Stem Cell Clinic

Living with leukaemia: ‘My ethnicity means I’ve only a 37% chance of … – inews

By Stem Cell Medicine

I didnt really notice when it all began. I just assumed, round about December, that I had flu. It was very odd, though, as it just wouldnt go away. I had it for five weeks. I tested myself for Covid. I just couldnt work out why it wouldnt go away.

I got antibiotics and steroids from my GP. I struggled to get an appointment because the nurses were on strike, so I didnt really know I had anything other than flu and a really bad sore throat I even went hoarse as well.

I was about to start a new job on 16 January this year, so on the day before I said to my husband Im going to A&E, because I wanted to start the new job and feel healthy, and I felt so unwell.

Whenever my husband and I go to A&E we always drop each other off, we never stay with each other because we know its going to take at least four hours to be seen. So I went in and they did all the various tests. They did a blood test and this particular doctor came up to me and told me that they were going to have to keep me in longer. I said no. no, no. I start a new job on Monday. But she said: Janice, you cannot go anywhere. You have leukaemia. You have blood cancer.

I asked if they had made a mistake and then phoned my husband telling him he better come to the hospital. Thats all how it started. Me just wanting to find out what was going on. Then another doctor came in and confirmed it with my husband there, as I was in disbelief at this stage.

My white blood cells count was 136. If it was a mistake my white blood cells would have been between 5 and 26. You cannot make a mistake with 136. Then they left the room, closed the curtain and thats when it really hit me. I wouldnt even say crying, I was bawling my eyes out. It was horrible. My husband was just hugging me.

I just thought this cant be real. I donate blood. I run. I do the odd Tesco cancer research run, I do the Macmillan one. I do all these runs raising money for charity and Im one of those people now. I couldnt believe it. I was shocked.

I was in Hillingdon Hospital, near Hayes, west London, for two days then they transferred me to Hammersmith Hospital and I was there for 42 days receiving chemotherapy treatment via IV and tablets, and other medications as well. I had blood transfusions 10 units of blood, 14 units of platelets. It was so much.

I knew within my community Im 56 and of Black British Caribbean descent, with Grenadian heritage that what I do need is a stem cell donor. And we dont donate enough blood, certainly not stem cells. So, from the get go, I wasnt going to lie down and cry. Im going to start raising awareness and thats exactly what Ive done.

I contacted Antony Nolan [the blood cancer charity] who saw my own posters, which said If I cannot save myself, maybe I can save someone else, and how much I was doing to raise awareness, we teamed up. Being positive has been my drive.

The place where I was going to work were willing to hold it for a couple of weeks, but it turned out I was in hospital for six weeks and sick with it as well so it would have been unfair, really. I wouldnt have had the strength to work. This is the first time in my life, since I was 17, that I havent been working. Ive always worked.

Im still in Hammersmith Hospital and going to be coming here for another four months so it wasnt worth thinking about work. The hospital lets you go home for your sanity for a week or 10 days or so. Now Im back for another month for all the treatment again. If youre okay the cycle repeats itself. Theyll keep doing that for five months. Hopefully, in the interim, theyll be looking for a donor.

They tried my two brothers and my sister but they were not a match because our antibodies conflicted. It takes about four weeks for them to do the initial blood test to wait to see if youre a match with your siblings. I had no doubt they would be a match 100 per cent Im going to be saved. Everything will be fine. On 8 March I got a call at home to say they were not a match. The older you get your antibodies change through having children, an infection, any sort of illness they are your defence mechanism. Theyre special for you and build up an immune system specifically for you. So I guess my siblings, whatever theyve had in their life, their antibodies have built up an immune system which conflicts with mine now.

I was just as devastated as when they told me I had leukaemia and I cried just the same, let me tell you. They also said there were no matches on any stem cell register around the world, so I kind of lost hope. What am I going to do? My brothers and sisters were supposed to be a 100 per cent match.

My two daughters are a 50 per cent match, meaning their antibodies might not be a problem so the doctors are going to look at them as a potential new option if something can be worked out. Im now waiting another month while they are tested. Its a waiting game. We dont know whats going to happen. I remain positive and hopeful that it has to be. Its very daunting.

The big issue for me is how difficult it is for non-White people to find a match [Currently people from a minority ethnic background have just a 37 per cent chance of finding an unrelated stem cell donor on the register, compared to 72 per cent for white Northern European patients]. I knew within the ethnic minority community we just dont donate enough, so I reached out to family and friends, my work colleagues. We know a lot of people between us all. I was targeting everyone of any colour my White friends, my Asian friends, they must know Black people just reach out and get the word out there.

In hospital, I have nine days of IV chemo and you get that twice a day. I feel fine with that one but now Im on a twice-a-day, 14-day chemo which makes me feel very nauseous, but they give you anti-sickness medication to help. If youre really bad they give you a shot in the arm, so theyre on board with any kind of side effects. The tablets really take it out of me though, so most of the time Im in bed. But I get up and try and do something.

Before I was sick I used to do my 10,000 steps a day. In here I cant really go that far walking in the room or in the corridor but Id do about 2,000 steps when I can, if Im well enough. Then its whether I need a blood or platelet transfusion. I think I respond well to treatment, because Ive always been a positive, strong person. If youre positive and strong that helps with our illnesses, Ive always thought. If youre wallowing in sorrow and feeling sorry for yourself, I dont think that helps at all.

So through this journey, every time the doctors come in theyve been very impressed with me. I say to people this is a temporary inconvenience and that is how Im going to see it. Although I dont want to be in hospital, if I was at home Id be cooking, cleaning, doing the washing Im seeing this as a holiday as well. I dont have to think about what to cook. I get three meals a day, I get my bed changed, I mean come on! I have to look at it positively.

I was told it normally takes between three and five months to find a donor. Usually, there is something they can do even if it is not a full match. Theres no real date. Its a waiting game. I cannot be on this treatment forever as youre prone to infection and its not good for your body anyway.

Ive set up a family WhatsApp group for daily updates as when everyone heard they were all devastated of course. My father died of prostate cancer 11 years ago. We saw how he went from being medium-sized to skin and bones. It was awful, so my family were so worried and thought the same thing would happen to me. Even I thought the same thing when I first heard my diagnosis. Am I going to lose my hair and am I going to die? Well, I did lose my hair, but Im still here, thank God.

Me being so positive is keeping my family upbeat and strong as well. They are all rooting for me. If Im feeling down I put it on the group chat, but most of the time its all positive. Believe you me, I really want to go home.

For more information about stem cell donation visit the following websites:

https://www.dkms.org.uk/

https://www.anthonynolan.org

htttps://wmda.info/

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Living with leukaemia: 'My ethnicity means I've only a 37% chance of ... - inews

Abbas Assesses the Use of Allogenic Transplant In MPNs – Targeted Oncology

By Stem Cell Medicine

CASE SUMMARY

A 68-year-old woman presented to her physician with symptoms of mild fatigue, moderate night sweats and abdominal pain/fullness lasting 4 months; she also reported increased bruising and unexplained weight loss. Her spleen was palpable 8 cm below the left costal margin. Genetic testing showed she was negative for a JAK2V617F or CALR mutation. Her karyotype was 46XX and a bone marrow biopsy showed megakaryocyteproliferation and atypia with evidenceof reticulin fibrosis.

A blood smear revealedleukoerythroblastosis and she was diagnosed with primary myelofibrosis with a DIPSS (Dynamic International Prognostic Scoring System) risk score of intermediate-2 and also had an intermediate MIPSS70 risk score.

DISCUSSION QUESTIONS

In your practice:

JONATHAN ABBAS, MD: Is this a patient where from day 1 youre talking about an allogeneic [hematopoietic stem cell] transplant [HSCT] referral? Is this a patient that a transplanter would want to see early in the disease course or is this something that you might want to hold off on a HSCT consult until something isn't behaving as well as it could?

Jonathan Abbas, MD

Director, Acute Leukemia Program

Ascension St. Thomas Midtown Hospital

Tennessee Oncology

Nashville, TN

JEREMY PANTIN, MD: The [patient is] approaching the age limit where things are going to start getting [difficult] and not somebody that we'll take straight to allogeneic HSCT transplant, but you probably want to consider therapy to reduce that spleen size. If the patient appears to not have comorbidities and may be a good candidate for HSCT, the intermediate-2 or greater risk will certainly allow them to move forward, in terms of the favorable risk-to-benefit ration, if everything is aligned.

MICHAEL T. BYRNE, MD: I think we used to argue about this, not argue [necessarily], but these were the hard patients because nobody knows what to do with them. She's the right age for transplant, but also, transplant is not without risk. Quality of life is probably worse after an allogeneic HSCT than it could be without, so I don't know. I think you plug her in then you see what her donor search looks like, and regardless of whether she goes to treatment, I think this is somebody that you probably treat if for no other reason than to try and improve her quality of life.

OLALEKAN O. OLUWOLE, MBBS, MD: I completely agree with what my colleague just said. We have several targeted therapies in this area, and we can just find 1 to give them to control their symptoms.1 If that fails, there will be another. There are many in development, so for those who are not keen on getting transplanted, there is a viable pathway to just keep treating them. Now for the patient who says, I want to see what the odds are, like what [Dr. Bryne] said, find out if they have a donor, talk about the risk-benefit, and go for it.

ABBAS: From my HSCT days, I would totally agree with you. I think this is a patient I would want to see early, to explain that you might not need me now, but you might need me one day. You've potentially got years left of transplant eligibility, and we dont have a crystal ball about how your response to treatment is going to be and where this disease is going.

Then just to be the devil's advocate for the case, this is a lucky one where we had intermediate risk with 1% blasts. If this [patient] had 6% or 7% of 8% blasts and we were now nudging closer to high risk, that might sway all of us to maybe think initially therapy might be more of a bridge to HSCT, because there might be a little bit less stable disease.

[This] is a symptomatic patient. Is there anybody out there who would watch and wait with this patient regardless of whether they are seeing the allogeneic HSCT team or not? Or does everyone feel this patient warrants some therapy?

RYAN CARR, MD: Yes, based on her symptoms, if you tried to watch and wait, so [the patient] might end up seeing somebody else.

ABBAS: I agree with you. She will certainly be finding another group in town if you said, You have [myelofibrosis], but it's not that big a deal. Let's just see you back in 3 months. I think it's unanimous this is a [patient] who's not a watch-and-wait case. They are out there, but this is not her.

CASE UPDATE

Additional lab values showed the following counts:

DISCUSSION QUESTIONS

ABBAS: [If there is] thrombocytopenia at baseline, I guess we have 2 options for this. One would be; are we comfortable still sticking with ruxolitinib [Jakafi], which we all agree on [in a patient case like this], but dose modifying potentially for thrombocytopenia or would just any thrombocytopenia necessarily make us think about another agent, if anybody wants to weigh in on it?

BRYNE: I think a thrombocytopenia of 140 109/L is different than thrombocytopenia of 30 109/L. That's quite a difference [between the level where a patient should receive] ruxolitinib vs pacritinib [Vonjo].

ABBAS: Yes, I would agree with you. Without the specific measurements, it's hard to say. Just also remember you certainly can, and we've been doing for years is dose decreasing the ruxolitinib with a lot of benefit.2 Unless you're in that extreme situation like down below 50 109/L platelet count, I still think there's a window to go with the tried and true [method here].

How about frailty? How about if this woman, let's say she was extremely frail and it wasn't necessarily a disease-related frailty, just other comorbidities? Would that sway us? Do we feel that JAK inhibitors are particularly tough on patients? Would this factor in at all if she were 78 years old or if she was 88 years old?

JACK ERTER, MD: No. I think this drug is, all things considered, quite on target and easy to take for most patients. I would certainly have no hesitation to give an 88-year-old a trial at a dose-modified start of ruxolitinib.

References

1. Li B, Rampal RK, Xiao Z. Targeted therapies for myeloproliferative neoplasms. Biomark Res. 2019 Jul 16;7:15. doi: 10.1186/s40364-019-0166-y

2. Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013 Oct 22;6:79. doi: 10.1186/1756-8722-6-79

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Abbas Assesses the Use of Allogenic Transplant In MPNs - Targeted Oncology

Allogeneic CAR T-Cell Therapy Potentially Reduces GVHD Risk – Targeted Oncology

By Stem Cell Clinic

Michael Tees, MD, a hematologist-oncologist at Colorado Blood Cancer Institute, discusses the preliminary safety outcomes observed for an allogeneic chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma.

CAR T-cell therapies made with donor cells can potentially be given more quickly and affordably than autologous therapies that are currently available, but allogeneic CAR T-cell therapies, like allogeneic hematopoietic stem cell transplants, can cause graft-vs-host disease (GVHD).

ALLO-501A, which was studied in this trial, has a disrupted TCR gene meant to reduce the likelihood of transplanted immune cells harming the host. Tees says that in early trials of this product, there was only 1 documented case of GVHD, which was a patient with possible low-level GVHD of the skin.

Tees notes that this is not the only safety signal to be concerned with, as cytokine release syndrome (CRS) and neurotoxicity can also limit the use of CAR T-cell therapies. As trials of this agent continue, he hopes that a donor-derived CAR T-cell product will also help reduce the incidence of CRS.

TRANSCRIPTION:

0:08 | What ALLO-501A is, is a genetically reengineered product to reduce the likelihood of an argument between the donor and the recipient. One of the initial concerns was using someone else's T cells to fight the malignancy is that potential risk of GVHD, and that's what we see in [patients with] allogeneic stem cell transplant where donor hematopoietic stem cells grow into an immune system that can potentially argue with the recipient. In early ALLO-501 trials, I want to say that there was 1 patient with low-level, cutaneous GVHD, and its a question on whether that was a true [adverse event]. That risk has really been demonstrated to not be an issue. We can safely infuse these T-cell products from a different donor into a recipient.

1:09 | The next phase of this is efficacy and safety. There are other safety signals that we need to be looking at for CAR T-cell therapies such as cytokine release syndrome [CRS] and neurotoxicity. The current products that are available for patients commercially do have a high incidence of CRS and neurotoxicity. I am hopeful that perhaps having a donor-derived product can reduce the severity of CRS.

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Allogeneic CAR T-Cell Therapy Potentially Reduces GVHD Risk - Targeted Oncology

Maintenance Therapies Needed to Prevent Relapse After Transplant – Targeted Oncology

By Stem Cell Clinic

Oncologists are on the cusp of helping to prevent relapse patients with cancer after transplant with the use of maintenance therapies. For patients with hematologic malignancies like acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), one type of therapy making headway is tyrosine kinase inhibition.

Prior to transplant, clinicians also utilize immunotherapy conjugates for their patients. Now, these agents are starting to be assessed in the post-transplant setting.

Years ago, when I started in transplantation, we viewed a transplant as the last gasp [or] what we do at the end of a patient's treatment course to try to save them and try to cure them of their malignancyThese days, however, transplant is much better tolerated. We have the opportunity to combine transplantation with a variety of agents, both chemotherapy agents, immunotherapy agents, cellular therapy approaches, to actually treat relapse, or even better, prevent relapse using these agents in a maintenance setting, Robert J. Soiffer, MD, said in an interview with Targeted OncologyTM.

According to Soiffer, the chair, Executive Committee for Clinical Programs, vice chair, Department of Medical Oncology, chief, Division of Hematologic Malignancies and institute physician at Dana-Farber Cancer Institute, and a presentation he gave at the 4th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies, researchers must now focus their efforts on maintenance therapies and the prevention of relapse.

By further understanding which patients are most likely to relapse, which therapies to use, and how to provide patients with those treatments, patients with many hematologic malignancies, including leukemia, lymphoma, myeloma, etc., will have improved outcomes and less of a chance for relapse after transplant.

In the interview, Soiffer discussed relapse after transplant for patients with cancer and what is important to note moving forward with research.

Targeted Oncology: Can you discuss the current role of transplantation? Why is it important to discuss relapse after transplant for patients with cancer?

Soiffer: Oftentimes, when we consent patients for transplant, we concentrate on complications, like organ toxicity, infection, graft-vs-host disease, but we often don't address the elephant in the room, which is relapse after transplant, which is, of course, the real reason we're doing the transplant in the first place. Indeed, in patients who are beyond day 100 of relapse represents the primary reason for cause of death. We really have to make a concerted effort to address the issue of relapse.

Years ago, when I started in transplantation, we viewed a transplant as the last gasp [or] what we do at the end of a patient's treatment course to try to save them and try to cure them of their malignancy. It usually wasn't much to do after transplant or in conjunction with transplant because transplant itself was so toxic. These days, however, transplant is much better tolerated. We have the opportunity to combine transplantation with a variety of agents, both chemotherapy agents, immunotherapy agents, cellular therapy approaches, to actually treat relapse, or even better, prevent relapse using these agents in a maintenance setting.

Are there any ongoing trials or recent research that has caught your eye in this space?

There are a number, and they largely revolve around maintenance efforts to try to prevent patients from relapsing. These include the use of targeted agents and tyrosine kinase inhibitors that are now becoming much more popular and have become a standard of care in the treatment of many patients with AML and ALL, as well as immunotherapy conjugates that are used to treat patients prior to transplant. They're now being looked at in the post-transplant setting as maintenance.

Can you discuss the role of stem-cell transplant for hematological malignancies prior to the availability of CAR T-cell products?

Prior to the advent of CAR T-cell or immune effector cell approaches allogeneic transplant or autologous transplant represented the main cellular therapy for patients with blood cancers. They could be employed in a variety of circumstances, either in the autologous transplant setting in patients with non-Hodgkin lymphoma or Hodgkin lymphoma, and multiple myeloma, or the allogeneic setting for these very same diseases or those individuals with acute leukemia, MDS, or myelofibrosis.

They were used quite frequently in many circumstances. We didn't use them in all patients, as there were patients who were considered good risk patients by their biologic characteristics or their clinical characteristics. We wouldn't expose those patients to transplant because of the potential toxicity of transplant, hoping that standard therapy would be sufficient to cure them. Those individuals who were high-risk patients by their clinical or genomic characterization or those individuals who had not responded to primary therapy with those individuals are those individuals who we employ hematopoietic stem cell transplant for.

What unmet needs still exist regarding transplants?

We have been doing transplants for 50-60 years at this point. I've been doing it for just about 40 years, and we've made some good progress, but we have a long way to go. Transplant is still too toxic. There is a mortality associated with it, particularly with allogeneic transplants. Even if we've improved substantially, we want to have a therapy that we can offer patients that doesn't put their life at jeopardy. We need to continue to improve the safety of transplant. As I said, we've come a long way there.

The topic of my talk from Miami discussed relapse after transplant. There we have to cooperate. Those who work with allogeneic transplants have to collaborate with disease focused colleagues, whether it be leukemia, lymphoma, myeloma, or other diseases, to work together to try to bring down that risk of relapse, first by getting patients more ready for transplant and at a better minimal disease state going into transplant, and then working on ways to continue that therapy after transplant to try to suppress the risk of relapse.

What is important to note about relapse after transplant?

The real focus needs to be on maintenance therapies and the prevention of relapse. We must understand who is likely to relapse, how to deploy those therapies, and work together with our disease experts in leukemia, lymphoma, myeloma, and more, to combine the best of non-transplant therapies with transplants.

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Maintenance Therapies Needed to Prevent Relapse After Transplant - Targeted Oncology

Personalizing Therapies for Optimal Outcomes in Multiple Myeloma – Targeted Oncology

By Stem Cell Clinic

How clinicians choose to sequence treatment for patients with multiple myeloma to provide a more personalized approach has played an important role in managing this disease over time. According to Paul Richardson, MD, treating multiple myeloma is never a one-size-fits-all approach, so it is important to tailor treatments for each patient.

Multiple myeloma is a highly heterogeneous disease. It's full of multiple subgroups of patients. In that context, the ability to have rational combination strategies that integrate small molecule approaches, immune therapies, transplantation and so forth, is an absolutely vital way forward, said Richardson, Clinical Program Leader of the and Director of Clinical Research at the Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Institute, as well as the RJ Corman professor of Medicine at Harvard Medical School, in an interview with Targeted OncologyTM.

When choosing between the available regimens for patients with multiple myeloma, experts look at the disease characteristics of patients, including stage, age, kidney function, response to prior therapies, and more, to create this more personalized approach and improve the quality-of-life of patients.

In the interview, Richardson highlighted his presentation from the 4th Annual Miami Cancer Institute Global Summit on Immunotherapies for Hematologic Malignancies on updates and personalization of treatments for patients with multiple myeloma.

Targeted Oncology: Can you discuss the importance of personalizing treatments for patients with multiple myeloma?

Richardson: It was my privilege to present this [topic] at the fourth meeting, led by Guenther Koehne, MD, PhD. It was an outstanding meeting and I'm very grateful to the organizers for inviting me. My remit was to frame the immune rationale or the immune therapy rationale in myeloma and contextualize it in the incredibly exciting environment we have with multiple treatment options for our patients, recognizing the promise of immune therapies, and at the same time, recognizing the value of backbone approaches that have continued to provide benefit.

The overarching thrust of my presentation was to share that this is never a case of one-size-fits-all, but rather all hands to the pump. We need all the tools that we're fortunate enough to have. Multiple myeloma is a highly heterogeneous disease. It's full of multiple subgroups of patients. In that context, the ability to have rational combination strategies that integrate small molecule approaches, immune therapies, transplantation and so forth, is an absolutely vital way forward.

What are some of the currently available options for patients with multiple myeloma?

In the upfront space, triplets are established as a standard of care. That involves a proteasome inhibitor, an immunomodulator, and a steroid. Now, we have the quadruplets where that exact same platform is integrated with a monoclonal antibody classically targeting CD38. In this case, daratumumab [Darzalex] has led that charge. Isatuximab [Sarclisa]is coming up behind, but nonetheless, I think it offers real value, particularly in the relapse setting.

Why is it impoartnt to personalize treatments for patients with multiple myeloma?

Basically, tailoring therapy to frailty to access, to minimize hospitalization, and to improve quality of life, all of these factors become important. Given that this platform is so highly active, I think it is very exciting and great that we could [tailor treatments].

Is there any ongoing research in this space that has recently caught your eye?

[I must] acknowledge the incredible advances from immunotherapy platforms and my colleagues who have led those efforts. We've seen tremendous excitement around bispecifics, we've seen tremendous excitement around chimeric antigen receptor [CAR] T, but also, [it is important] to recognize that behind that requires other approaches that are perhaps more practical, perhaps a little easier to operationalize, and these are equally valuable, in my opinion, because we have to be able to provide to our patients who are frail, elderly, perhaps on minority communities in which hospitalization is much less attractive, we may need to be able to move these new opportunities into the clinics in an absolute sense, ie become truly community based. I think that's in the future, and I think it will happen with some of the very exciting immunotherapies.

But right now, we have oral options that could also address that, as well as infusional ones that are relatively straightforward to administer, and are clearly clinically beneficial. I think amongst the oral options, we must focus on talking about the emerging excitement around CELMoDs and how useful those are. It's been my privilege to research mezigdomide [CC-92480], a particular agent that is attracting attention because it's oral and it seems to work very well, even in the face of triple-class refractory and quad refractory or BCMA-exposed disease. For patients this is an exciting way forward.

For the community oncology audience, what recommendations would provide to those treating patients with multiple myeloma?

I would offer one of continued hope, but also one of continued excitement around the novel therapies that are increasingly available. Also, understand that this complexity is understandable, and you can make sense of it. I think for some of my community oncologists, they get a little dazzled and sort of think, what do we do next? I would simply say, you can think through a paradigm now of proteasome inhibition, immunomodulation, CD38 targeting, BCMA targeting, and then how you can revisit these classes of drugs, recombine them, look at newer agents, such as the CELMoDs, such as bispecifics, and CAR T therapies, and the appropriate patient.

At the same time, also recognize that in some patients, there may be value to autologous stem cell transplant with high-dose melphalan flufenamide [Pepaxto] or newer approaches that seek to try and emulate that. I think there are a variety of takeaways that are important, and I am also excited by some of the ongoing work with immunoconjugates and antibody approaches that are simple and relatively easy to give.

See more here:
Personalizing Therapies for Optimal Outcomes in Multiple Myeloma - Targeted Oncology

Gain Therapeutics Announces Grant Award by Eurostars with Innosuisse for Alpha-1 Antitrypsin Deficiency Research Program – Marketscreener.com

By Stem Cell Clinic

Grant awarded to consortium led by Gain Therapeutics to advance the development of proprietary allosteric small molecule regulators against Alpha-1 Antitrypsin (AAT) Deficiency

BETHESDA, Md., March 21, 2023 (GLOBE NEWSWIRE) -- Gain Therapeutics, Inc. (Nasdaq: GANX), a biotechnology company transforming drug discovery with its proprietary computational discovery platform identifying novel allosteric binding sites and creating small molecule treatments, today announced that Eurostars and Innosuisse have awarded a grant in the aggregate amount of 1.2 million to a consortium led by Gain Therapeutics which includes the Institute for Research in Biomedicine, Newcells Biotech and the University of Helsinki. This grant supports a research project to develop novel small molecule allosteric regulators against Alpha-1 Antitrypsin (AAT) Deficiency, a rare genetic condition that can result in serious lung and liver diseases.

We are pleased that Eurostars and Innosuisse recognize that Gain Therapeutics allosteric small molecule regulators provide a new approach to address AAT deficiency-related metabolic diseases. We look forward to advancing our AAT program with this consortium, which combines our unique targeting approach with novel in vitro and in vivo models. This grant validates the capability of our computational discovery platform SEE-Tx to identify previously unknown allosteric binding sites on protein targets in CNS, oncology and now metabolic disease, said Dr. Manolo Bellotto, Chief Strategic Officer and General Manager at Gain Therapeutics.

Prof. Dr. Maurizio Molinari, group leader of the Protein Folding and Quality Control research team from the IRB Bellinzona and Adjunct Professor at the cole Polytechnique Fdrale de Lausanne (EPFL) added, The support by Eurostars and Innosuisse is a rewarding recognition for our long-standing activity in the field of rare diseases. The transnational collaboration with Gain Therapeutics, Newcells Biotech and the University of Helsinki will hopefully offer the opportunity to translate into the clinic, the research activity performed at the IRB and aims at understanding how perturbations in protein folding may cause severe diseases.

Dr. Mike Nicholds, CEO of Newcells Biotech added, Newcells is excited to contribute to this project and collaborate to advance an innovative therapy by applying our novel in-vitro stem cell tissue models of the liver and lung to enable efficacy and safety studies.

Dr. Satu Kuure, Principal Investigator and Head of the GM-unit at University of Helsinki commented: We are excited to participate in the Eurostars-3 project, where our task is to generate unique in-vivo models of A1AT deficiency manifesting both liver and lung symptoms. These models encompass the localized organ specific and systemic effects of A1AT deficiency. Consequently, these models will be used as a disease model where lead small molecules therapeutic power can be tested in a physiological setting.

About Alpha-1 Antitrypsin DeficiencyAlpha-1 antitrypsin deficiency is a genetic disorder that affects the production of a protein called alpha-1 antitrypsin (AAT), which is mainly produced in the liver and released into the bloodstream. AAT plays an important role in protecting the lungs from damage caused by inflammation. In people with AAT deficiency, mutations of the SERPINA1 gene cause misfolding of AAT, which then cannot be effectively released into the bloodstream. As a result, there is a buildup of the misfolded protein in the liver cells, which can cause liver damage and may lead to liver disease. Additionally, insufficient amounts of AAT in the bloodstream can lead to lung damage and the development of chronic obstructive pulmonary disease (COPD). AAT deficiency occurs in approximately 100,000 people in the United States and may qualify as an orphan disease. Gain Therapeutics has applied its drug discovery platform SEE-Tx to identify small molecules binding to a novel allosteric site on AAT to restore proper folding of the protein and halt the disease cascade leading to AAT deficiency and its associated diseases.

About Gain Therapeutics, Inc. Gain Therapeutics, Inc. is transforming drug discovery with its proprietary computational discovery platform identifying novel allosteric binding sites and creating small molecule treatments to address unmet medical needs. The ability to identify never-seen-before allosteric targets on proteins involved in diseases across the full spectrum of therapeutic areas provides opportunities for a range of drug-protein interactions, including protein stabilization, protein destabilization, targeted protein degradation, allosteric inhibition, and allosteric activation. Gains pipeline spans neurodegenerative diseases, lysosomal storage disorders (LSDs), metabolic disorders, as well as other diseases that can be targeted through protein degradation, such as oncology. Gains lead program in Parkinsons disease has been awarded funding support from The Michael J. Fox Foundation for Parkinsons Research (MJFF) and The Silverstein Foundation for Parkinsons with GBA, as well as funding support from Eurostars-3 which is part of the European Partnership on Innovative SMEs: the partnership is co-funded by the European Union through Horizon Europe and Innosuisse Swiss Innovation Agency and SERI - The State Secretariat for Education, Research and Innovation. For more information, please visit https://www.gaintherapeutics.com.

About Institute for Research in Biomedicine (IRB)The Institute for Research in Biomedicine was founded in 2000 with the clear and ambitious goal of advancing the study of human immunology, with particular emphasis on the mechanisms of host defense. The activities of the 13 research groups now extend beyond immunology to include the fields of DNA repair, rare diseases, structural and cell biology. Located in Bellinzona, capital of the Italian-speaking Canton of Ticino, the IRB is an affiliated institute of the USI Faculty of Biomedical Sciences. For more information, visit:www.irb.usi.ch

About Newcells BiotechNewcells Biotech Ltd applies its expertise and proprietary technologies in stem and primary cell biology to develop and commercialize micro-physiological systems (MPS) that closely mimic human and other species in vivo biology. Newcells unique models of the kidney and retina comprise a comprehensive suite of in-vitro MPS based assays that provide predictive insights on efficacy, safety and pharmacokinetics. The recently launched lung tissue fibrosis assay is part of a range of pulmonary models for disease modelling created by the development team that has also developed an advanced in vitro liver model.

About University of HelsinkiThe University of Helsinki is one of the worlds leading multidisciplinary research universities, renowned for its high-quality teaching, research and innovation. It is proud to be the only Finnish university constantly ranked among the top one hundred best universities in the world. The University of Helsinki has a long standing commitment for sustainability, responsibility and reflected in the motto: With the Power of Knowledge. Established in 1640, the University of Helsinki is the oldest university in Finland.

About EurostarsEurostars is a part of the Horizon Europe program that supports SMEs and project partners (universities, research organizations and other types of organizations) by funding international collaborative R&D and innovation projects. Eurostars is run by EUREKA, an intergovernmental network, which involves 37 countries.

Cautionary Note Regarding Forward-Looking Statements This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases, you can identify these statements by forward-looking words such as "may," "might," "will," "should," "expect," "plan," "anticipate," "believe," "estimate," "predict," "goal, " "intend," "seek, " "potential" or "continue," the negative of these terms and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. All statements, other than historical facts, included in this press release are forward-looking statements. These statements include, but are not limited to, statements regarding: the development of the Companys current or future product candidates; expectations regarding timing for reporting data from ongoing preclinical studies or the initiation of future clinical trials, including the timing for completion of IND-enabling toxicology studies and submission of the dossier requirement for commencement of a Phase 1 clinical program for GT-02287 for GBA1 Parkinsons disease and the potential therapeutic and clinical benefits of the Companys product candidates; the selection and development, and timing thereof, of future programs, or any potential business development opportunities for product candidates; the Companys financial position and ability to execute on the next phase of its strategy; and the Companys anticipated cash runway guidance, including the ability for the Companys current and projected cash to allow the Company to meet value inflection points. Each of these forward-looking statements involves risks and uncertainties that could cause the Companys preclinical and future clinical development programs, future results or performance to differ materially from those expressed or implied by the forward-looking statements. These statements are not historical facts but instead represent the Company's belief regarding future results, many of which, by their nature, are inherently uncertain and outside the Company's control. Many factors may cause differences between current expectations and actual results, including the impacts of the COVID-19 pandemic and other global and macroeconomic conditions on the Companys business; clinical trials and financial position; unexpected safety or efficacy data observed during preclinical studies or clinical trials, clinical trial site activation or enrollment rates that are lower than expected; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; and unexpected litigation or other disputes. Other factors that may cause the Companys actual results to differ from those expressed or implied in the forward-looking statements in this press release are identified in the sections titled Risk Factors, Managements Discussion and Analysis of Financial Condition and Results of Operations and elsewhere in the Companys Annual Report on Form 10-K, Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission from time to time. New risks and uncertainties arise over time, and it is not possible for us to predict all such factors or how they may affect us. You should not place undue reliance on forward-looking statements. All information in this press release is as of the date of the release, and we are under no duty to update this information after the date of this release, except as required by law. You should not rely on it as representing our views as of any date subsequent to the date of this press release.

Investor & Media Contact:Argot PartnersNoor Pahlavi(212) 600-1902Gain@argotpartners.com

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Gain Therapeutics Announces Grant Award by Eurostars with Innosuisse for Alpha-1 Antitrypsin Deficiency Research Program - Marketscreener.com

What makes blood stem cells transform? Regulation of RNA splicing … – Science Daily

By Stem Cell Medical Center

Researchers at Lund University Faculty of Medicine have determined a novel mechanism linking the metabolism of ribonucleic acids, RNA, to the development of leukemia in myelodysplastic syndrome patients, MDS. In a study published in the Molecular Cell journal, they explain what makes hematopoietic stem cells acquire malignant traits in cancer.

RNA splicing is a major nexus of gene expression regulation, shaping cellular identity during development, frequently altered in human cancers. This process is mediated by a complex molecular machinery known as the spliceosome, which enables the production of multiple and functionally distinct proteins from single genes.

A team of researchers led by Dr. Cristian Bellodi recently discovered a hardwired genetic control mechanism modulating individual spliceosomal components, known as splicing factors, in cells harboring oncogenic lesions common in human cancers.

This work highlighted core splicing proteins, including SF3B1, frequently mutated in various cancers. Splicing factor mutations are particularly prevalent in MDS, a group of heterogeneous hematological disorders characterized by defective blood stem cells and a high risk of leukemia development. "Accumulating evidence is highlighting a role for aberrant splicing in cancer even in the absence of splicing factors mutations. However, little is known about the contribution of the non-mutated splicing factors in tumor evolution," explain the researchers.

The team began by investigating how the levels of non-mutated SF3B1, a core spliceosome component, contribute to the MDS disease. With Prof. Eva Hellstrm-Lindberg's group at the Karolinska Institute, Maciej Ciela and coworkers discovered dynamic regulation of SF3B1 levels during the malignant transformation from MDS to leukemia.

"Strikingly, we found that SF3B1 protein accumulates in MDS patients to ensure genome integrity via splicing regulation. Blocking this mechanism drastically accelerates progression to aggressive leukemia," remarks Maciej Ciela, a postdoctoral fellow in the RNA and Stem Cell Biology group at tLund University Stem Cell Center and first author of the study. Now, a group leader at IMOL, Poland.

The authors further investigated the molecular determinants controlling the SF3B1 production during the transition to leukemia. These studies led to the breakthrough discovery that SF3B1 synthesis depends on a single RNA chemical modification mark, known as N6-methyladenosine, m6A, deposited on its messenger RNA.

"We found that the presence of m6A RNA modification provides a "stop signal" that regulates SF3B1 production, a critical event that impacts accumulation of DNA damage in leukemic cells," explains Maciej Ciela.

"Our results revealing a new critical connection between RNA metabolism and genome integrity in leukemic stem cells, provide important insights into the complex underlying mechanisms fueling cancer development in MDS patients. Our findings are particularly timely, as increasing evidence indicates that RNA modification and splicing alterations represent new therapeutic vulnerabilities for treating hematological and solid cancer patients," concludes Cristian Bellodi, Associate Professor, Division of Molecular Hematology and Lund Stem Cell Center, Lund University.

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What makes blood stem cells transform? Regulation of RNA splicing ... - Science Daily

UCLA-led study uses base editing to correct mutation that causes … – UCLA Newsroom

By Stem Cell Medical Center

Key takeaways

A new UCLA-led study suggests that advanced genome editing technology could be used as a one-time treatment for the rare and deadly genetic disease CD3 delta severe combined immunodeficiency.

The condition, also known as CD3 delta SCID, is caused by a mutation in the CD3D gene, which prevents the production of the CD3 delta protein that is needed for the normal development of T cells from blood stem cells.

Without T cells, babies born with CD3 delta SCID are unable to fight off infections and, if untreated, often die within the first two years of life. Currently, bone marrow transplant is the only available treatment, but the procedure carries significant risks.

In a study published in Cell, the researchers showed that a new genome editing technique called base editing can correct the mutation that causes CD3 delta SCID in blood stem cells and restore their ability to produce T cells.

The potential therapy is the result of a collaboration between the laboratories of Dr. Donald Kohn and Dr. Gay Crooks, both members of the Eli and Edythe Broad Center ofRegenerative Medicine and Stem Cell Research at UCLA and senior authors of the study.

UCLA Broad Stem Cell Research Center

Dr. Donald Kohn and Dr. Gay Crooks

Kohns lab has previously developed successful gene therapies for several immune system deficiencies, including other forms of SCID. He and his colleagues turned their attention to CD3 delta SCID at the request of Dr. Nicola Wright, a pediatric hematologist and immunologist at the Alberta Childrens Hospital Research Institute in Canada, who reached out in search of a better treatment option for her patients.

CD3 delta SCID is prevalent in the Mennonite community that migrates between Canada and Mexico. Because newborns are not screened for SCID in Mexico, I often see babies who have been diagnosed late and are returning to Canada quite sick, Wright said.

When Kohn presented Wrights request to his lab, Grace McAuley, then a research associate who joined the lab at the end of her senior year at UCLA, stepped up with a daring idea.

Grace proposed we try base editing, a very new technology my lab had never attempted before, said Kohn, a distinguished professor of microbiology, immunology and molecular genetics, and of pediatrics.

Base editing is an ultraprecise form of genome editing that enables scientists to correct single-letter mutations in DNA. DNA is made up of four chemical bases that are referred to as A, T, C and G; those bases pair together to form the rungs in DNAs double-helix ladder structure.

While other gene editing platforms, like CRISPR-Cas9, cut both strands of the chromosome to make changes to DNA, base editing chemically changes one DNA base letter into another an A to a G, for example leaving the chromosome intact.

I had a very steep learning curve in the beginning, when base editing just wasnt working, said McAuley, who is now pursuing an M.D.-Ph.D. at UC San Diego and is the studys co-first author. But I kept pushing forward. My goal was help get this therapy to the clinic as fast as was safely possible.

McAuley reached out to the Broad Institutes David Liu,the inventor of base editing, for advice on how to evaluate the techniques safety for thisparticular use. Eventually, McAuley identified a base editor that was highly efficient at correcting the disease-causing genetic mutation.

UCLA Broad Stem Cell Research Center

Dr. Gloria Yiu and Grace McAuley

Because the disease is extremely rare, obtaining patient stem cells for the UCLA study was a significant challenge. The project got a boost when Wright provided the researchers with blood stem cells donated by a CD3 delta SCID patient who was undergoing a bone marrow transplant.

The base editor corrected an average of almost 71% of the patients stem cells across three laboratory experiments.

Next, McAuley worked with Dr. Gloria Yiu, a UCLA clinical instructor in rheumatology, to test whether the corrected cells could give rise to T cells. Yiu used artificial thymic organoids,which are stem cell-derived tissue models developed by Crooks lab that mimic the environment of the human thymus the organ where blood stem cells become T cells.

When the corrected blood stem cells were introduced into the artificial thymic organoids, they produced fully functional and mature T cells.

Because the artificial thymic organoid supports the development of mature T cells so efficiently, it was the ideal system to show that base editing of patients stem cells could fix the defect seen in this disease, said Yiu, who is also a co-first author of the study.

As a final step, McAuley studied the longevity of the corrected stem cells by transplanting them into a mouse. The corrected cells remained four months after transplant, indicating that base editing had corrected the mutation in true, self-renewing blood stem cells. The findings suggest that corrected blood stem cells could persist long-term and produce the T cells patients would need to live healthy lives.

This project was a beautiful picture of team science, with clinical need and scientific expertise aligned, said Crooks, a professor of pathology and laboratory medicine. Every team member played a vital role in making this work successful.

The research team is now working with Wright on how to bring the new approach to a clinical trial for infants with CD3 delta SCID from Canada, Mexico and the U.S.

This research was funded by theJeffrey Modell Foundation, the National Institutes of Health, the Bill and Melinda Gates Foundation, the Howard Hughes Medical Institute, the V Foundation and the A.P. GianniniFoundation.

The therapeutic approach described in this article has been used in preclinical tests only and has not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans. The technique is covered by a patent application filed by the UCLA Technology Development Group on behalf of the Regents of the University of California, with Kohn and McAuley listed as co-inventors.

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UCLA-led study uses base editing to correct mutation that causes ... - UCLA Newsroom

Chimera research opens new doors to understanding and treating … – Drug Discovery News

By Stem Cell Medical Center

When I was in college, my mother needed a heart transplant, said Mary Garry, a cell biologist at the University of Minnesota. Even though she was only in her fifties, Garrys mother was told that she was too old to receive a transplant; there simply were not enough hearts available.

My mother died in 1980, said Garry. The number of donor hearts that are available today is really not much more than the number that was available later on in the 1980s.

The need for organs, especially kidneys, livers, and hearts, far outstrips availability. Today, more than 100,000 people in the United States alone are on the national transplant waiting list (1). Many will die while waiting.

As scientific understanding of stem cells, gene editing, and organism development improved, Garry felt that her career path was clear. When the technologies became available to solve this problem, it seemed very much like the right thing to do.

Today, Garry and her husband Dan, a transplant cardiologist, are pioneers in the field of interspecies chimera research, the study of organisms containing cells from two different species. Their team focuses on using human induced pluripotent stem cells to grow human tissues inside pigs.

Other scientists, including Jun Wu, a stem cell biologist at the University of Texas Southwestern Medical Center, are also studying chimeras with the ultimate goal of one day being able to grow enough human organs to meet the enormous need for transplants, potentially saving hundreds of thousands of lives. Human pluripotent stem cells harbor the potential to provide an inexhaustible supply of donor cells or tissues or organs for transplantation, Wu wrote in an email.

In Greek mythology, the chimera was a fire-breathing monster part goat, part snake, part lion that terrorized the people of Lycia before being slain by the hero Bellerophon. In biology, a chimera is much less monstrous; it is any organism that contains two or more sets of DNA. This can range from the relatively pedestrian, such as a person who received a bone marrow transplant, to creatures that seem more at home in science fiction, such as animals containing cells or tissues belonging to other species.

Lab-created interspecies chimeras are not especially new. Scientists at the ARC Institute of Animal Physiology announced their creation of sheep-goat hybrids known as geeps in 1984 (2). Early chimera research was difficult and inexact. Scientists painstakingly removed tissue from one embryo and grafted it into another embryo (3). However, advances in stem cell research in the 2000s revolutionized the field, opening up new possibilities and new applications for multispecies organism research.

In 2007, a team at Kyoto University created pluripotent stem cells from adult human somatic cells (4). Researchers began to dream of a future in which a patients own cells, perhaps from the blood or the skin, could be converted into these induced pluripotent stem cells and grown into whatever organ the patient needed. Not only would this provide an adequate supply of organs, but it would also eliminate the need for patients to take potentially dangerous immunosuppressant drugs; since the new organs would be made from their own cells, they wouldnt have to worry about organ rejection.

Jun Wu helped create rat-mouse chimeras like those pictured above. The brown fur was generated from rat cells.

credit: Carlos Pinzon Arteaga, UT Southwestern

Some researchers are attempting to use stem cells to bioengineer human organs in the lab in vitro, rather than inside another species (5). While Garry readily acknowledges the importance of multiple approaches, she said that there are important advantages to growing organs in developing animals rather than in vitro.

We think that the developmental cues that exist in the pig will help to guide the human cells inside the porcine embryo. In the in vitro approach, there is a physical scaffold that exists, but the biological cues like the growth factors or the sheer force of blood flow or other things of that nature that are present in the living organism are missing, she said. Scientists may not yet know enough to accurately mimic all of the developmental cues that instruct the cells to become a specific organ. Nature knows more than we do because we can't reinvent all those things in vitro, said Garry.

One method for growing an organ from one animal inside of a different species is blastocyst complementation. Researchers knock out a gene that drives the development of a specific organ in the host blastocyst and implant pluripotent stem cells from a donor species.

Early studies demonstrated that this technique worked, at least in some closely related species. In 2010, stem cell biologist Hiromitsu Nakauchi and his team at the University of Tokyo deleted a gene that drives pancreas formation in mouse embryos and injected rat pluripotent stem cells to fill the empty niche. The resulting mice were born with functional pancreases made of mostly rat cells (6).

Since then, Nakauchi and others have created chimeric organisms with replacement livers, lungs, and kidneys (79). Despite these successes in rodent models, translating these findings to human organs is proving to be much more challenging.

How closely animals are related seems to be an important factor in determining how easily an interspecies chimera can be created. In this sense, it might be easiest to grow human organs in closely related nonhuman primates. However, many scientists believe that logistically, pigs are the most suitable species for large-scale production of human organs: Pigs mature quickly, have large litters, and their physiologies are similar to humans in many ways (10). At 90 to 200 pounds, a miniature pigs body size is more similar to a humans than a typical research monkeys; male rhesus macaques are only about 17 pounds on average, which could present difficulties when trying to grow human-sized organs (11).

Even though pigs are optimal for growing human organs in some respects, their evolutionary distance from humans creates some difficulties. During his postdoctoral research at the Salk Institute for Biological Studies, Wu explored strategies for making human stem cells more suitable for this task.

Jun Wu studies the barriers to interspecies chimerism.

credit: UT Southwestern

By coaxing human pluripotent stem cells into an intermediate form, somewhere in between a nave stem cell and a primed stem cell, Wu, along with other researchers at the Salk Institute, produced the first human-pig chimeric embryos in 2017 (12). Although this was a major step forward, it was a far cry from pigs with fully human organs. Researchers estimated that the embryos contained about one human cell for every 100,000 pig cells (12,13).

Deleting pig genes that drive development of specific organs, as Nakauchi did in mice and rats, can help more human stem cells grow in pig embryos, but its still not enough to produce a fully human organ or tissue type. The Garrys knew that the human cells needed an extra boost, so they used human cells that overexpressed BCL2, an antiapoptotic factor. By combining these boosted human cells with pig blastocysts that lacked the master regulator gene ETV2, the Garrys successfully produced a pig embryo with a fully human endothelium, the tissue that lines the vascular system, including the heart and blood vessels (14).

While endothelium transplants arent feasible, Garry said that this is still an important step forward. In other models, the kidney or pancreas may be made of cells from another species, but the endothelium was still made of host cells, which play a large role in organ rejection by the transplant recipient.

The endothelium is so important that it's possible that just knocking out the vasculature with a single gene deletion ETV2 may be enough to make every porcine organ compatible to transplant into humans. The site of rejection is primarily the endothelium that lines the vasculature, Garry said.

The Garrys also created pig embryos with human skeletal muscle tissue, this time deleting the p53protein in the human cells to boost growth (15). While these studies show that growing human tissues in pigs is possible, these growth-boosting strategies arent necessarily appropriate for creating organs for transplant into humans, as both genetic alterations also come with an increased risk of cancer growth.

Garrys team is currently working on understanding the relationship between the human stem cells and the pig cells of the host embryo, which may lead to strategies to increase the growth of the human cells that are more suitable for organs destined for transplantation.

We think that the efficiency of the chimerism really comes down to immunological barriers, she said. So, were working with various other groups that are really experts in immunobiology, including David Sachs group at Columbia University, who are helping us to understand all these factors that present hurdles for advancement.

Garry estimated that organs grown in pigs could be ready for trials in humans in as little as five years.

Other researchers are exploring alternative strategies to increase efficiency even in evolutionarily distant animals (16,17).

Wu hopes to make progress in this area by exploring differences in chimerism between closely and more distantly related organisms. Comparing differences of human extended pluripotent stem cells in mouse and monkey blastocysts in culture will help us understand species barriers during early development due to genomic evolution and develop better strategies to overcome these barriers to enable more robust contribution of human chimerism in evolutionarily more distant species, e.g. pigs, wrote Wu.

To this end, Wu, along with a team of researchers from the Salk Institute for Biological Studies and the Kunming University of Science and Technology, created the first human-monkey chimeric embryos in 2021 (18).

Wu also identified cell competition between animal and human cells during development as an important factor in chimerism failure (19). Cell competition is known to serve as a quality control mechanism to selectively remove unfit cells from a developing embryo. Human pluripotent stem cells are thus treated as unfit cells in a growing animal embryo and are targeted for elimination," wrote Wu.

By investigating the mechanisms underlying this process, Wus team identified ways to help human cells survive in animal embryos. When growing mouse-human embryos, they found upregulation of genes related to the NF-B signaling pathway in the human cells. This pathway controls many different cellular functions, including response to stress and apoptosis, a type of cell death. By genetically altering this pathway, the researchers improved the survival of human cells in the mouse embryos (19).

Jian Feng develops mouse-human chimeric embryos, like the above mouse embryo at embryonic day 17, with human cells labeled with green fluorescent protein.

credit: Zhixing Hu

Jian Feng, a stem cell researcher at the University at Buffalo, is developing another technique to encourage human cells to grow in mouse embryos. Unlike Garry and Wu, Fengs goal is not to grow human organs, but to improve our understanding of neurodegenerative disease.

Feng was originally trained as a molecular biologist, but early on, he became interested in studying Parkinsons disease, especially the early-onset form of the disease caused by a mutation in the PRKN gene. I felt that I could use the full power of molecular biology to study a complex human disease, he said.

Feng soon encountered the difficulties of studying human diseases in mice. When he knocked out the PRKN gene in the mice, they didnt seem affected at all. So, when he read about the creation of mouse induced pluripotent stem cells, followed shortly by the generation of the human versions in the 2000s, he knew immediately that he wanted to use these human cells to study this human disease.

Studying the cells in culture wasnt necessarily the answer though. If we want to study human CNS problems, we have to have a circuit, said Feng. Furthermore, the dopaminergic neurons of the substantia nigra, which degenerate in Parkinsons disease, cant be easily re-created in a dish. These are very unique cells. They have extremely complicated axon arborization, said Feng. We needed to find a surrogate that could allow us to make these cells in vivo.

Like other researchers, Feng has been working on strategies to improve the efficiency of human-animal chimerism. By temporarily inhibiting the signaling protein mTOR, Feng converted human pluripotent stem cells into a form that displayed improved growth when transplanted into mouse embryos; after 17 days, some of the mouse embryos had as many as four percent human cells (16).

Jian Feng studies mouse-human chimeric embryos with the goal of building better models of Parkinsons disease.

credit: Sandra Kicman

Eventually, Feng wants to use chimera technology to create better models of Parkinsons disease, such as mice with human dopaminergic neurons in the substantia nigra. However, he noted that there are still many technical issues to overcome.

While creating rodents with human brain cells is a daunting task, it isnt completely without precedent. In 2017, a group at the University of Rochester created chimeric mice with glial cells, the non-neuronal cells of the central nervous system, frominduced pluripotent stem cells derived from human patients with schizophrenia (19). The glial cells developed abnormally, and the mice displayed anxiety, impaired social behavior, and disrupted sleep patterns, suggesting that glial cells likely play a role in the development of schizophrenia, and that these mice could be used as improved models for developing new therapies.

More recently in the fall of 2022, researchers at Stanford University transplanted a human stem cell derived cortical organoid into the brain of a newborn rat (20). The human neurons integrated into the rat brain; activating them sufficiently provoked certain behaviors.

While researchers still have lots of work ahead of them, they hope that one day their efforts will provide organs for transplants and a deeper understanding of neuropsychiatric diseases, saving lives and alleviating suffering around the world.

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Chimera research opens new doors to understanding and treating ... - Drug Discovery News

Grandmother on mission to find bone marrow match for grandson … – KSTP

By Stem Cell Medical Center

A Minnesota grandmother is traveling hundreds of miles across two states in the hopes of finding a bone marrow donor for her grandson.

Ari Chambers-Baltz, 22 months old, is diagnosed with hyper IgM, a rare immune disorder.

One out of a million boys get this. All will pass away by the age of 30 if they dont get a transplant, said Sharon Chambers, Aris grandmother.

Chambers said so far, there is no perfect match for Ari through Be the Match, the national marrow registry.

Thirty-nine million people, and theres no match for Ari yet, Chambers said. But it just takes one. Im looking for that one person out there.

The family is now hosting sign-up drives at malls, churches and colleges across Minnesota and Wisconsin.

5 EYEWITNESS NEWS was there as dozens of college students stepped up to swab their cheeks Friday at Bethel University, which is Aris parents alma mater.

Its just an easy thing that means nothing to me but can mean a lot to somebody else, said Aiden St. George, who signed up for the registry during Fridays drive.

Ari and his parents currently live in Illinois, although much of their family is in Minnesota.

If Ari finds a match, his stem cell transplant will take place at M Health Fairview Masonic Childrens Hospital in Minneapolis.

His doctor told 5 EYEWITNESS NEWS a transplant would represent a cure for Ari, and he would likely go on to lead a full, healthy life.

Masonic Childrens Hospital has already done five stem cell transplants for kids with hyper IgM and all have been successful.

If there is a match, 90% of the time, we would collect stem cells through your blood, similar to donating plasma. It takes about four to six hours to donate. In 10% of cases, we take the marrow out of your hip bone, which is a surgical procedure, said Keesha Mason, account manager for Be the Match.

Mason said 500 people have stepped up to join the registry after hearing Aris story.

All those people that have registered for Ari, the masses of people, they might not be a match for Ari, but they could be a match for someone along the road, Mason said. Theres something about believing in miracles and being a part of something bigger than you know.

Aris family hopes his match is out there.

We know we need help, and were not afraid to ask because it is a life-and-death situation, Chambers said. Were choosing to hope. And we need Minnesota and Wisconsin to help us the rest of the way.

If you would like to join the Be the Match Registry on behalf of Ari, text AriMN to 61474.

There are in-person sign-up drives happening on these days as well:

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Grandmother on mission to find bone marrow match for grandson ... - KSTP

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