 There are a lot of promises in the stem cell field, but all of them are failing in the clinic. If you read those literatures, they have one thing in common, the cells after transplantation didn't survive. The major reason for that was they were not in the right environment or the micro-environment where they can survive and then do the job they were sent in for. Let's create a micro-environment so that the cells once transplanted, they should be there and then do their job. We specialize there in engineering the matrix in a tissue-specific manner. So the first one we have designed, it is designed for the brain. So we have tuned the stiffness, the porosity of the matrix to a level that matches the compliance of the brain. And so when they are cultured in AMGEL, this matrix, they feel that they're in a brain-like environment and that's why they become neuron. Boom, what's up everyone? Welcome to Simulation. We are back at IndieBio Demo Day. We are talking to Subadip Das. Hi. Thanks for joining us coming on the show. Thank you. I really appreciate you. Congrats on Demo Day. Convales. That's great. Convales. So brain-like micro-environments, this is some weird stuff that I haven't heard of yet. So let's unpack this and talk about it. On the way to that, I want to learn more about who you are and how you even got here. Okay. So how did you even get to the point of making this company? Okay. So this started as my PhD project and back then I was interested in solving the science problem because there was a huge pending problem in the stem cell field that there were a lot of promises in the stem cell field but all of them are failing in the clinic. And if you read those literatures, they have one thing in common which is the cells after transplantation didn't survive. And the major reason for that was they were not in the right environment or the micro-environment where they can live or they can survive and then do the job they were sent in for. And then it started that, okay, let's create a micro-environment so that the cells once transplanted, they should be there and then do their job. Okay. So the cells being transplanted and then dying was the problem and then the solution is creating a micro-environment that makes the cells live when they get transplanted. Yes. Now, okay, does this work for all different cells that they don't need different micro-environments? They need and of course they need because if you think about, just think about your different organs. Every organ has two critical things. One is the cells of this organ like your heart cell and your kidney cells are different. Totally. What people do not get it obvious is that the matrix of kidney and heart is also different. And we specialize there in engineering the matrix in a tissue-specific manner. So the first one we have designed, it is designed for the brain. So we have tuned the stiffness, the porosity of the matrix to a level that matches the compliance of the brain. So the stem cells are mechanosensitive. Interesting. So when they are cultured in AMGEL, this matrix, they feel that they're in a brain-like environment and that's why they become neuron. Okay. So this is the AMGEL matrix. Yes. Is your proprietary. Exactly. Okay. So then this AMGEL matrix is going to change for brain versus heart versus kidney because it's just going to need to be a different pressure and porosity, if you're saying. Yep. And then within the, what about the external variables? So even though the AMGEL is, even though that is a certain proprietary assemblage of yours, what about the externalities? Is it just like in a vacuum or what is it in to prevent, I guess, what are the other variables that you have to accomplish? What are the variables that you have to account for as you grow the cells, as you transplant the cells? Okay. So what we do is our approach is when you think of engineering a particular matrix, we start looking at the natural organ which is present in the human body and then what are the components of those matrix? Yes. Substrate. There is always a base matrix and then what we have, we have mimicked that base matrix using some self-assembled peptides and then we add complexities like tissue-specific factors. This could be biochemical factors. It could be other extracellular factors that are required and that are exclusive to one particular tissue. And then we add those components to our matrix in a specific time of the matrix generation so that they get incorporated within the matrix and then when you culture cells on them, the cells take very specific cues from the matrix. Yes. The metrics are kind of like the variables of the environment that the brain lives in. Yes. So you take and you kind of, if you take all, you understand the variables of the brain environment and then you bring it into an amgel external from the brain into an environment and then those, that then is able to house and grow the stem cells. Yes. Now what is the, is this being, like what is this neurodegenerative disease as the main? Like when do I want to grow more neuronals? Yeah. So the target is that the brain, what happens if you lose those neurons and the diseases that we are targeting say for Parkinson's, neurons in a specific region of the brain, they die. And once they're dead, the system is not capable of regenerating or regenerating those lost neurons. So again that's because the micro environment of those that diseased region is not suitable for a regeneration. So what we are doing, giving is assisted regeneration. Yes. So you put the stem cells mixed with the amgel in the very specific region you want the cells to grow and the cells will stay there and grow into the target neuron type you want. So do I need to take a stem cells from my brain to be able to? No. So now we are talking about which type of stem cells to use for an effective therapy. Okay. And there are multiple types of stem cells like it could be derived from your bone marrow. It could be derived from your skin cells and reprogrammed what we call IPSCs. And we have tested that it works for a wide variety of stem cells. But then it needs to go back into where Parkinson's is. Yes. Killed in my brain. Yes, exactly. But then how do you administer it to go back to where Parkinson's? So your brain is, there is a 3D map of your brain. So doctors can tell from scans that okay this is the region where the regeneration is. Yes. And then in that region the cells could be delivered using the amgel via what we call a stereotactic surgery. Stereotactic surgery. Stereotactic surgery. So there are like longitudes and latitudes of your brain. Yes, yes. And then they can calculate okay that this much distance from the exact position. But then how do they put it in? So they drill a hole in the skull. Jesus. And then, but that's again, I'm telling you, that's a minimally invasive procedure. You don't have to open the skull. That's something. Just a small drill. Just a small drill. Just good enough for a needle to go in. The needle goes in, dumps off the load. The load. Yeah. Which is a stem cell mixed in amgel. Amgel. Yeah. Stem cell mixes in amgel. Wow. And you can take it from either like skin or bone marrow. It doesn't need to come from the brain. No. It doesn't need to come from the brain. Interesting. Okay. Go ahead. Yeah. Because it's like we do prefer certain types of stem cells. But the thing is that we are optimizing protocols for each type of stem cells. Because the stem cells that are derived from a bone marrow follows a particular pattern of differentiation or growing into neurons. So the formulation is a bit different if it's a bone marrow derived cell. The formulation will be a little bit different if it's an IPSC. That kind of thing. Yeah. Can the bone marrow or the skin stem cell, can that make a heart cell as well? Or can you still commit? Yes. Yes. Yes. That's why you need state first manipulation of those cells. Because the last thing you would want is a kidney growing in your brain. So yeah. Yeah. So it's like you have to control the fate of the cells in such a controlled manner that you know that yes, this is what it is going to be. And that's AMGEL. That's AMGEL. So you manufacture the AMGEL and then do you sell that? Do you also take the stem cell from a bone marrow or a skin cell and then add it in and then make sure it works? And then do you sell what part of the process? So our aim is to provide the complete therapy. From start to finish? Yeah. From start to finish. So you actually go and put it back into the brain as well. Yeah. The neurosurgeon does that for us. So the target is that a patient gets enrolled, comes to the hospital, the doctor does a scan and then based on the situation, if the doctor feels that a stem cell transplantation is required or maybe beneficial for the patient, then she recommends a stem cell transplantation. Then we come to know that such and such patient in such and such hospital requires stem cell transplantation. We send them the vial of cells and the vial of gel. So what is done is those are mixed and then the surgeon performs the surgery to transplant the cell and then the patient goes off. Oh man. Okay. So this is first for Parkinson's is the big target. Yeah. And is this like a couple million people per year? Yeah. Parkinson's, there are 10 million people worldwide suffering from Parkinson's. Wow. In U.S. every year, 60,000 people are diagnosed with PD every year, like new patients. Yeah. Yeah. But I think this therapy will be primarily for the patients which are not responding to the current treatment because the current treatment just gives symptomatic relief. Yeah. It just gives you, recommends you levodopa or dopamine precursors but eventually it's a progressive neurodegenerative disease. So it means that you are losing every day, losing some neurons every day, losing your life every day and that cannot be reversed unless and until you have new neurons in the brain. Are you also ready to just continuously over time just continue adding as the brain degenerates? Can you just continue adding new neurons? Yeah. So right now what we're aiming is to see the efficacy of a single shot because that would be of course better that you don't have to take it like maybe one shot, five years later another shot. We want to give a single shot and make it effective. So on animal models we are right now optimizing the best shot so that we can have an idea of that, what kind of lesion size could be managed with how many number of cells, those kind of things. And then what does the next steps look like for you to get this into the hands of PD patients? Well, now we have done most of the basic science. It's thorough and it has shown efficacy in animal models. The next step is to do some of the GLP study for talks which will enable us to file our IND to the FDA. And then so our next immediate milestone is to check first the safety in human patients. That's what we will do in our phase one trial. And then we might have secondary endpoints from there to understand that what kind of efficacy the transplants are giving. But first of all it would be just a safety study to see whether... And that's why we are working with these neurosurgeons who are advising us on the writing down the protocols, what kind of protocols should be there, what should be the clinical endpoints and all those kind of things. And then what is... One more time on the AMGEL is made up. You said your peptides. Okay, so you figured out how to make the specific peptides which would make that environment for the neurons. Exactly, exactly. So it's a specific sequence and once you give a trigger those peptides start assembling and they develop into nanofibers. Once the nanofiber reaches beyond the critical concentration it entraps the solvent and give you a gel. And that gel, now you can alter the properties of the gel by adding or removing components before inducing the gelation. So there are a lot of factors which you can control so that you can tune the gel according to a particular purpose. And then that's how it can potentially work for the other organisms. Exactly. What else should we know? What else should we know before we come to a close? What else is important for us to know about what you're building? I think we are starting with Parkinson's but if we are able to successfully demonstrate that it works for one disease it will open up endless opportunities like subsequently engineering matrices for different indications where you require cell replacement. There are multiple conditions, not only in the brain, in other organs where if you replace those damaged cells your body works far better and you live a healthy life. So it can technically work for those. We have to just figure out the right composition of the matrix for individual organs. And then I'm just trying to envision all the other targets for this. I'm also trying to envision the actual delivery of the amgel neuron into the mixture of the brain, like where the dead neurons are to be able to deliver your neurons and then to have that start working but in a location where the dead ones are already taking up space. So once they're dead, in some of the conditions, they're lesions, they're actually voids because once they're dead there are regions of the brain which are, like the brain has its own immune cells which comes into play and sort of cleans up the region and then creates a scar in the brain. So we want to prevent that. Once we know that this is the region where there is a degeneration, so you can put your cells in there because once the cells are gone from that region you can fill it up. And also another thing is that this matrix, this has a very specific property of self-healing which means that when you're putting it it will flow and go in as liquid. But after it goes in, it will fill up whatever void space is there and then form a gel. Interesting. I'm looking forward to seeing how this pans out. This one's really interesting. It's so much different than the other companies that we've had to talk to about it. It's good to be this different. You're taking a big leap. I like this. I like this. Yeah. Awesome. This has been super fun. Yep. And also another thing which I think another potential area is that we might be able to be at a stage someday where we'll be able to make parts of organs in a dish because if we uncover what's the exact composition of these matrices and what kind of cells to add to them to develop parts of organs and we can do that as well. Yes. That's very exciting. No. I wonder where that ranks in... But that's a completely different area. Totally different area. But also that... I'm always very interested in biotech when people are exploring different keys. Yeah. I'm always wondering what's the golden one to the whole, like either an urge generation or maybe a degeneration of some other organ system. Yep. And so we have friends that are printing the 3D organ right away. Yeah. So then the idea is when does it become completely better to just try and... Get the whole organ replaced? Or like we're also, you know, what are the... You know, as like other people are doing with anti-aging, just trying to figure out how to just reverse the aging process back to the youthful states. Yeah. Because I'm always wondering what the most optimal biotech... Yeah, yeah, yeah. I think definitely the type of approaches I would say for... especially for organ generation, everyone has a different type of approach and I think that's good. Because you don't know which one will work. Yeah. And the more options you have and maybe sometimes I think the best thing works when you combine two solutions and then get something, oh wow, I didn't think about this. Yeah, yeah, that's a good point too. So when you're trying the different... the one they can almost combine. Yeah. So what a pleasure, my man. Yeah. This has been super fun. Thank you. Thank you for coming on the show and talking to us. We appreciate it. Best of luck as you continue to grow. Thank you for your contact. Thanks everyone for tuning in.