and 72 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 59-60 and 73-74 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 61-62 and 75-76 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 63-65 and 77-79 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 66-68 and 80-82 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 70 and 84 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 71 and 85 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 86 and 87 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 92-94 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 99 and 100 or a sequence having at least 90% identity thereto, any one of SEQ ID NOs: 103 and 104 or a sequence having at least 90% identity thereto, or any one of SEQ ID NOs: 88-91, 95-98, and 101-102 or a sequence having at least 90% identity thereto.
  9. 9 . The RNA molecule according to claim 8 , wherein the RNA molecule comprises a untranslated region (3′UTR) and a 5′ untranslated region (5′UTR) selected from the group consisting of any one of the following: 1) the 3′UTR comprises the sequence set forth in SEQ ID NO: 58 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 2) the 3′UTR comprises the sequence set forth in SEQ ID NO: 59 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 3) the 3′UTR comprises the sequence set forth in SEQ ID NO: 60 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 4) the 3′UTR comprises the sequence set forth in SEQ ID NO: 61 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 5) the 3′UTR comprises the sequence set forth in SEQ ID NO: 62 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 6) the 3′UTR comprises the sequence set forth in SEQ ID NO: 63 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 7) the 3′UTR comprises the sequence set forth in SEQ ID NO: 64 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 8) the 3′UTR comprises the sequence set forth in SEQ ID NO: 65 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 9) the 3′UTR comprises the sequence set forth in SEQ ID NO: 66 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 10) the 3′UTR comprises the sequence set forth in SEQ ID NO: 67 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 11) the 3′UTR comprises the sequence set forth in SEQ ID NO: 68 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequences set forth in SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 12) the 3′UTR comprises the sequence set forth in SEQ ID NO: 69 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 13) the 3′UTR comprises the sequence set forth in SEQ ID NO: 70 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 14) the 3′UTR comprises the sequence set forth in SEQ ID NO: 71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72-104 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72-104; 15) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 72 or a sequence having at least 90% identity thereto; 16) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 73 or a sequence having at least 90% identity thereto; 17) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 74 or a sequence having at least 90% identity thereto; 18) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 75 or a sequence having at least 90% identity thereto; 19) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 76 or a sequence having at least 90% identity thereto; 20) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 77 or a sequence having at least 90% identity thereto; 21) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 78 or a sequence having at least 90% identity thereto; 22) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 79 or a sequence having at least 90% identity thereto; 23) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 80 or a sequence having at least 90% identity thereto; 24) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 81 or a sequence having at least 90% identity thereto; 25) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 82 or a sequence having at least 90% identity thereto; 26) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 83 or a sequence having at least 90% identity thereto; 27) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 84 or a sequence having at least 90% identity thereto; 28) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 85 or a sequence having at least 90% identity thereto; 29) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 86 or a sequence having at least 90% identity thereto; 30) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 87 or a sequence having at least 90% identity thereto; 31) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 88 or a sequence having at least 90% identity thereto; 32) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 89 or a sequence having at least 90% identity thereto; 33) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 90 or a sequence having at least 90% identity thereto; 34) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 91 or a sequence having at least 90% or 95% identity thereto; 35) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 92 or a sequence having at least 90% identity thereto; 36) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 93 or a sequence having at least 90% identity thereto; 37) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 94 or a sequence having at least 90% identity thereto; 38) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 95 or a sequence having at least 90% identity thereto; 39) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 96 or a sequence having at least 90% identity thereto; 40) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 97 or a sequence having at least 90% identity thereto; 41) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 98 or a sequence having at least 90% identity thereto; 42) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 99 or a sequence having at least 90% identity thereto; 43) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 100 or a sequence having at least 90% identity thereto; 44) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 101 or a sequence having at least 90% identity thereto; 45) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 102 or a sequence having at least 90% identity thereto; 46) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 103 or a sequence having at least 90% identity thereto; or 47) the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 58-71 or a sequence having at least 90% identity to any one of SEQ ID NOs: 58-71, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 104 or a sequence having at least 90% identity thereto.
  10. 10 . The RNA molecule according to claim 8 , wherein: the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 69-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72, 86, 87, and 89 or a sequence having at least 90% identity to any one of SEQ ID NOs: 72, 86, 87, and 89; optionally, the 3′UTR comprises the sequence set forth in SEQ ID NO: 69 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72, 86, 87, and 89 or a sequence having at least 90% identity thereto; the 3′UTR comprises the sequence set forth in SEQ ID NO: 70 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72, 86, 87, and 89 or a sequence having at least 90% identity thereto; the 3′UTR comprises the sequence set forth in SEQ ID NO: 71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in any one of SEQ ID NOs: 72, 86, 87, and 89 or a sequence having at least 90% identity thereto; the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 69-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 72 or a sequence having at least 90% identity thereto; the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 69-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 86 or a sequence having at least 90% identity thereto; the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 69-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 87 or a sequence having at least 90% identity thereto; or the 3′UTR comprises the sequence set forth in any one of SEQ ID NOs: 69-71 or a sequence having at least 90% identity thereto, and the 5′UTR comprises the sequence set forth in SEQ ID NO: 89 or a sequence having at least 90% identity thereto.
  11. 11 . The RNA molecule according to claim 8 , further comprising: (c) a polyadenylic acid (poly-A) tail and/or (d) a 5′ cap structure (5′Cap), wherein optionally, the poly-A tail is selected from the group consisting of A120, A30L70, HGH polyA, SV40 polyA, BGH polyA, rbGlob polyA, and SV40late polyA; wherein the A120 comprises 120 adenine nucleotides, and the A30L70 comprises the sequence set forth in SEQ ID NO: 52 or a sequence having at least 90% or 95% identity thereto; the 5′Cap is selected from the group consisting of Cap0, Cap1, Cap2, Cap3, Cap4, ARCA, modified ARCA, inosine, N1-methyl-guanosine, 2′-fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine, 3′-O-Me-m7G(5′)ppp(5′)G, m7G(5′)ppp(5′)(2′OMeA)pU, m7Gppp(A2′O-MOE)pG, m7G(5′)ppp(5′)(2′OMeA)pG, m7G(5′)ppp(5′)(2′OMeG)pG, m7(3′OMeG)(5′)ppp(5′)(2′OMeG)pG, and m7(3′OMeG)(5′)ppp(5′)(2′OMeA)pG; optionally, the RNA molecule comprises one or more modifications, wherein optionally the modifications include backbone modifications, sugar modifications, base modifications, and/or lipid modifications: more preferably, the base modifications are uracil modifications.
  12. 12 . The RNA molecule according to claim 8 , wherein the ORF encodes hepatocyte growth factor (HGF), an antibody or an antigen-binding fragment thereof, preferably human hepatocyte growth factor (hHGF), an anti-PD-1 antibody or an antigen-binding fragment thereof; optionally, the ORF comprises any one selected from the group consisting of the following 1)-2): 1) a nucleic acid sequence encoding the amino acid sequence set forth in SEQ ID NO: 109; and 2) an RNA sequence set forth in any one of SEQ ID NOs: 128-131 or an RNA sequence having at least 90%, preferably at least 95%, identity thereto; or, the ORF comprises any one selected from the group consisting of the following 1)-3): 1) a nucleic acid sequence encoding a heavy chain amino acid sequence set forth in SEQ ID NO: 117, and/or a nucleic acid sequence encoding a light chain amino acid sequence set forth in SEQ ID NO: 118; 2) a nucleic acid sequence encoding a HCDR1, a HCDR2, and a HCDR3 in the heavy chain amino acid sequence set forth in SEQ ID NO: 117, and a nucleic acid sequence encoding a LCDR1, a LCDR2, and a LCDR3 in the light chain amino acid sequence set forth in SEQ ID NO: 118, the CDRs being defined according to the Kabat, IMGT, Chothia, AbM, or Contact numbering scheme, preferably the Kabat numbering scheme; and 3) an RNA sequence set forth in SEQ ID NO: 121 or an RNA sequence having at least 90% identity thereto, and/or an RNA sequence set forth in SEQ ID NO: 122 or an RNA sequence having at least 90% identity thereto.
  13. 13 . (canceled)
  14. 14 . (canceled)
  15. 15 . (canceled)
  16. 16 . An isolated polynucleotide, comprising (a) an open reading frame (ORF), the ORF comprising the sequence set forth in any one of SEQ ID NOs: 111-113 and 129-131 or a sequence having at least 90% identity thereto, wherein optionally, the polynucleotide comprises any one of the following (b)-(d) or any combination thereof: (b) a 5′UTR and/or a 3′UTR, (c) a poly-A tail, and (d) a 5′Cap; preferably, the poly-A tail is selected from the group consisting of A120, A30L70, HGH polyA, SV40 polyA, BGH polyA, rbGlob polyA, and SV40late polyA; more preferably, the poly-A tail is A120 or A30L70; preferably, the 5′Cap is selected from the group consisting of ARCA, 3′-O-Me-m 7 G(5′)ppp(5′)G, m 7 G(5′)ppp(5′)(2′OMeA)pU, m 7 Gppp(A2′O-MOE)pG, m 7 G(5′)ppp(5′)(2′OMeA)pG, m 7 G(5′)ppp(5′)(2′OMeG)pG, m 7 (3′OMeG)(5′)ppp(5′)(2′OMeG)pG, and m 7 (3′OMeG)(5′)ppp(5′)(2′OMeA)pG; preferably, the polynucleotide comprises one or more modifications selected from the group consisting of backbone modifications, sugar modifications, base modifications, and/or lipid modifications, wherein the base modifications are preferably pseudouridine modifications.
  17. 17 . (canceled)
  18. 18 . (canceled)
  19. 19 . A vector, comprising the nucleic acid construct according to claim 1 .
  20. 20 . A host cell, comprising the vector according to claim 19 .

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase of International PCT Application No. PCT/CN2023/093851 filed on May 12, 2023, which claims priority to Chinese Patent Application No. CN202210522056.8 filed on May 13, 2022 and entitled “NUCLEIC ACID CONSTRUCT COMPRISING UTR AND USE THEREOF,” the contents of which are incorporated herein by reference in their entireties. SEQUENCE LISTING This application incorporates by reference the material in the ST.26 XML file titled CHENG-73_Revised_Sequence-listing, which was created on Jul. 1, 2025 and is 209,097 bytes. TECHNICAL FIELD The present disclosure belongs to the field of nucleic acids and relates to a nucleic acid construct comprising UTRs and use thereof for preventing or treating a disease. The nucleic acid construct can comprise a nucleic acid sequence that expresses human hepatocyte growth factor (hHGF) and is used as a gene therapy drug for diseases such as critical limb ischemia and diabetic foot ulcer. BACKGROUND Gene therapy and genetic vaccination can offer highly specific and personalized treatment and prevention plans for a variety of diseases, including genetic diseases, autoimmune diseases, cancer or tumor-related diseases, and inflammatory diseases. Both DNA and RNA can be used in gene therapy or genetic vaccination. DNA is stable and easy to manipulate but involves a risk of mutational events (e.g., loss of function of a damaged gene) and the like due to the insertion of a DNA fragment into the genome of the patient. RNA can avoid unwanted genomic integration but is prone to degradation due to ubiquitous RNases. Therefore, it is necessary to improve RNA stability, allowing its encoded protein product to accumulate in vivo so as to realize disease treatment or prevention, and maintaining the structural and functional integrity of RNA during storage and administration. Naturally occurring eukaryotic mRNA molecules have been found to contain stabilizing elements, such as untranslated regions (UTRs) at the 5′ and 3′ ends, and other structural features such as the 5′ cap structure and the 3′ polyadenylic acid tail. The 5′UTR and 3′UTR are premature mRNA elements, and during mRNA processing, structural features unique to mature mRNA (such as the 5′ cap and the 3′ polyadenylic acid tail) are added to the transcribed (premature) mRNA. Regarding the correlation between UTRs and mRNA stability, studies have shown that the 3′UTR of α-globin mRNA is an important factor in α-globin mRNA stability (Nancy D Rodgers et al, RNA. 2002 December; 8(12):1526-37; Z Wang et al, Mol Cell Biol. 1999 July; 19(7):4552-60). Peripheral artery disease (PAD) refers to a non-coronary arterial system syndrome caused by a range of structural and functional abnormalities in the arteries supplying the limbs, internal organs, and brain, is characterized by narrowing, occlusion, and tumor-like pathological changes in the non-coronary blood circulation, and affects the aorta and branch arteries. In PAD, ischemic diseases of the lower limbs are most clinically common. The main causes include atherosclerosis obliterans (ASO), diabetic artery obliterans (DAO), and thrombosis angiitis obliterans (TAO). Critical limb ischemia (CLI) is an advanced stage of ASO, and diabetic foot ulcer (DFU) is a type of DAO. Both are peripheral vasculopathic diseases characterized by pain, ulcers, and necrosis in the lower limbs due to narrowing or blockage of the lower limb blood vessels and insufficient distal blood perfusion. Currently, revascularization through operation or intracavity intervention is an effective treatment for CLI and DFU. However, more than 40% of patients are not eligible for revascularization due to age, comorbidities, etc., leaving conservative treatment with drugs as the only option. Drug therapy can only slow disease progression and cannot cure it. Hepatocyte growth factor (HGF) is a multifunctional mesenchyme-derived growth factor. When binding to the cell membrane surface receptor c-met, it triggers phosphorylation of intracellular tyrosine residues, recruits adapter proteins, enhances kinase activity, and thereby activates downstream signaling pathways. HGF is an important regulatory factor in processes such as embryonic development, tissue and organ regeneration, wound healing, and angiogenesis. It can promote the proliferation and migration of endothelial cells and smooth muscle cells, promote microvascular network reconstruction in ischemic areas, and inhibit apoptosis. Research has shown that intramuscularly injecting naked plasmids to deliver hHGF-cDNA can significantly promote blood perfusion in ischemic lower limbs of rats and domestic rabbits (Y Taniyama et al. Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. Gene Ther. 2001 February; 8(3):181-9). Clinical data show that injecting naked plasmids into calf