“Regenerative medicine news under the microscope” is a monthly feature highlighting a selection of impactful research findings and headlines across the many subfields of regenerative medicine.
Throughout the past month, I’ve spotted some notable trends emerging in the rapidly evolving field of cell therapy. In this special edition of “Regenerative Medicine News Under the Microscope,” I cover three prominent lines of investigation that each made multiple headlines in May.
Pick of the Month
Stem cells are transplanted into the brain of a patient with Parkinson’s disease at Skåne University Hospital as part of an ongoing clinical trial. Credit: Skåne University Hospital.
Regenerating the Parkinsonian brain
Parkinson’s disease (PD) affects more than 10 million people across the globe. It is a neurodegenerative disorder primarily affecting dopamine neurons, resulting in profound effects on a patient’s motor control. You might not be surprised to hear that stem cell researchers are currently working on therapies that replace diseased dopamine neurons with healthy ones (see recent Signals coverage of this topic by Kevin Robb and me. In fact, according to Clinical Trials Arena, there are at least 55 cell therapies for Parkinson’s being developed at the moment.
Three of these made noteworthy progress this month:
- BlueRock Therapeutics
Select investigational regenerative medicines may qualify for the U.S. Food and Drug Administration’s (FDA) accelerated approval pathway, offered through their Regenerative Medicine Advanced Therapy (RMAT) program. To receive this designation, a drug candidate must intend to cure, reverse, modify, or treat a serious or life-threatening disease, and it also has to show preliminary promise in the clinic.
BlueRock Therapeutics’ stem cell therapy for PD, bemdaneprocel, received the FDA’s RMAT designation after positive results in a Phase 1 clinical trial. Their protocol involves the reprogramming of embryonic stem cells (ESCs) to dopamine precursor cells, which are subsequently implanted into the patient’s brain. Dosing in these studies is reported as the number of cells injected per putamen, a part of the brain implicated in PD. The putamen is a paired structure, meaning it exists in both hemispheres symmetrically. A low-dose group of five patients received 0.9 million cells per putamen (1.8 million total), and a high-dose group of seven received 2.7 million per putamen (5.4 million total). Their therapy was found to be well-tolerated with no major safety concerns over the course of 18 months (with immunosuppressant drugs administered for the first year). While this trial was not necessarily designed to assess efficacy, as Phase 1 is mainly for safety and dosing, but patients did appear to improve with regard to exploratory clinical endpoints – particularly those in the group receiving a higher dose. BlueRock is now proceeding with Phase 2 trials.
- STEM-PD
You may have seen this Euronews article that’s made the rounds. It details Mr. Thomas Matsson’s story as the first Parkinson’s patient to receive a total of 3.5 million cells per putamen (7 million total) in a Phase 1/2a trial. As is the case with Phase 1 trials, Phase 1/2a trials are designed to assess safety and dosing, but can also provide an early window into efficacy. You might notice, however, that these trials are sometimes classified as Phase 1 on ClinicalTrials.gov, as is the case with STEM-PD and Aspen’s Phase 1/2a trial, discussed in the next section.
The STEM-PD study also involves ESCs reprogrammed to become dopamine precursor cells, which, as above, are injected into the patient’s brain. After a successful run with four patients at this dosage, the clinical trial is proceeding to its next phase, which will see double the number of stem cells administered to the next four patients (7 million/putamen, for a total of 14 million). Immunosuppressant drugs are also used in this study to prevent transplant rejection.
While Mr. Matsson’s story is a sample size of one – and we can’t interpret the effects of a treatment based on a single case – it does inspire cautious optimism. He describes his life before receiving treatment in February 2023 as “walking through a syrup.” At the time of the Euronews interview, he reports that “the syrup is gone,” along with an outline of other positive changes to his quality of life and physical abilities. He also recalls a startling psychosis that lasted the first 10 days after his 13-hour stem cell procedure, but that apparently subsided, and the cause is still unknown. Overall, it’s a very interesting read, but I’ll again warn that this is a single case out of many more that will need to be rigorously studied before this treatment is approved. To read more about the science, head to their Cell Stem Cell paper published last year.
- Aspen Neuroscience
Aspen Neuroscience is making headlines for securing 8 million dollars to support the clinical development of their investigational stem cell therapy, which is now the subject of an ongoing Phase 1/2a clinical trial. This grant was awarded by the California Institute for Regenerative Medicine (CIRM).
Aspen Neuroscience’s approach involves the collection of skin cells from a patient, which are then reprogrammed to induced pluripotent stem cells (iPSCs). From there, they are differentiated to dopamine precursor cells, then transplanted into the patient’s brain to develop into mature dopamine neurons. The fact that this procedure involves the patient’s own cells marks a significant difference in protocol, as it eliminates any requirement for immunosuppressive drugs during treatment.
The first patient received their transplant in April, so no results are available, as of yet. However, you can read more about the science in Stem Cells and Development.
I’ll be keeping a close eye on this overall line of investigation as these studies roll into the next phase of trials. As I discussed in my February-March doubleheader, I think it will be interesting to see how future studies might benefit from the use of hydrogels, which may improve transplanted cell survival and overall efficiency.
Stem cells, the immune system, and Alzheimer’s disease
Last month, I highlighted a rodent study reporting a rare margin for iatrogenic Alzheimer’s disease (AD), found to manifest following bone marrow transplants from donors with an AD-linked mutation. This month, I have updates from the other side of the coin, as stem cells are also being examined as potential therapies for the neurodegenerative condition.
As we age, our immune systems decline. We produce fewer immune cells, our immune repertoire – an indicator of how many diseases we’ve fought before and can thus fight again – becomes less diverse, and our bodies accumulate more dysfunctional immune cells. Together, these phenomena are referred to as immunosenescence, and may contribute to AD in certain individuals.
Research by Sun et al. in this month’s Science Advances suggests that immune system rejuvenation could serve as a potential therapeutic avenue for AD patients in future. The authors take advantage of a genetically engineered mouse model of AD in their study, and these aged AD mice received bone marrow transplants from young donor animals of the same strain. Such an approach ensured age – and not genetic background – would be the variable in question. Changes across relevant measures showed significant improvements, with notable reductions in neural degeneration, Aβ plaque burden, neuroinflammation (see a great definition here, plus a relevant review here), and behavioural deficits. The authors point to blood monocytes as a main driver for these improvements, speculating that younger cells may be better able to phagocytose (engulf and eliminate) Aβ. The authors also mention that they cannot necessarily rule out similar enhancements in microglia.
If you’re interested in related research involving AD and stem cells:
- Xiong et al. investigated stem cells for AD from quite an interesting source: Human dental pulp. Their paper was also published this month.
- Mishra et al. used healthy, non-mutant hematopoietic stem and progenitor cell (HSPC) transplantation to treat a different genetic mouse model of AD – some key differences to the study highlighted above include a focus on the genetic background of the donor rather than age, the isolation of HSPCs from bone marrow rather than using all bone marrow cells harvested, and a special focus on microglial involvement in this effect. Find it in Cell Reports, published August 2023.
- Longeveron recently wrapped their Phase 2a CLEAR MIND trial involving mesenchymal stem cells with positive results reported this past December. You can also read about their Phase 1 study in a recent paper, and view their Phase 1 clinical trial record here.
Onboard with CAR T-cell therapy for lupus
Lupus is an incurable autoimmune disorder that causes the body to attack itself. B cells, and their long-lived progeny, plasma cells, generate antibodies that target the patient’s healthy tissue (autoantibodies). Such coordinated attacks lead to inflammation and serious organ damage; the brain, heart, blood, lungs, kidneys, joints and skin can all be subject to harm. This month, a collection of research updates lend further preliminary support to CAR T cells as a promising future avenue for lupus treatment.
CAR T cells are currently approved by the FDA for the treatment of certain cancers (although, as is the case with any treatment, there are risks patients should be aware of). CAR T cell therapy has also been adopted in the fight against other diseases that could benefit from the same track-and-kill paradigm, including lupus. Stacey Johnson, Editor of Signals, covered the very first clinical trial results from this line of investigation back in 2022.
In a new Phase 1 study by iCell Gene Therapeutics, CAR T cells were engineered to detect a protein found on the surface of B cells (CD19), in addition to a protein found on both B cells and plasma cells (BCMA). The authors emphasize that this dual-targeting approach is important because other lupus therapies don’t always prioritize the targeting of plasma cells, which can continue producing harmful autoantibodies. The treatment, termed compound CAR (cCAR) T-cell therapy, was found to be well-tolerated in a group of 13 patients, with reports of only mild cytokine release syndrome – a common concern with this type of treatment. These cases resolved as a result of supportive care.
The majority of patients in the trial, two of whom also suffered from lymphoma in addition to lupus, appear to have achieved medication-free remission of the disease that lasted the entire follow-up period (up to 46 months for some patients). According to the authors, the data indicate that CAR T cells “reset” the immune system without compromising its function; for instance, it was reported that disease-causing B cells were depleted within 10 days of the intervention, followed by re-population with healthy B cells between two and six months afterwards. Still, expectations must be managed as it is very early days; larger studies are a must given that this was only a Phase 1 trial, and iCell’s upcoming investigational new drug (IND) application should help with that.
If you’re interested in this field, here are a few related resources and headlines:
- This piece in Nature Reviews Drug Discovery is an excellent and accessible primer on CAR T for lupus and autoimmune diseases, covering excitement around the first clinical trial results published back in 2022, the many other trials that were inspired afterwards, and some important questions (and concerns) that will need to be addressed. It’s a great read and really contextualizes the highlight above. The author makes an interesting point about how targeting plasma cells, in addition to B cells, necessitates re-immunization against infectious diseases post-treatment.
- Related stories out this month include reports of the first woman to be treated in Fate Therapeutics’ iPSC-based CAR T trial for lupus, and a clinical trial for pediatric patients slated to kick off this summer at Seattle Children’s Hospital.
Additional recommendations
This month was packed with great research – there’s so much to talk about. Here are some additional papers and headlines that might interest you:
Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived islet tissue. Wu et al. in Cell Discovery. This was technically published end of day April 30th, so it just missed the cut for last month’s edition.
Progentos Therapeutics Closes $65 Million Series A Financing to Advance Treatments for Multiple Sclerosis and Other Degenerative Diseases. Progentos Therapeutics via Business Wire. I find the concept of remyelination really fascinating. Read more in this piece by Jacob Bell over at BioPharma Dive, and this one by Dr. Andrea Lobo for Multiple Sclerosis News Today. Each cover the news and add interesting context from a business perspective (Bell) and a scientific perspective (Lobo).
Heart failure promotes multimorbidity through innate immune memory. Nakayama et al. in Science Immunology. ATTN epigenetics enthusiasts: If you still think about the Dutch Hunger Winter papers every once in a while at dinner, this one’s likely right up your alley.
A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice. Jin et al. in Nature Immunology.
Baby born deaf can hear after breakthrough gene therapy. National Institute for Health and Care Research.
Combination therapy with oncolytic virus and T cells or mRNA vaccine amplifies antitumor effects. Fu et al. in Signal Transduction and Targeted Therapy.
An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Huang et al. in Science.
Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells. Maulana et al. in Cell Stem Cell.
Immunologic responses to the third and fourth doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in cell therapy recipients: a systematic review and meta-analysis. Aliabadi et al. in Virology Journal.
Modeling blood-brain barrier formation and cerebral cavernous malformations in human PSC-derived organoids. Dao et al. in Cell Stem Cell.
Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside. Ashmore-Harris et al. in npj Regenerative Medicine.
Multimodal decoding of human liver regeneration. Matchett et al. in Nature.
Harnessing developmental dynamics of spinal cord extracellular matrix improves regenerative potential of spinal cord organoids. Sun et al. in Cell Stem Cell.
Cell therapy could help curb progression of heart failure. Catherine Eckford for European Pharmaceutical Review.
Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling. Rezvan et al. in Nature Cancer.
Bone marrow mesenchymal stem cell-derived exosomes shuttle microRNAs to endometrial stromal fibroblasts that promote tissue proliferation/regeneration and inhibit differentiation. Bonavina et al. in Stem Cell Research & Therapy.
Breakthrough therapies are saving lives, but can we afford them? Lisa Krieger for Medical Xpress.
Fact Check: No evidence of mRNA cancer ‘explosion’ in Japan, no national emergency declared. Reuters Fact Check.
Factors determining utilization of stem cell transplant for initial therapy of multiple myeloma by patient race: exploring intra-racial healthcare disparities. Ailawadhi et al. in Blood Cancer Journal.
Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Lin et al. in Nature.
Bone-marrow-homing lipid nanoparticles for genome editing in diseased and malignant haematopoietic stem cells. Lian et al. in Nature Nanotechnology.
Stem cells derived exosomes as biological nano carriers for VCR sulfate for treating breast cancer stem cells. Farouk et al. in Scientific Reports.
Mesenchymal stem cells pretreated with interferon-gamma attenuate renal fibrosis by enhancing regulatory T cell induction. Kurawaki et al. in Scientific Reports.
FDA moves to support TSHA-102, potential Rett gene therapy. Marisa Wexler for Rett Syndrome News.
Highly variable biological effects of statins on cancer, non-cancer, and stem cells in vitro. Gbelcová et al. in Scientific Reports.
The immune system can sabotage gene therapies — can scientists rein it in? Heidi Ledford for Nature News.
Biomimetic artificial islet model with vascularized microcapsule structures for durable glycemic control. Li et al. in Materials Futures.
Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo. Aubert et al. in Nature Communications.
A nonprofit does deals in Brazil and India to make low-cost CAR-T cell therapies widely available. Ed Silverman for STAT News.
EPHA2 is a novel cell surface marker of OCT4-positive undifferentiated cells during the differentiation of mouse and human pluripotent stem cells. Intoh et al. in Stem Cells Translational Medicine.
Generation of allogeneic CAR-NKT cells from hematopoietic stem and progenitor cells using a clinically guided culture method. Li et al. in Nature Biotechnology.
New stromal cell treatment for chronic inflammatory diseases being trialled. University of Birmingham News.
Yale Cancer Center to Offer a New Cellular Therapy for an Aggressive Skin Cancer. Colleen Moriarty and Michael Masciadrelli for Yale School of Medicine News.
TOP CAR with TMIGD2 as a safe and effective costimulatory domain in CAR cells treating human solid tumors. Nishimura et al. in Science Advances.
The CDC issues a report about infections from stem cell treatments in Mexico. The Associated Press via CityNews.
Airway hillocks are injury-resistant reservoirs of unique plastic stem cells. Lin et al. in Nature.
Gene Editing for CEP290-Associated Retinal Degeneration. Pierce et al. in The New England Journal of Medicine.
Acinar to β-like cell conversion through inhibition of focal adhesion kinase. Dahiya et al. in Nature Communications.
Mapping variant effects on anti-tumor hallmarks of primary human T cells with base-editing screens. Walsh et al. in Nature Biotechnology.
Salidroside promotes the repair of spinal cord injury by inhibiting astrocyte polarization, promoting neural stem cell proliferation and neuronal differentiation. Qian et al. in Cell Death Discovery.
Lyla El-Fayomi
Comments