Gene therapy treatment

{
  "publication_number": "US2026103494A1",
  "country": "US",
  "kind": "A1",
  "title": "Gene therapy treatment",
  "abstract": "This disclosure concerns transcription cassettes comprising nucleic acid molecules comprising a nucleotide sequence encoding AP-4 subunits; vectors comprising said transcription cassettes; pharmaceutical compositions comprising said vector; and vectors or compositions for use in the treatment of AP-4-Hereditary Spastic Paraplegia.",
  "claims": [
    "1. An isolated nucleic acid molecule comprising: a transcription cassette comprising in a 5′ to 3′ direction between first and second inverted repeat sequences: i) a promoter adapted for expression in a mammalian neurone wherein said promoter is associated with an enhancer nucleotide motif; ii) an intron nucleotide sequence; and iii) a polyadenylation signal nucleotide sequence; wherein said cassette further comprises a nucleic acid molecule comprising a nucleotide sequence that encodes at least one protein of the AP-4 complex. 2. The isolated nucleic acid molecule according to claim 1 wherein said enhancer motif is a CMV enhancer. 3. The isolated nucleic acid molecule according to claim 2 wherein said CMV enhancer motif comprises or consists of the nucleotide sequence in SEQ ID NO: 1, or polymorphic nucleotide sequence variant thereof, 4. The isolated nucleic acid molecule according to claim 1, wherein said polyadenylation signal is a growth hormone (GH) polyadenylation signal. 5. The isolated nucleic acid molecule according to claim 4 wherein said GH polyadenylation signal comprises or consists of the nucleotide sequence in SEQ ID NO: 4, or polymorphic sequence variant thereof. 6. The isolated nucleic acid molecule according to claim 1, wherein said promoter is the chicken beta actin promoter, a JeT promoter, a hSyn promoter, a MeP229 promoter, or a AP4B1 promoter. 7. The isolated nucleic acid molecule according to claim 6 wherein said chicken beta actin promoter comprises or consists of the nucleotide sequence in SEQ ID NO: 3 or 28. 8. (canceled) 9. The isolated nucleic acid molecule according to claim 1, wherein said transcription cassette comprises or consists of the nucleotide sequence in SEQ ID NO: 9. 10. The isolated nucleic acid molecule according to claim 1, wherein said transcription cassette comprises a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of: i) a nucleotide sequence, or polymorphic sequence variant, as set forth in SEQ ID NO: 15 (AP4B1); ii) a nucleotide sequence wherein said sequence is degenerate as a result of the genetic code to the nucleotide sequence defined in (i); iii) a nucleic acid molecule the complementary strand of which hybridizes under stringent hybridization conditions to the sequence in SEQ ID NO: 15 (AP4B1) wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex; iv) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence as represented in SEQ ID NO: 16 (AP4B1); and v) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence wherein said amino acid sequence is modified by addition deletion or substitution of at least one amino acid residue as represented in iv) wherein said polypeptide forms a complex with polypeptides comprising the AP-4 complex. 11. The isolated nucleic acid molecule according to claim 1, wherein said transcription cassette comprises a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of: i) a nucleotide sequence, or polymorphic sequence variant, as set forth in SEQ ID NO: 17 (AP4E1); ii) a nucleotide sequence wherein said sequence is degenerate as a result of the genetic code to the nucleotide sequence defined in (i); iii) a nucleic acid molecule the complementary strand of which hybridizes under stringent hybridization conditions to the sequence in SEQ ID NO: 17 (AP4E1); wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex; iv) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence as represented in SEQ ID NO: 18 (AP4E1); and v) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence wherein said amino acid sequence is modified by addition deletion or substitution of at least one amino acid residue as represented in iv) wherein said polypeptide forms a complex with polypeptides comprising the AP-4 complex. 12. The isolated nucleic acid molecule according to claim 1, wherein claim said transcription cassette comprises a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of: i) a nucleotide sequence, or polymorphic sequence variant, as set forth in SEQ ID NO: 19 (AP4M1); ii) a nucleotide sequence wherein said sequence is degenerate as a result of the genetic code to the nucleotide sequence defined in (i); iii) a nucleic acid molecule the complementary strand of which hybridizes under stringent hybridization conditions to the sequence in SEQ ID NO: 19(AP4M1); wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex; iv) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence as represented in SEQ ID NO: 20 (AP4M1); and v) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence wherein said amino acid sequence is modified by addition deletion or substitution of at least one amino acid residue as represented in iv) wherein said polypeptide forms a complex with polypeptides comprising the AP-4 complex. 13. The isolated nucleic acid molecule according to claim 1, wherein said transcription cassette comprises a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of: i) a nucleotide sequence, or polymorphic sequence variant, as set forth in SEQ ID NO: 21 (AP4S1); ii) a nucleotide sequence wherein said sequence is degenerate as a result of the genetic code to the nucleotide sequence defined in (i); iii) a nucleic acid molecule the complementary strand of which hybridizes under stringent hybridization conditions to the sequence in SEQ ID NO: 21 (AP4S1); wherein said nucleic acid molecule encodes a polypeptide that forms a complex with polypeptides comprising the AP-4 complex; and iv) a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence as represented in SEQ ID NO: 22 (AP4S1); a nucleotide sequence that encodes a polypeptide comprising an amino acid sequence wherein said amino acid sequence is modified by addition deletion or substitution of at least one amino acid residue as represented in iv) wherein said polypeptide forms a complex with polypeptides comprising the AP-4 complex. 14. An expression vector comprising the isolated nucleic acid molecule according to claim 1. 15. The expression vector according to claim 14 wherein said expression vector is a viral based expression vector. 16.- 20. (canceled) 21. The expression vector according to claim 15 wherein said viral based vector comprises the nucleotide sequence set forth in SEQ ID NO: 10, 11, 12, 13, 14, 23, 24, 25, 26, or 27. 22.- 30. (canceled) 31. A pharmaceutical composition comprising the expression vector according to claim 14 and an excipient or carrier. 32. (canceled) 33. A method for treating AP-4 Hereditary Spastic Paraplegias in a subject, comprising administering an effective amount of the expression vector according to claim 14 to the subject. 34. The expression vector according to claim 33 wherein said subject is a paediatric subject. 35. A method for measuring the efficacy of the treatment of hereditary spastic paraplegia in a subject wherein said subject is treated with the expression vector according to claim 14, comprising: a) measuring the level of neurofilament L (NFL) in a biological sample obtained from the subject suffering from hereditary spastic paraplegia prior to administration of the expression vector, and b) comparing said levels to the levels of NFL in a biological sample obtained from the subject suffering from hereditary spastic paraplegia after the administration of the expression vector, and wherein i) if the NFL levels are lower when compared to the levels obtained in step a) the treatment with the expression vector or composition is paused, or ii) if the levels are the same as the levels in step a) the treatment with the expression vector is continued. 36. (canceled) 37. The method according to claim 35 wherein said sample under b) is obtained between 1-6 days or 1-4 weeks. 38. A method for measuring efficacy of hereditary spastic paraplegia in a subject suffering from hereditary spastic paraplegia and wherein said subject is treated with the expression vector according to claim 14, comprising: a) measuring the level of neurofilament L (NFL) in a biological sample obtained from the subject suffering from hereditary spastic paraplegia and treated with said expression vector or composition, and b) comparing said level with that of control subjects. 39. (canceled) 40. The method according to claim 38 further comprising c) wherein when said levels in a biological sample obtained from the subject suffering from hereditary spastic paraplegia are the same or lower than the NFL levels in a biological sample obtained from the control subject the treatment is effective and paused, or c) wherein when said levels in a biological sample obtained from the subject suffering from hereditary spastic paraplegia are higher than the NFL levels in a biological sample obtained from the control subject the treatment is ineffective and the treatment with the expression vector is continued. 41. (canceled)"
  ],
  "description_excerpt": "This disclosure concerns transcription cassettes comprising nucleic acid molecules comprising a nucleotide sequence encoding at least one subunit of the heterotetrametric adaptor protein complex 4 (AP-4); vectors comprising said transcription cassettes; pharmaceutical compositions comprising said vector; and vectors or compositions for use in the treatment of AP-4 hereditary spastic paraplegias.\n\nHereditary Spastic Paraplegias (HSPs) are a family of rare inherited, progressive, lower-limb spasticity disorders with an overall prevalence of 0.5-5.5 individuals per 100,000. Hereditary spastic paraplegia (HSP) in young patients is often characterised by weakness and spasticity (stiffness) of the legs and can later in life lead to further complications and may require the assistance of a cane, walker or wheelchair. There are a variety of genetic types of HSP such as autosomal dominant, autosomal recessive, X-linked, and maternally inherited (mitochondrial) forms with the autosomal dominant form most commonly found affecting between 75-80% of HSP patients. A variety of diagnostic methods for the identification of mutations in genes responsible for different forms of HSP, such as autosomal-recessive HSP (AR-HSP) caused by mutations in genes KIAA1840 (U.S. Pat. No. 10,519,503) or ZFYVE26 (US2017152562), or autosomal-dominant HSP caused by mutations in SPG3A, are disclosed in CN1958605.",
  "cpc": [
    "C07K 14/47",
    "A61K 38/1709",
    "A61K 48/0058",
    "A61P 25/28",
    "C12N 15/86",
    "C12N 2750/14143",
    "C12N 2830/008",
    "C12N 2830/50",
    "G01N 2800/28",
    "G01N 2800/52",
    "G01N 33/6896"
  ],
  "ipc": [
    "A61K 38/17",
    "A61K 48/00",
    "A61P 25/28",
    "C07K 14/47",
    "C12N 15/86",
    "G01N 33/68"
  ],
  "assignees": [
    "University of Sheffield"
  ],
  "inventors": [
    "Mimoun Azzouz",
    "Christopher Webster"
  ],
  "filing_date": "2023-10-12",
  "publication_date": "2026-04-16",
  "priority_date": "2022-10-14",
  "application_number": "US-202319116588-A",
  "family_id": "84818418",
  "cited_by_count": 0
}