Search

EP-4735596-A2 - ANTISENSE TREATMENT

EP4735596A2EP 4735596 A2EP4735596 A2EP 4735596A2EP-4735596-A2

Abstract

The disclosure provides methods, compounds (molecules) and/or compositions for the treatment and/or prevention of diseases and/or conditions caused or contributed to by TAR DNA-binding protein 43 (TDP-43) dependent mis-splicing of its downstream target genes.

Inventors

  • SIBLEY, CHRIS
  • CARDONA-ALBERICH, Aida

Assignees

  • The University Court Of The University of Edinburgh

Dates

Publication Date
20260506
Application Date
20240626

Claims (20)

  1. 1 . A compound for use in the treatment or prevention of (i) diseases or conditions with TDP-43 pathology; (ii) TDP-43 proteinopathies; (iii) Neurodegenerative diseases; (iv) Motor neurone disease; (v) Amyotrophic Lateral Sclerosis (ALS); (vi) frontotemporal dementia (FTD); (vii) Alzheimer’s disease; (viii) primary lateral sclerosis; (ix) progressive muscular atrophy; (x) facial onset sensory and motor neuronopathy; (xi) limbic-predominant age-related TDP-43 encephalopathy; (xii) cerebral age-related TDP-43 with sclerosis; (xiii) inclusion body myopathy; (xiv) Perry disease; or (xv) Parkinson’s disease wherein said compound prevents the mis-processing or mis-splicing of genes which are downstream targets of TDP-43.
  2. 2. The compound for use of claim 1 , wherein the compound is an antisense oligonucleotide.
  3. 3. The compound for use of claim 2, wherein the antisense oligonucleotide comprises a sequence complementary to a mis-spliced or mis-processed gene transcript.
  4. 4. The compound for use of claim 3, wherein the mis-spliced or mis-processed transcript is derived from a gene which is a downstream target of TDP-43.
  5. 5. The compound for use of claims 3 or 4, wherein the transcript comprises a cryptic exon
  6. 6. The compound for use of claims 3-5, wherein said antisense oligonucleotide partially overlaps with, or is in close proximity to, a splicing-modulating cis-element of one or more cryptic exons present in the transcript.
  7. 7. The compound for use of any preceding claim, wherein the one or more downstream target genes of TDP-43 is ATG4B and/or RANBP1.
  8. 8. The compound for use of claims 3-6, wherein the transcript is derived from ATG4B and/or RANBP1.
  9. 9. The molecule for use of any one of claims 2-8, wherein said compound comprises a sequence selected from SEQ ID NO: 1 to 5.
  10. 10. An antisense oligonucleotide molecule comprising a sequence selected from the group consisting of: SEQ ID NO: 1 ; SEQ ID NO: 2; SEQ ID NO: 3; SEQ ID NO: 4; and SEQ ID NO: 5.
  11. 11. The antisense oligonucleotides of claim 10, for use in medicine or for use as a medicament.
  12. 12. A method of preventing and/or modulating aberrant TDP-43 activity in a cell, said method comprising contacting a cell with an antisense oligonucleotide according to claim 10.
  13. 13. The method of claim 12, wherein said aberrant TDP-43 activity comprises mis-splicing or mis-processing of one or more downstream target genes of TDP-43, mislocalisation of TDP-43 and/or aggregation of TDP-43.
  14. 14. The antisense oligonucleotide of any of claims 10 to 13 further comprising one or more modifications to prevent cellular degradation, to provide greater stability and/or to improve solubility.
  15. 15. A composition comprising the antisense oligonucleotide of any of claims 10 to 14.
  16. 16. The composition of claim 15, wherein said composition is a pharmaceutical composition.
  17. 17. The composition of claims 15 to 16 further comprising one or more pharmaceutically acceptable excipients, diluents and/or carriers.
  18. 8. The antisense oligonucleotide of any of claims 10 to 14 or the composition of any of claims 15 to 17 for use in the treatment or prevention of: (i) diseases or conditions with TDP-43 pathology; (ii) TDP-43 proteinopathies; (iii) Neurodegenerative diseases; (iv) Motor neurone disease; (v) Amyotrophic Lateral Sclerosis (ALS); (vi) frontotemporal dementia (FTD); (vii) Alzheimer’s disease; (viii) primary lateral sclerosis; (ix) progressive muscular atrophy; (x) facial onset sensory and motor neuronopathy; (xi) limbic-predominant age-related TDP-43 encephalopathy; (xii) cerebral age-related TDP-43 with sclerosis; (xiii) inclusion body myopathy; (xiv) Perry disease; or (xv) Parkinson’s disease.
  19. 19. ATG4B and/or RANBP1 or a functional fragment thereof, for use in medicine or for use as a medicament.
  20. 20. An ATG4B and/or RANBP1 transcript for use in medicine or for use as a medicament.

Description

ANTISENSE TREATMENT FIELD The present disclosure provides molecules and compounds for use in medicine and for the treatment or prevention of proteinopathies. BACKGROUND Amyotrophic lateral sclerosis (ALS) is a rapidly progressing and fatal disease with 1 :400 lifetime risk, and it is the most common motor neuron disease (MND). At present, there are limited therapeutic options approved for ALS treatment; of those that are available, Riluzole (the only drug approved for ALS in the UK) provides symptomatic relief and extends life expectancy by approximately 3 months. Over 95% of all ALS cases display TDP-43 pathology, where TDP-43 loss of function and/or gain in TDP-43-mediated toxicity are widely believed to be pathogenic. In addition to ALS, TDP-43 pathology has been reported in approximately 50% of frontotemporal dementia cases, in approximately 57% of Alzheimer’s disease cases, and all limbic-predominant age-related TDP-43 encephalopathy cases. Further, it is seen in Parkinson’s disease, primary lateral sclerosis, progressive muscular atrophy, facial onset sensory and motor neuronopathy, cerebral age-related TDP-43 with sclerosis, inclusion body myopathy and Perry disease. Despite the relevance of TDP-43 in the pathology of various diseases, the mechanism by which TDP-43 contributes to the pathogenesis of such diseases remains elusive. It is amongst the objectives of the present disclosure to develop a novel approach to prevent and/or treat neurodegenerative diseases and other TDP-43 proteinopathies. SUMMARY The present disclosure is based in part on the finding that TAR DNA-binding protein 43 (TDP-43) dependent mis-splicing of certain downstream target genes may result in, or contribute to, a variety of different disease and/or conditions. Accordingly, this disclosure provides methods, compounds (molecules) and/or compositions for the treatment and/or prevention of those diseases and/or conditions. In this regard, the term ‘diseases’ and/or ‘conditions’ may embrace any one or more of the following: (i) diseases or conditions with TDP-43 pathology (ii) TDP-43 proteinopathies; (iii) Neurodegenerative diseases; (iv) Motor neurone disease; (v) Amyotrophic Lateral Sclerosis; (ALS) (vi) frontotemporal dementia; (FTD) (vii) Alzheimer’s disease; (viii) primary lateral sclerosis, (ix) progressive muscular atrophy, (x) facial onset sensory and motor neuronopathy, (xi) limbic-predominant age-related TDP-43 encephalopathy, (xii) cerebral age-related TDP-43 with sclerosis, (xiii) inclusion body myopathy (xiv) Perry disease; and (xv) Parkinson’s disease. It should be noted that the terms “comprise”, “comprising” and/or “comprises” is/are used to de-note that aspects and embodiments of this invention “comprise” a particular feature or features. It should be understood that this/these terms may also encompass aspects and/or embodiments which “consist essentially of” or “consist of” the relevant feature or features. The disclosure provides molecules, compounds and/or compositions disclosed herein for use in treating or preventing of any one or more of the diseases or conditions listed above as (i)-(xv). The disclosure further provides use of any the disclosed molecules, compounds and/or compositions in the manufacture of a medicament for treating or preventing of any one or more of the diseases or conditions listed above as (i)-(xv). Moreover, the disclosure provides a method of treating or preventing of any one or more of the disease or conditions listed above as (i)-(xv), the method comprising administering a subject in need thereof, a molecule, compound or composition of this disclosure. Without wishing to be bound by theory, it is suggested that loss of TDP-43 (or loss of TDP- 43 function) is associated with a reduction in the expression of certain proteins, including proteins involved in autophagy and nucleo-cytoplasmic transport. Moreover, it has been shown that dysfunction of these proteins (via the mechanisms described herein) may impact TDP-43 homeostasis, driving a ‘toxic loop’ that promotes further TDP-43 associated pathology. Again, without wishing to be bound by theory, loss of TDP-43 or loss of TDP-43 function, may lead to certain pre-messenger RNAs (pre-mRNAs) being mis-processed such that they are subject to the inclusion of cryptic exons. Whereas cryptic exons are considered part of an intron (as they usually remain excluded from host transcripts), under certain pathological circumstances they can become incorporated into the mRNA. Under normal conditions, cryptic exons may be directly repressed from being included in mRNA by TDP-43. However, when TDP-43 repression is lost, their inclusion can result in defective mRNA molecules that are, for example, truncated and/or degraded. This in turn leads to a reduction in the level of the corresponding protein. By way of specific example, normal function and/or expression of TDP-43 prevents missplicing events in the ATG4B and RANBP1 genes. However, when TDP-4