Search

EP-4741009-A2 - MYOGENIC PROGENITOR CELLS FOR USE IN AN OPTIMIZED METHOD FOR THE PREVENTION AND TREATMENT OF ANAL INCONTINENCE

EP4741009A2EP 4741009 A2EP4741009 A2EP 4741009A2EP-4741009-A2

Abstract

The present invention relates to myogenic progenitor cells (MPCs) for use in a method for the prevention and/or treatment of anal incontinence in a subject, wherein said subject is at risk to develop anal incontinence or suffers from anal incontinence for 20 years or less than 20 years, more preferably for about 6 months to about 20 years or for about 6 months to about 10 years. The present invention also refers to a pharmaceutical composition comprising MPCs and a pharmaceutical acceptable excipient and/or carrier for use in a method for the prevention and/or treatment of anal incontinence according to the present invention.

Inventors

  • THURNER, Marco
  • MARKSTEINER, RAINER

Assignees

  • Innovacell GmbH

Dates

Publication Date
20260513
Application Date
20220805

Claims (15)

  1. Myogenic progenitor cells (MPCs) for use in a method for the prevention and/or treatment of anal incontinence in a subject, wherein said subject is at risk to develop anal incontinence or suffers from anal incontinence for 20 years or less than 20 years, more preferably for about 6 months to about 20 years or for about 6 months to about 10 years, wherein the MPCs are (i) characterized by a positive expression of the markers of CD56 and CD90, in particular wherein at least 60 % of the MPCs express CD56 and at least 60 % of the myogenic progenitor cell express CD90, or (ii) skeletal muscle derived cells (SMDCs) characterized in that more than about 60% of said SMDC express CD56 and A2B5, or (iii) obtained by a method comprising the steps of: (a) cooling of an obtained muscle biopsy; (b) processing and cooling of the sample; (c) resuspending the sample of step (b) in medium with serum comprising at least one enzyme and heating up to 38°C for 1 to 20 hours; pelleting the sample, in particular wherein step (c) is conducted at a temperature in the range of 25 to 38°C, and (d) resuspending the pellet of the sample of step (c) to provide a single cell suspension from the sample of step (c), thereby obtaining MPCs, or (iv) characterized by an AChE activity of about 20 mU rel to about 1000 mU rel , more preferably of about 30 mU rel to about 800 mU rel , more preferably about 50 to about 700 mU rel , wherein said AChE activity is determined per 2*10 5 cells.
  2. The MPCs for use according to claim 1, wherein the subject's anal incontinence or risk to develop anal incontinence is caused by muscle damage.
  3. The MPCs for use according to claim 1 or 2, wherein the subject has a severity of incontinence defined as more than 6, preferably more than 7, preferably more than 8, preferably more than 9 or preferably more than 10 weekly incontinence episodes prior to treatment.
  4. The MPCs for use according to any one of claims 1 to 3, wherein the subject has a severity of incontinence defined as more than 2 weekly incontinence episodes classified as little or more prior to treatment.
  5. The MPCs for use according to any one of claims 1 to 4, wherein the MPCs are administered into or adjacent to the anal sphincter apparatus of said subject, preferably into the external anal sphincter muscle, into the internal anal sphincter muscle and/or into the puborectalis muscle.
  6. The MPCs for use according to any one of claims 1 to 5, wherein the method comprises stimulation of the anal sphincter apparatus prior to and/or after administration of MPCs.
  7. The MPCs for use according to claim 6, wherein stimulation comprises at least 2 weeks of anal sphincter apparatus stimulation after administration of MPCs, more preferably at least 2 weeks of anal sphincter apparatus stimulation prior to and after administration of MPCs.
  8. The MPCs for use according to claim 6 or 7, wherein the stimulation is performed by Kegel exercise and/or by percutaneous electrical stimulation.
  9. The MPCs for use according to claim 8, wherein the percutaneous electrical stimulation is performed daily and preferably at least twice or at least trice per day.
  10. The MPCs for use according to any one of claim 6 to 9, wherein each stimulation is for at least 10 minutes, more preferably for at least 20 minutes.
  11. The MPCs for use according to any one of claims 1 to 10, wherein the MPCs are a cell population of skeletal muscle derived cells (SMDCs), wherein at least 60 % of the cells are positive for CD56, at least 80 % of the cells are positive for CD90, and at most 10% of the cells are positive for CD34, in particular wherein also at least 60% of the cells are positive for desmin and preferably at most 10% of the cells express MyoD.
  12. The MPCs for use according to any one of claims 1 to 11, wherein the MPCs are isolated from a human subject.
  13. The MPCs for use according to any one of claims 1 to 12, wherein the method comprises the administration of an effective amount of MPCs, preferably (i) the administration of about 1 to about 200 million MPCs, about 4 to about 60 million MPCs, about 4 to about 6 million MPCs or about 40 to about 60 million MPCs, and/or (ii) the administration of an amount of MPCs having a total AChE activity of about 1*10 2 mU rel_total to about 1*10 6 mU rel_total , more preferably of about 1*10 3 mU rel_total to about 5*10 5 mU rel_total and even more preferably of about 7*10 4 mU rel_total to about 2*10 5 mU rel_total .
  14. The MPCs for use according to any one of claims 1 to 13, wherein the MPCs are administered by one or more injections into and/or adjacent to the anal sphincter apparatus of said subject, preferably by one or more injections into the external anal sphincter muscle, the internal anal sphincter muscle and/or into the puborectalis muscle.
  15. The MPCs for use according to any one of claims 1 to 14, wherein the MPCs are comprised in a pharmaceutical composition comprising a pharmaceutical acceptable excipient and/or carrier.

Description

FIELD OF THE INVENTION The present invention relates to myogenic progenitor cells (MPCs) for use in a method for the prevention and/or treatment of anal incontinence in a subject, wherein said subject is at risk to develop anal incontinence or suffers from anal incontinence for 20 years or less than 20 years, more preferably for about 6 months to about 20 years or for about 6 months to about 10 years. The present invention also refers to a pharmaceutical composition comprising MPCs and a pharmaceutical acceptable excipient and/or carrier for use in a method for the prevention and/or treatment of anal incontinence according to the present invention. BACKGROUND OF THE INVENTION Anal incontinence and its epidemiology The ability to maintain continence is fundamental for our well-being as social beings. The loss of anal continence results in physical, physiological, and social handicaps. Generally, it is thought, that primarily elderly and handicapped people suffer from anal incontinence, however, these symptoms can occur in people of every age. The spectrum of anal incontinence, i.e., the loss of control of the content of the intestine, ranges from minor feces marks (traces) in the underwear to the loss of flatus up to massive episodes of uncontrolled defecation of soft or solid feces. The reasons for this can be multilayered and complex. Independently of the extremely impaired life quality for the affected individual, impaired anal continence results in a not to be underestimated cost factor for the public health system. In the USA more than 400 million dollars are spent per year for anal incontinence help programs. Furthermore, anal incontinence is the second most frequent reason for hospitalization in nursery homes (more frequently than dementia). One third of the elderly people in nursery homes or hospitals are incontinent for feces. Anatomy and physiology of anal continence Anatomic structures necessary for anal continence were studied in more detail in the last decade due to the possibility of endoanal imaging techniques. This also let to an improved understanding of the anal continence mechanism and the factors responsible for maintaining anal continence. Anal continence requires the coordination of different anatomic structures with different physiological functions. An intact sensibility ensures the perception of the status of rectal filling and recognition of the quality of feces. A functional innervation enables the specialized ring-shaped muscles (sphincters) to respond to an increased anal "closing request" in an appropriate manner (voluntarily and involuntarily). Finally, if the sphincter muscles are intact, they provide for the complete occlusion of the anal canal until defecation is appropriate. The dysfunction of one of these structures results in a disturbance of anal continence. Functionality of the sphincter apparatus is based on the involuntary resting pressure of the Musculus sphincter ani internus (internal anal sphincter), consisting of smooth muscle tissue, and the involuntary resting pressure and voluntary squeeze pressures originating from the Musculus sphincter ani externus (external anal sphincter). The constant base line tonus of the M. puborectalis results in a "contortion" of the anorectal transition towards the symphysis forming an angle of 90° between the anal canal and the rectum. This anorectal angle also contributes to the maintenance of anal continence. However, maintaining continence is not possible by the M. puborectalis alone. The anal continence is further provided by an interaction of the internal and external anal sphincters. The hemorrhoidal cushions of the anal canal mucosa squeezed together by the sphincter muscles ultimately provide for airtight occlusion. In the resting state the anal canal is occluded by the constant tonic activity of the external anal sphincters and the base line resting pressure of the internal anal sphincter. The internal anal sphincter, which is a continuation and enlargement of the circular smooth muscle layer of the colon, provides for about 75-85% of the base line pressure of the closed anal canal. The activity of this smooth muscle component is completely inhibited by a rectal distension, the so called rectal anal inhibitory reflex. This relaxation is accompanied by a reflex contraction of the external anal sphincter and M. puborectalis to prevent defecation if inappropriate. If defecation at that time is convenient, the external anal sphincter and puborectalis muscle relax, leading to an involuntary colorectal motor activity resulting in a greater rectal pressure than anal pressure followed by fecal expulsion. If the defecation is inconvenient at the time of occurring urge to defecate, defecation can be deferred by voluntary contraction of the puborectalis and external anal sphincter muscle thereby pushing back the feces into rectum until defecation is convenient. Cause of anal incontinence The importance of the described structures in