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EP-4735612-A1 - VIRAL VECTORS FOR TREATING BLADDER DISEASES

EP4735612A1EP 4735612 A1EP4735612 A1EP 4735612A1EP-4735612-A1

Abstract

The present invention provides a method and a pharmaceutical composition for the treatment of overactive bladder (OAB) and/or bladder pain syndrome (BPS) comprising the viral expression vector carrying a transcription cassette that harbors transgene(s) inhibiting/silencing neurotransmission or synaptic transmission of afferent neurons.

Inventors

  • EPSTEIN, Alberto L.
  • HAAG MOLKENTELLER, Cornelia Charlotte

Assignees

  • EG 427

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1. A viral expression vector for use in the treatment of overactive bladder (OAB) and/or bladder pain syndrome (BPS), wherein said viral vector comprises at least: a) one promoter active selectively in afferent neurons of the bladder, b) at least one transcription cassette comprising a nucleotide sequence operably linked to said promoter, wherein said nucleotide sequence silences or inhibits the transduction of the neurotransmitter signal in a postsynaptic cell when transcribed, and c) one sequence conferring long-term expression operably linked to said transcription cassette.
  2. 2. The viral expression vector according to claim 1, wherein said vector is an adeno- associated virus (AAV) vector or a herpes simplex virus (HSV) vector.
  3. 3. The viral expression vector according to claim 1 or 2, wherein said vector is a herpes simplex virus (HSV) vector.
  4. 4. The viral expression vector according to claim 2 or 3, wherein said herpes simplex virus (HSV) vector is a HSV-1 vector.
  5. 5. The viral expression vector according to any one of claims 1-4, for use in the treatment of OAB.
  6. 6. The viral expression vector according to any one of claims 1-4, for use in the treatment of BPS.
  7. 7. The viral expression vector according to claim 6, wherein the BPS is interstitial cystitis (IC).
  8. 8. The viral expression vector according to any one of claims 1-7, wherein said nucleotide sequence silences or inhibits neurotransmission or synaptic transmission of afferent neurons when transcribed by disrupting the SNARE complex and/or the ribosome complex, and/or by activating GABA(A) receptors, and/or by inducing conditionally targeted neuron ablation.
  9. 9. The viral expression vector according to any one of claims 1-8, wherein said promoter is a promoter selected from promoters of genes coding for sensory neuroreceptors.
  10. 10. The viral expression vector according to any one of claims claim 1-9, wherein said at least one nucleotide sequence is transcribed into a non-coding nucleotide sequence inhibiting the synthesis of at least one protein selected from the group consisting of VAMP, SNAP-25 and syntaxin.
  11. 11. The viral expression vector according to claim 10, wherein said non-coding nucleotide sequence is selected from the group consisting of antisense RNA (asRNA), small hairpin RNA (shRNA), and microRNA (miRNA).
  12. 12. The viral expression vector according to any one of claims 1-9, wherein said at least one nucleotide sequence codes for a wild-type or a modified bacterial neurotoxin disrupting the SNARE complex or an active fragment thereof, a wild-type or a modified GAD67 protein or an active fragment thereof, a wild-type or a modified ribosome inactivating protein (RIP) or an active fragment thereof, or a wild type or a modified nitroreductase (NTR) or an active fragment thereof.
  13. 13. The viral expression vector according to claim 12, wherein said active fragment of the wild-type or modified bacterial neurotoxin is the light chain of said bacterial neurotoxin.
  14. 14. The viral expression vector according to claim 12, wherein said bacterial neurotoxin is the neurotoxin of Clostridium botulinum of any serotype or the tetanus neurotoxin of Clostridium tetani.
  15. 15. The viral expression vector according to claim 12, wherein said bacterial neurotoxin is the light chain of the botulinum neurotoxin A (BoNT- A), the light chain of the botulinum neurotoxin B (BoNT-B), the light chain of the botulinum neurotoxin Cl (BoNT-Cl), the light chain of the botulinum neurotoxin E3 (BoNT- E3), the light chain of the botulinum neurotoxin Fl (BoNT-Fl) and the light chain of the tetanic neurotoxin (TeNT).
  16. 16. The viral expression vector according to claim 1, which comprises at least: a) one nucleotide sequence coding for a wild type or modified neurotoxin of Clostridium tetani or botulinum or for an active fragment thereof; and/or b) one nucleotide sequence whose transcripts inhibit the synthesis of the protein VAMP, SNAP-25 and/or syntaxin; and/or c) one nucleotide sequence coding for a wild type or modified GAD67 protein or an active fragment thereof; and/or d) one nucleotide sequence coding for a wild type or modified RIP or an active fragment thereof and/or e) one nucleotide sequence coding for a wild type or modified NTR or an active fragment thereof.
  17. 17. The viral expression vector according to claim 1, wherein: i. said one sequence conferring long-term expression is operably linked to two of said at least one transcription cassette; or ii. two sequences conferring long-term expression are both operably linked to one of said at least one transcription cassette; and wherein: a) one of said at least one transcription cassette harbors a coding nucleotide sequence for a wild-type or a modified bacterial neurotoxin disrupting the SNARE complex or an active fragment thereof, a wild-type or a modified GAD67 protein or an active fragment thereof, a wild-type or a modified ribosome inactivating protein (RIP) or an active fragment thereof, or a wild type or a modified nitroreductase (NTR) or an active fragment thereof, and the second of said at least one transcription cassette harbors a nucleotide sequence that is transcribed into a non-coding nucleotide sequence inhibiting the synthesis of at least one protein selected from the group consisting of VAMP, SNAP-25 and syntaxin; or b) both transcription cassettes harbor a nucleotide sequence coding for a non-coding nucleotide sequence for a wild-type or a modified bacterial neurotoxin disrupting the SNARE complex or an active fragment thereof, a wild-type or a modified GAD67 protein or an active fragment thereof, a wild-type or a modified ribosome inactivating protein (RIP) or an active fragment thereof, or a wild type or a modified nitroreductase (NTR) or an active fragment thereof; or c) both transcription cassettes harbor a nucleotide sequence coding for a wild type or modified neurotoxin of Clostridium tetani and/or Clostridium botulinum or for an active fragment thereof; or a wild type or modified GAD67 protein or for an active fragment thereof; or a wild type or modified RIP or for an active fragment thereof; or for a wild type or modified NTR or for an active fragment thereof
  18. 18. The viral expression vector according to any one of claims 1-17, wherein said at least one sequence conferring long-term expression is an LTE and/or DNA insulator from the HSV-1 genome.
  19. 19. The viral expression vector according to claim 9, wherein said promoter is a promoter of the TRP gene family or promoters of genes coding for sensory neuromodulators or sensory neurotransmitters .
  20. 20. The viral expression vector according to claim 19, wherein said promoter is a promoter of TRPV1 or TRPM8, or a promoter of substance P, PACAP, CGRP, or ADVL.

Description

VIRAL VECTORS FOR TREATING BLADDER DISEASES RELATED APPLICATION This application claims the benefit of U.S. Provisional Application No. 63/524,486, filed on June 30, 2023. The entire teachings of the above application are incorporated herein by reference. SEQUENCE LISTING The sequence listing submitted via EFS, in compliance with 37 CFR § 1.52(e)(5), is incorporated herein by reference. The sequence listing XML file submitted via EFS contains the file “42873006 WO Seq List.xml”, created on June 27, 2024, which is 65,362 bytes in size. BACKGROUND The present invention is directed to a viral expression vector and a pharmaceutical composition thereof that selectively modulates or silences the afferent nerves of the bladder, as a gene therapy strategy for the treatment of overactive bladder (OAB) and/or interstitial cystitis (IC). Abnormal bladder function is a common problem which significantly affects the quality of life of millions of men and women in the United States. There are two principal clinical manifestations of altered bladder physiology: the atonic bladder and the hyperreflexic bladder. The atonic bladder or detrusor underactivity has diminished capacity to empty its urine contents because of ineffective contractility of the detrusor smooth muscle (the outer smooth muscle of the bladder wall). Conversely, the hyperreflexic, uninhibited, or bladder that exhibits detrusor overactivity contracts spontaneously during the filing of the bladder, this may result in urinary frequency, urinary urgency and urge incontinence, where the individual is unable to control the passage of urine. Ranging from light to highly debilitating forms, overactive bladder is a very common disease affecting 15-33% of general population, with a strong unbalance towards women, characterized by the urgent need to go to the bathroom up to 40 times per day, with or without incontinence. Major impact on quality of life and self-esteem is concurrent with mental health impact with depression and anxiety. The frequent need to urinate may occur during the day, at night, or both. Overactive bladder is characterized by a group of four symptoms: urgency, urinary frequency, nocturia, and urge incontinence. Defined as a chronic pain from the pelvic area in the absence of urinary infection, Interstitial cystitis (IC), a type of painful bladder syndrome (PBS), is chronic pain in the bladder and pelvic floor. Symptoms include feeling the need to urinate right away, needing to urinate often, and pain with sex. IC/PBS is associated with depression and lower quality of life. Many of those affected also have irritable bowel syndrome and fibromyalgia. IC/PBS is estimated to affect 0.9% of US population, with a 2-fold increase incidence over the past decades. Those patients have, however, very limited medical options with only one approved drug that have demonstrated limited effects. Medications that have been used to treat hyperreflexic bladder are usually only partially effective and have severe side effects that limit the patient's use and enthusiasm. The currently- accepted treatment options (e.g., oxybutynin and tolteradine) are largely nonspecific and most frequently involve blockade of the muscarinic- receptor pathways and/or the calcium channels on the bladder myocytes. Given the central importance of these two pathways in the cellular functioning of many organ systems in the body, such therapeutic strategies are not only crude methods for modulating bladder smooth muscle tone they are also virtually guaranteed to have significant and undesirable systemic effects. Over time, most OAB patients do not respond to the standard pharmacological approaches to treatment, such as oral antimuscarinics and beta-3 agonists that have systemic off-target effects and are thus poorly tolerated by many patients. Local injections of botulinum toxins basically paralyse the bladder muscle, thus requiring in 15% of cases, patients to empty their bladder using catheterization 4 to 6 times a day, with an associated higher risk of urinary infections. For OAB, implantable medical devices have been approved requiring costly surgical procedures. Accordingly, there is a great need for improved treatment options for bladder dysfunction. DESCRIPTION OF THE FIGURES The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. The following examples merely intend to illustrate the present invention. FIG. 1. Genome of recombinant defective HSV-1 vectors. (A): The upper part of the figure describes the backbone of the HSV-1 genome used in this invention. The HSV-1 genome contains two unique regions,