Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06590142
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-02-22
Brief Title:
Hirschsprungs Advances Working Towards Autologous tIssue therapIes
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Investigating the Interaction of the Enteric Nervous System With the Extrinsic Nervous System and the Immune System in Children and Development of Cell Therapies for Hirschsprungs Disease
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HAWAII
Brief Summary:
Children with Hirschsprungs Disease HSCR have no normal nerve cells in the lower end of their bowel This can cause babies to die if left untreated treated Currently the part of bowel that doesnt have normal nerves is removed with an operation but this can have long-term complications including needing a permanent bag on the tummy for poo stoma Because of this there is an urgent need for better treatments
The investigators have found that children with HSCR have nerve stem cells throughout their bowel even in the lower end where the nerves havent grown normally We can grow these stem cells in the laboratory to form balls of nerve cells neurospheres The investigators want to find out whether these neurospheres grow into the nerves that are needed for the bowel to work normally First the investigators will see how the nerve stem cells from the lower end of the bowel grow compared to those from the normal bowel Then the investigators will see if the neurospheres change when the investigators put them with medications that affect growth of bowel nerves
At the end of this project the investigators hope to know whether the nerve stem cells at the lower part of the bowel in children with HSCR can turn into bowel nerve cells that might make the bowel work normally The investigators also hope to know whether the investigators can use medications to make the stem cells turn into normal nerves meaning that children with HSCR could avoid an operation and a stoma
The investigators have found that children with HSCR have nerve stem cells throughout their bowel even in the lower end where the nerves havent grown normally We can grow these stem cells in the laboratory to form balls of nerve cells neurospheres The investigators want to find out whether these neurospheres grow into the nerves that are needed for the bowel to work normally First the investigators will see how the nerve stem cells from the lower end of the bowel grow compared to those from the normal bowel Then the investigators will see if the neurospheres change when the investigators put them with medications that affect growth of bowel nerves
At the end of this project the investigators hope to know whether the nerve stem cells at the lower part of the bowel in children with HSCR can turn into bowel nerve cells that might make the bowel work normally The investigators also hope to know whether the investigators can use medications to make the stem cells turn into normal nerves meaning that children with HSCR could avoid an operation and a stoma
Detailed Description:
The gastrointestinal GI tract is responsible for many functions essential to life such as digestion absorption and excretion all of which are under the control of its own intrinsic nervous system the enteric nervous system ENS The ENS is part of the autonomic peripheral nervous system and provides the intrinsic innervation of the bowel - the submucosal and myenteric plexuses are the two networks that comprise the ENS and consist of bundles of enteric neurons and glia - the enteric ganglia that are connected by nerve fibres The ENS is essential for the autonomic regulation of gastric motility and secretion
Hirschsprungs disease HSCR is a gut motility disorder affecting 1 in 5000 people worldwide HSCR is characterised by the absence of ganglia and nerve fibres of the ENS to various extents of the bowel 80 of cases affect the distal colon and internal anal sphincter but 10 of cases have total colonic aganglionosis and 1 total intestinal aganglionosis Between the ganglionic and aganglionic bowel there is a transition zone The transition zone is abnormally innervated due to a reduced number of enteric ganglia
Initial presentation of neonates with HSCR typically includes distal intestinal obstruction with symptoms including abdominal distention or vomiting andor failure to pass meconium within the first 48hrs of life Children with HSCR can also have difficulty feeding severe constipation and symptoms of HSCR- associated enterocolitis HAEC
Due to its lack of ENS the aganglionic region of HSCR bowel is tonically contracted This results in constipation and without treatment is fatal The current gold-standard treatment for HSCR is a surgical pull-through procedure in which the aganglionic region and TZ is resected in an attempt to restore normal function
The investigators have previously demonstrated the presence of enteric nervous system progenitor cells ENSPCs in the aganglionic bowel of children with HSCR ENSPCs have both a multipotent nature and proliferative capacity There has been a significant amount of research into the feasibility of using ENSPCs to reduce or correct bowel dysmotility in mouse and rat models of ENS neuropathies ENSPCs have commonly been cultured as neurospheres Neurospheres are free-floating cultures of neural stem cells that also contain neurons and glia and in the case of enteric neurospheres ENSPCs
ENSPCs cultured in neurospheres have the potential to be used as an autologous therapy for HSCR which would avoid the risk of immune rejection and can be isolated from embryonic and postnatal mouse rat and human tissue Enteric neurospheres have been shown to contain cells expressing various progenitor neuronal and glial markers In our lab demonstrated that both embryonic mouse caecum derived neurospheres and postnatal human colonic neurospheres expressed the proliferation marker BrdU and the neuronal subtype markers NOS and VIP showing that neurosphere cells were capable of proliferation and differentiation This work was further explored in the investigators group and neurospheres were cultured from tissue from the aganglionic bowel of patients with HSCR This demonstration indicates the potential for autologous therapies using the patients own aganglionic bowel due to the presence of progenitor cells that were capable of differentiation into different neuronal subtypes in vitro
The transplantation of enteric neurospheres to aganglionic bowel has provided insight into the ability of such cells to rescue a model with a HSCR phenotype Using ex vivo models of aganglionic tissue multiple groups have demonstrated that transplanted neurospheres can integrate into tissue and differentiate into enteric glia and electrophysiologically active neurons
Recently the investigators have found that there is an interaction in the transition zone of children with HSCR between the intrinsic ENS and the extrinsic nerves of the aganglionic bowel As the transition zone is also resected during surgery for HSCR this could provide a source of ENSPCs to use for autologous transplantation However transition zone neurospheres have not yet been characterised The investigators plan to include transition zone neurospheres in our investigation to determine whether these cells may be useful for transplantation This forms part of our next set of experiments to investigate future therapies for HSCR
The clinical outcomes of children with Hirschsprungs Disease have been poorly reported Recently a core outcome set has been developed to help to standardise how childrens outcomes are reported and to encourage reporting of patients experiences as well as clinicians experiences After pull-through 30 of patients suffering constipation or incontinence with clear constipation and rapid transit phenotypes being evident This may be caused by abnormal motility of the ganglionic region or by the fact that the aganglionic internal anal sphincter remains after surgery Future therapies for HSCR aim to reduce long term morbidities associated with HSCR but a key part of this includes drawing together childrens lived experience with the findings within the laboratory The investigators are currently undertaking a study of the long-term outcomes of children and adults with Hirschsprungs Disease REC 18NNW0608 and this study offers an opportunity to combine clinician and patient reported data with immunohistochemical data
Hirschsprungs disease HSCR is a gut motility disorder affecting 1 in 5000 people worldwide HSCR is characterised by the absence of ganglia and nerve fibres of the ENS to various extents of the bowel 80 of cases affect the distal colon and internal anal sphincter but 10 of cases have total colonic aganglionosis and 1 total intestinal aganglionosis Between the ganglionic and aganglionic bowel there is a transition zone The transition zone is abnormally innervated due to a reduced number of enteric ganglia
Initial presentation of neonates with HSCR typically includes distal intestinal obstruction with symptoms including abdominal distention or vomiting andor failure to pass meconium within the first 48hrs of life Children with HSCR can also have difficulty feeding severe constipation and symptoms of HSCR- associated enterocolitis HAEC
Due to its lack of ENS the aganglionic region of HSCR bowel is tonically contracted This results in constipation and without treatment is fatal The current gold-standard treatment for HSCR is a surgical pull-through procedure in which the aganglionic region and TZ is resected in an attempt to restore normal function
The investigators have previously demonstrated the presence of enteric nervous system progenitor cells ENSPCs in the aganglionic bowel of children with HSCR ENSPCs have both a multipotent nature and proliferative capacity There has been a significant amount of research into the feasibility of using ENSPCs to reduce or correct bowel dysmotility in mouse and rat models of ENS neuropathies ENSPCs have commonly been cultured as neurospheres Neurospheres are free-floating cultures of neural stem cells that also contain neurons and glia and in the case of enteric neurospheres ENSPCs
ENSPCs cultured in neurospheres have the potential to be used as an autologous therapy for HSCR which would avoid the risk of immune rejection and can be isolated from embryonic and postnatal mouse rat and human tissue Enteric neurospheres have been shown to contain cells expressing various progenitor neuronal and glial markers In our lab demonstrated that both embryonic mouse caecum derived neurospheres and postnatal human colonic neurospheres expressed the proliferation marker BrdU and the neuronal subtype markers NOS and VIP showing that neurosphere cells were capable of proliferation and differentiation This work was further explored in the investigators group and neurospheres were cultured from tissue from the aganglionic bowel of patients with HSCR This demonstration indicates the potential for autologous therapies using the patients own aganglionic bowel due to the presence of progenitor cells that were capable of differentiation into different neuronal subtypes in vitro
The transplantation of enteric neurospheres to aganglionic bowel has provided insight into the ability of such cells to rescue a model with a HSCR phenotype Using ex vivo models of aganglionic tissue multiple groups have demonstrated that transplanted neurospheres can integrate into tissue and differentiate into enteric glia and electrophysiologically active neurons
Recently the investigators have found that there is an interaction in the transition zone of children with HSCR between the intrinsic ENS and the extrinsic nerves of the aganglionic bowel As the transition zone is also resected during surgery for HSCR this could provide a source of ENSPCs to use for autologous transplantation However transition zone neurospheres have not yet been characterised The investigators plan to include transition zone neurospheres in our investigation to determine whether these cells may be useful for transplantation This forms part of our next set of experiments to investigate future therapies for HSCR
The clinical outcomes of children with Hirschsprungs Disease have been poorly reported Recently a core outcome set has been developed to help to standardise how childrens outcomes are reported and to encourage reporting of patients experiences as well as clinicians experiences After pull-through 30 of patients suffering constipation or incontinence with clear constipation and rapid transit phenotypes being evident This may be caused by abnormal motility of the ganglionic region or by the fact that the aganglionic internal anal sphincter remains after surgery Future therapies for HSCR aim to reduce long term morbidities associated with HSCR but a key part of this includes drawing together childrens lived experience with the findings within the laboratory The investigators are currently undertaking a study of the long-term outcomes of children and adults with Hirschsprungs Disease REC 18NNW0608 and this study offers an opportunity to combine clinician and patient reported data with immunohistochemical data
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None