Cell Therapies: Mass General
Rewriting the Rules for GI Disorders—One Cell at a Time
What if you could regenerate the gut’s nervous system with a simple cell therapy? In this episode of unNatural Selection, Dr. Allan Goldstein—Surgeon-in-Chief at Mass General for Children and Chief of Pediatric Surgery at Massachusetts General Hospital—discusses his work on neurosphere-based treatments for Hirschsprung disease. This novel approach could transform care not only for children with this rare condition, but also for millions suffering from broader gastrointestinal motility disorders. We explore the biology, the hurdles, and the future potential of rewiring the gut with living cells.
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Doctor Allan Goldstein is surgeon in chief at Mass General for Children and chief of pediatric surgery at Massachusetts General Hospital, as well as the Marshall K Bartlett Professor of Surgery at Harvard Medical School.
A Yale and Harvard trained physician, he specializes in neurointestinal diseases like Hirschbrung disease.
1:31
He Co directs the Pediatric Neuro Gastroenterology program and leads a long standing NIH funded research lab focused on the enteric nervous system.
Doctor Goldstein has authored over 170 peer reviewed papers and is a recognized leader in both clinical and translational pediatric surgery.
1:49
Allen, welcome to a natural selection.
1:52
Speaker 1
Thank you, Nat.
1:53
Speaker 2
I always start with the same question, Alan, just to level set and give people some context about what we're going to be talking about South in the simplest way possible, could you please let us know what field you're innovating in and what major breakthrough or improvement are you working to bring about?
2:08
Speaker 1
Great.
Well, thanks again for this opportunity to talk about my work.
I'm in interested in a field called neurointestinal disease.
These are conditions that are caused by abnormalities in the nervous system that controls the gastrointestinal tract.
2:25
The gut is fascinating in that it can function without any central nervous input.
So if you take a piece of intestine and put it in a dish, if you put a pellet inside that intestine, it knows how to move that pellet from the beginning to the end of the gut.
2:43
And so when nervous system is that complicated, problems happen.
And kids are either born with conditions that affect that nervous system of the gut or they acquire it later in life.
And those conditions cause a great deal of morbidity since truly eating is one of the joys of life.
3:02
And these are conditions that affect our ability to to either eat or to to absorb nutrients or to evacuate waste product.
So those are the conditions that that fascinate me and that is the field that I focus on.
3:16
Speaker 2
Excellent.
And can you tell us what is the current standard of care for these conditions and and where does it fall short?
3:23
Speaker 1
All of these conditions, and I'll name a few in case they they sort of sound familiar, There's hearchprung disease, which we can certainly talk about more since it's the focus of what I do.
But there's also gastroparesis where the stomach doesn't empty well, colonic dysmotility, which is associated with terrible Constipation that often doesn't respond to medicines, or esophageal achalasia, where the esophagus doesn't work and people have difficulty swallowing food.
3:54
The all of the treatments we have now are really treating symptoms.
We don't have a curative therapy.
So for Constipation, we give laxatives, either they, they make the stool soft or maybe they help the colon to squeeze a little better.
Or for esophageal achalasia, we, we cut the muscle or stretch the muscle of the esophagus to let food pass more easily.
4:16
So where it falls short is really in, in, in just I understanding the fundamental underlying problem and treating that.
If the problem is with the nerves, the treatment should be with the nerves.
But we're not there yet.
4:30
Speaker 2
We get to the fascinating part about this, which is your approach.
4:33
How neurosphere-based cell therapies work and what makes them uniquely suited to this challenge
So how do neurosphere based cell therapies work and and what makes them uniquely suited to this challenge?
4:43
Speaker 1
So if we use the example of Hirschsprung disease, that's a congenital disease.
Babies are born with the failure of nerve cells to develop in the lower part of the intestine.
Nerve cells develop in the gut during early development, they start in the foregut, the esophagus, and they migrate all the way down to the bottom.
5:03
But in one in 5000 babies, they don't make it to the bottom.
So that last part of the colon can be a small part, It can be the whole colon doesn't have nerve cells and therefore does not function, cannot evacuate waste.
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And right now our only treatment is to remove that segment.
But like I said earlier, if the problem is an absence of nerve cells, the treatment should be to replace the nerve cells.
There's no better way to treat a disease than to actually treat the cause of the disease, though.
5:34
Neurospheres are neuronal stem cells that grow in in these in not in non adherent floating conditions.
In the proper substrate, the proper media.
With growth factors, we can make neuronal stem cells form spheres of stem cells that can then be expanded, grown to large numbers, and transplanted into the part of the intestine that has no nerves.
6:04
We isolate the neuronal stem cells either from the patient's own intestine, the part that's healthy, or we can also harvest neuronal stem cells from the subcutaneous fat.
Both of those sources generate stem cells that we can grow into these spheres and use for cell therapy.
6:22
Speaker 2
If the procedure works as planned, is this a a treatment or is it a cure for these diseases?
6:32
Speaker 1
We're hoping that that that'll be the cure.
The fundamental problem of the disease is the absence of nerve cells.
We know in mouse models with the disease that we can isolate the nerve cells, grow them and put them back into the part of the gut that has no nerve cells and we see a restoration of function.
6:52
We see the return of motility in the in that segment of the gut.
So in that respect, we're optimistic that cell therapy can serve as a cure.
Until we do the clinical trials, though, we won't know for sure, but we're hoping that this will allow children to not need major surgery during infancy and all of the complications associated with them.
7:17
Speaker 2
You know, it's fascinating.
I, one of my backgrounds is in stem cell biology.
That's part of the work that he did in Graduate School.
And as you're talking about this, I'm hearing about all the complexity that goes into this.
And so if we think about the work that you're doing, what what were some of the key technical and biological hurdles that he had to overcome to make this even theoretically possible?
7:40
Challenges to the project
Yeah, there are there are many challenges to this.
One is we want to use autologous cells.
We feel that in a baby especially we don't want to put in allogeneic cells that would require immunosuppression.
So we're going to use autologous cells from the baby's own body and therefore avoid the need for, you know, for immunosuppression.
8:02
The the question is if we ice, where do we isolate those cells from so we can take them from the healthy part of the intestine.
But those are the nerve cells that didn't develop normally, you know, in that in that child's development.
So the first step was showing that actually the nerve cells that did develop are just fine.
8:21
They just didn't finish their journey during embryologic development.
But the ones that did make some of the journey are perfectly usable.
And that took time to sort out both at the at the genetic, molecular and cellular level.
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Next is knowing how do we how do we grow those cells?
Because we really need to generate a lot of cells and they have to be of the right type.
We don't know that, you know, when we isolate these neuronal progenitor cells from the gut, we get a lot of other cells.
We get fibroblasts and some immune cells.
8:54
We get neurons and glial cells and we get progenitors.
So a lot of work focused on how do we expand that progenitor population, which we think is the important cell type and that took years to sort out the growth factor conditions that do that for us.
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There's also the issue of cell delivery.
How are we going to deliver all these cells into a segment of intestine that can be, you know, relatively long.
We've worked with large animal models to show that we can do that using endoscopy, colonoscopy combined with ultrasound so that we can target the proper layers of the gut wall.
9:34
But, you know, so again, we actually at this point aren't exactly sure how many cells we have to deliver, how many points in the gut will we need to inject.
And it's, it's hard to model that because there's no large animal with Hirschsprung disease.
9:49
Mice are not a great model for this when it comes to cell delivery because their colon is tiny compared to the human colon.
So again, some of it is going to boil down to good educated guesses based on preliminary data and then just seeing how it works in the human condition.
10:07
Speaker 2
This work is mainly in the clinical trial phase.
10:11
Delivery, safety, and manufacturing challenges
Presumably after this there are going to be delivery, safety, manufacturing challenges to address as well before it gets out to patients with this disease.
10:21
Speaker 1
Yes, absolutely.
We're, we're in the late preclinical stage.
We're just finishing some final experiments and actually that last topic of how many cells, how many injections is a part of that work.
Then you write the manufacturing phase comes next, that we're working with the CDRO and a cell manufacturing facility both could show that we can do the tech transfer.
10:45
And then another facility with all of the GMP, you know, qualities is able to generate cells of the same quality, same numbers that we do in the lab.
And the toxicity studies that will have to be done to make sure that there aren't any unintended consequences, that the cells don't migrate to other sites that weren't anticipated and certainly that they don't grow out of control to form something we don't want them to.
11:13
We have some good data for from following these cells in mice for up to a year that that we're not that show none of those consequences.
So we feel confident, but those are all the steps that are going to have to happen next.
11:29
Speaker 2
And if this therapy succeeds, how could it shift the way we think about treating not only Hirschbrung disease, but a wider range of GI disorders?
11:37
How could this therapy shift the way we think about treating GI disorders?
Yeah, that's what's exciting about it 'cause we consider this neural stem cell therapy as a platform approach.
The ability to isolate neural stem cells from a patient, whether it's from the gut for gut disease or from the subcutaneous fat, which is really easily accessible, is exciting.
11:55
Hirschburg disease, pretty rare disease at one in 5000.
Kids suffer and even with a good operation, 50% of kids will have lifelong problems with GI function, fecal incontinence, severe Constipation.
But there are many other conditions that are more prevalent.
12:12
For example, gastroparesis effects a huge number of patients.
Half of patients with gastroparesis or poor gastric emptying have diabetes.
We know it again in in preclinical rodent models that these cells can help to improve gastric emptying.
12:30
Well, we're going to have to figure out who the right candidates are.
Is it everybody with gastric emptying problems or is it a subpopulation who are either missing neurons or neuronal subtypes?
We're not clear yet on who the right eligibility will be.
12:47
The interesting thing is in addition to neurointestinal diseases, we've been working on a model of peripheral nerve injury.
We can take out a segment of sciatic nerve, which is the major nerve that controls motor and sensory function to the leg.
13:04
We can remove a segment in the mouse and replace it with a scaffold that contains these neural progenitor cells.
We've we've learned to isolate and expand and we can show that those nerve cells are able to bridge the gap and improve function in the leg, not get it back to normal, but at this stage improving motor function, a less muscle atrophy, better ambulatory status for the mouse.
13:31
So that's really exciting that the nerve cells in the gut come from the neural Crest in the embryo.
So does the entire peripheral nervous system.
So we think there's an opportunity here not just to treat Hirsprung disease and not just to expand it to many other neurointestinal diseases, but also potentially to treat peripheral nerve injury, which grows the market quite a bit and shows us that we can really help a large number of patients with a variety of conditions.
14:01
Speaker 2
That really is interesting.
It's exciting.
So if I can ask you one more question, Alan, zooming way out and, and mainly for non clinician audiences, when your technology in this platform succeeds and and it's exciting to hear that it has a broader application across the body.
14:22
How will this technology change the way we approach human health and diseases?
So when your technology succeeds, how could this innovation change the way that we approach human health and diseases, not just in the gut, but broader diseases?
What could this mean for patients that are sick or even in cases of prevention for people in, say, 5 or 10 years?
14:44
Speaker 1
Yeah, that's such an interesting question.
One thing that I I think of as a fundamental sort of paradigm for innovation is to 1st not be satisfied with the status quo.
15:00
The way we treat Hirschbrung disease now, removing that segment that has no nerve cells, is the same way that it was treated starting in 1948 by Doctor Orvar Swenson, a pioneer in the disease at the time.
But in nearly 80 years, we're still doing the same thing and we need to accept the fact.
15:21
And it's only been shown probably from studies in the last 10 years, the people don't do that well.
We thought we were doing a great job as pediatric surgeons.
And then you follow the patients longer and you realize you're not doing a great job.
So I think #1 is just that sort of larger view to say that we need innovation in many areas in medicine because we're not doing the best we can do for our patients.
15:47
So that I, I would think it is the first thing.
Secondly, but what I mentioned earlier is that if, when we finally understand the pathophysiology of disease, we really need to target treatments that fix the underlying problem, not just address the symptoms.
16:05
And so that takes, you know, that that that sort of general learning from what what I've been working on for me has been kind of enlightening.
You'd think it's intuitive, but we're often so satisfied with the way we're treating something, we fail to realize that we haven't fixed the problem.
16:24
Fixing the problem offers tremendous hope to families whose kids are born with these conditions, knowing that their child isn't going to have to have a big operation or take a medicine for the rest of their life.
So, and then lastly, I think cell therapy generally offers a tremendous opportunity to replace cells that just don't develop, stop working normally or, or do the wrong thing during life.
16:52
Cell therapy's relatively new, there's a lot of excitement about IPS cells, induced pluripotent stem cells.
The challenge with those is that unless they come from the person's own body, they had, they run the risk of, you know, of, of rejection and the need for lifelong immunosuppression, which has lots of complications associated with it.
17:15
So for now, using the the body's own cells, learning how to reprogram cells in the body to make them do to make them replace the cells that need to be replaced and giving them back to the same individual that autologous cell therapy think has brought applications in many areas, many diseases.
17:38
And I think it's an exciting time in in the cell therapy realm.
17:43
Speaker 2
Allen, I applaud you on this tremendous development, the work that you're doing.
I I very much appreciate your time and that you've taken and, and joining us.
And I look forward to meeting you in person at the World Medical Innovation Forum later on this year.
17:59
Speaker 1
Great.
I look forward to seeing you there and thank you again for this.
