Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived … – Nature.com

Type 2 diabetes (T2D) typically starts with insulin resistance in peripheral tissues and proceeds with gradual loss of islet function due to the reduction in -cell mass or dedifferentiation of cells1,2. More than 30% of T2D patients eventually rely on exogenous insulin treatment. Cadaveric islet transplantation is an effective treatment for insulin-dependent diabetes3,4. Notably, improved metabolic control after islet transplantation is associated with better kidney allograft function and long-term survival5,6. However, the application of islet transplantation is severely hampered due to the critical shortage of donor organs.

The pancreatic progenitor (PP) cells or islet tissues, generated from human pluripotent stem cells (hPSCs), have been shown to survive, function and reverse hyperglycemia in diabetic animal models7,8,9. In addition, a recent clinical trial has shown that, when subcutaneously implanted into T1D patients, the hPSC-derived pancreatic endodermal cells encapsulated with non-immunoprotective devices were able to further mature into meal-responsive -like cells and secrete insulin, albeit at the levels insufficient to achieve the independence of exogenous insulin10,11. Nevertheless, clinical applications of hPSC-derived cells are undermined by the complicated differentiation processes and the risk of having residual undifferentiated cells that may form teratomas in vivo. Recent studies have focused on identifying intermediate stem cell types, including the non-tumorigenic human endoderm stem cells (EnSCs)12, which appear to be more suitable as precursors for large-scale generation of islet cells.

Here, we report the intrahepatic implantation of islet tissue (E-islets) differentiated in vitro from autologous EnSCs in a T2D patient who had impaired insulin secretion. This is a pilot study of an investigator-initiated trial designed to investigate the safety and efficacy of E-islets for the treatment of insulin-dependent diabetic patients (Fig. 1a). The patient was a 59-year-old man with a 25-year history of T2D who developed end-stage diabetic nephropathy and underwent kidney transplantation in June of 2017 and displayed poor glycemic control since November of 2019, characterized by blood glucose level ranging from 3.6614.60mmol/L, mean amplitude of glycemic excursion (MAGE) of 5.54mmol/L, the time-in-the-tight-target-range (TITR, 3.97.8mM) of 56.7%, with daily hyperglycemic events (> 10.0mmol/L) of 0.7/d and hypoglycemic events (< 3.9mmol/L) of 0.3/d (Supplementary Table S1). Due to the major concerns of hypoglycemia and the detrimental effect of poor glycemic control on the long-term survival of the donor kidney, the patient agreed to pursue transplantation with autologous E-islets.

a Brief scheme of major procedures involved in the generation and quality control of E-islets and the safety/effectiveness evaluations of E-islet transplantation. bd E-islets reverse hyperglycemia in STZ-induced diabetic immunocompromised mice. Schematic illustration of kidney capsule transplantation of E-islets (b). Fasting blood glucose dynamics (blue line: sham group; red line: E-islet-transplanted group, c). Secretion of human C-peptide after fasting and 30min following an i.p. glucose bolus on days 90 and 180 post transplantation (d). eg Immunogenicity of E-islets in humanized mice. Schematic illustration of the syngeneic and allogeneic kidney capsule transplantation of patient-specific E-islets into the NCG-hIL15 diabetic mice humanized with the patients and a volunteers PBMCs (e). Fasting blood glucose dynamics (blue line represents the control group with the patient E-islets transplanted into three diabetic mice humanized with the volunteers PBMCs; red line represents the group with the patient E-islets transplanted into three diabetic mice humanized with the patients PBMCs, f). Secretion of human C-peptide after fasting and 30min following an i.p. glucose bolus on days 7 and 14 post E-islet transplantation (U.D. undetectable, g). h Clinical measurements of TITR, TIR and HbA1c, and the insulin dosage during 116 weeks. i Continuous interstitial glucose fluctuations derived from the CGM measurements at weeks 52 and 105 compared with pre-surgery levels. jl Serum levels of fasting and meal-stimulated circulating glucose (j), C-peptide (k) and insulin (l) from MMTT assays.

E-islets were generated from the autologous EnSCs that are established under the culture condition modified from our previous reports12 (see details in Supplementary methods), through two intermediate stages under GMP conditions. The morphology, purity, viability and microorganism contamination of EnSC-derived PPs, endocrine progenitor cells and E-islets were proven to meet the release criteria (Supplementary Figs. S1S3 and Table S6). E-islets displayed similar morphology (Supplementary Fig. S3a), endocrine cell composition (Supplementary Fig. S3b, c, e, f), gene expression patterns (Supplementary Fig. S3df) and in vitro functionality (Supplementary Fig. S3g) to human cadaveric islets, and showed functional efficacy in Streptozotocin (STZ)-induced diabetic mouse (Fig. 1bd) and monkey (Supplementary Fig. S4) models. The nontarget hepatic or intestinal lineages, when examined by either scRNA-seq (Supplementary Fig. S3f) or FACS (Supplementary Fig. S3h), were not detected. Neither tumor formation nor cystic/ductal structures that indicate cell proliferation were detected in the immunocompromised animals transplanted with either EnSCs or E-islets during the experiments (Supplementary Table S3). The patient-specific E-islets survived and functioned under the kidney capsules of the diabetic immunocompromised mice humanized with patients own PBMCs, but rejected by the ones humanized with PBMCs from an unrelated volunteer (Fig. 1eg; Supplementary Fig. S5), which suggests that patients immune system likely tolerates the autologous E-islets.

The patient underwent a percutaneous transhepatic portal vein transplantation with 1.2 million IEQs of E-islets delivered, conforming to the regulatory guidance from the clinical islet transplantation registration. At designated visits, examinations of endocrine function and diabetes-specific parameters by mixed-meal tolerance test (MMTT) were performed at baseline, 4, 8, 12, 16, 20, 24, 36 and 48 weeks and thereafter at specified time points (Supplementary Fig. S6a). The glycemic control of the patient was measured with a 24-h real-time continuous glucose monitoring system (CGM).

During the 116-week follow-up period, no tumor formation was detected either by MRI on the upper abdomen or by the measurements of serum tumor-related antigen markers. The treatment-emergent adverse events included: (1) temporary abdominal distension and loss of appetite within 48 weeks, relieved with methionyltrichloride; (2) restorable weight loss < 5% (from 80kg to 76kg).

The three major clinical outcomes, the glycemic targets, the reduction of exogenous insulin and the levels of fasting and meal-stimulated circulating C-peptide/insulin were monitored throughout the first 116 weeks (Supplementary Tables S4, S5). Marked changes in the patients glycemic control were observed as early as week 2 post transplantation, as the MAGE declined from 5.50mmol/L to 3.60mmol/L, and the TITR increased rapidly from 56.7% to 77.8% (Fig. 1h; Supplementary Table S1). Over the same period, the time-above-range (TAR) decreased by 55% from baseline, while the events of severe hyperglycemia (> 13.9mM) and hypoglycemia (<3.9mM) completely disappeared (Supplementary Fig. S7a, b and Table S1). During the period between weeks 4 and 12, a significant reduction in ambulatory mean glucose fluctuations (from 5.50 to 2.6mmol/L) (Supplementary Table S1) and a steady rise in TITR (from 81% to 90%) were observed (Fig. 1h; Supplementary Fig. S7ce and Table S1). After week 32, the patients TITR had readily reached 99% and was maintained thereafter (Fig. 1h, i; Supplementary Table S1), while MAGE, the gold standard of blood glucose variability, was reduced from 5.50mM to 1.60mM (Supplementary Figs. S6d, S7hl and Table S1). Importantly, no episodes of hypoglycemia or severe hyperglycemia were observed during the whole follow-up period of 116 weeks post surgery (Supplementary Fig. S7 and Table S1). Additionally, MMTT revealed a trend of stabilization in glycemic variability after surgery, as manifested by the stable fasting glucose concentrations and the significant reductions in the post-meal glucose concentrations (maximum of 21.3mM at baseline vs maximum of 9.1mM at week 105) (Fig. 1j; Supplementary Table S5). Consistently, the area under the curve (AUC) derived from the 5-point intravenous glucose values decreased to 40% of baseline (Supplementary Fig. S6b), confirmed by the AUCs of the values acquired from CGM (Supplementary Fig. S6c). The hemoglobin A1c levels decreased from 6.6% (baseline) to 5.5% (week 85) and 4.6% (week 113) (Fig. 1h; Supplementary Table S1).

Notably, the insulin requirements were reduced gradually until complete withdrawal at the end of week 11 (Fig. 1h), and the oral antidiabetic medications were tapered since week 44 and discontinued at weeks 48 (acarbose) and 56 (metformin) (Supplementary Fig. S6a).

The average post-surgery fasting C-peptide level (0.68 nmol/L) increased by 3-fold when compared to pre-surgery level (Fig. 1k; Supplementary Table. S5). Notably, the secretions of C-peptide (Fig. 1k) and insulin (Fig. 1l) measured by MMTT revealed significant elevations compared to those of the pre-surgery tests, as confirmed by the AUCs (Supplementary Fig. S6b).

Collectively, we report the first-in-human tissue replacement therapy using autologous E-islets for a T2D patient with impaired islet function. The first 27-month data revealed significant improvements in glycemic control, and provided the first evidence that stem cell-derived islet tissues can rescue islet function in late-stage T2D patients. The grafts were well tolerated with no tumor formation or severe graft-related adverse events.

The precedent clinical trials using cadaveric islets or encapsulated hPSC-derived PPs10,11, along with our study, have provided encouraging evidence that islet tissue replacement is an effective cure for diabetic patients. Notably, the derivation of islet tissues from either hPSCs or EnSCs provides unprecedented new sources for tissue-replacement therapy. Despite the common proof-of-concept purpose, there are some distinctions among the published trials10,11 and ours. First, EnSC-based islet regeneration system is unique, in that EnSCs are nontumorigenic in vivo12 and amenable for efficient mass production of islets as they are endoderm-specific and developmentally closer to pancreatic lineages. Second, our pilot study chose a T2D rather than T1D patient, which not only precluded the interference from autoimmune conditions for the assessment of engraftment and functionality of E-islets but also extended the scope of indications for islet transplantation. As for the limitations of this study, we cannot completely rule out the possibility that the residual endogenous islets benefitted from the surgery and acquired functional improvements. Therefore, an increase in sample size and additional trials of T1D patients with complete loss of islet cells will help draw definitive conclusions on the causative role of E-islets in the achievement of glycemic targets.

Future studies are warranted to address the pharmacodynamics of stem cell-derived islets as a drug, to extend the application of stem cell-derived islet transplantation to other subtypes of diabetes, and to generate universal islets as off-the-shelf products to cure diabetes without the need for immunosuppression.

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Treating a type 2 diabetic patient with impaired pancreatic islet function by personalized endoderm stem cell-derived ... - Nature.com

Regenerative Medicine Market Size Expected to Reach USD 154.05 Bn by 2033 – GlobeNewswire

Ottawa, April 26, 2024 (GLOBE NEWSWIRE) -- According to Precedence Research, the global regenerative medicine market size is calculated at USD 35.82 billion in 2024.Regenerative medicines are used in advancing healthcare, such as new treatments for injuries and diseases and gene therapies.

Regenerative Medicine Market Revenue, By Region ($ Million)

Regenerative Medicine Market Revenue, By Product ($ Million)

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The regenerative medicine market deals with regenerating, engineering, or replacing animal or human organs, cells, or tissues to restore normal functions. Regenerative medicine can include growing organs or tissues in laboratories and then implanting them into the body when it does not recover itself. Regenerative medicines focus on applying and developing new treatments to restore functions and to heal organs or tissues lost because of defects, damages, aging, or diseases.

Regenerative medicines are also used in tissue engineering, cell therapies, stem cells, and immunomodulation therapy. Regenerative medicine helps to support the body in restoring, repairing, and regenerating itself to a state of well-being and for unsatisfied patient needs among many medical specialties.

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Key Insights

Regional Stance

North America dominated the regenerative medicine market in 2023. The increasing incidence of joint diseases and bone diseases and advanced technologies in stem cell therapy and tissue engineering are the main factors that are causing the growth of the North American region. The emergency requirement for CAR-T cell therapies and rising investments in developing new regenerative drugs in the United States of the North American region help the growth of the market.

The U.S. regenerative medicine market size reached USD 13.44 billion in 2023 and is projected to surpass around USD 83.26 billion by 2033, expanding at a CAGR of 20% from 2024 to 2033.

Rising genetic diseases and trauma incidences contribute to the growth of the market. Stem cell therapy is used in the United States for medical treatments like the treatment of blood disorders and cancer, as well as specific diseases affecting cartilage, skin, and bone. The USFDA regulates the use of stem cell therapy for some stem cell treatments.

Asia-Pacific is estimated to be the fastest-growing region during the forecast period of 2024-2033.The supply chain of regenerative medicine therapies is growing in the Asia-Pacific region. In the CRO/CDMO space of Asia, growth is increasing. They build a hospital network that supports the development of the regenerative medicine market. Countries like Japan, China, India, and South Korea contribute to the growth of the region. Among all the Asian countries, Japan has a very large influence on the biotechnology and pharmaceutical markets, both of which are responsible for the markets growth. China, being the largest economy, provides endless opportunities for the expansion of the market.

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Scope of Regenerative Medicine Market

Report Highlights

By Product Type

The tissue engineering segment dominated the regenerative medicine market in 2023. Tissue engineering combined with inductive factors, cells, and scaffolds to replace or regenerate diseased or damaged tissue. Regenerative medicine is used in tissue engineering, along with other procedures, such as immunomodulation, cell-based therapy, and gene therapy, to induce organ or tissue regeneration in vivo. Regenerative medicine is a large field that includes tissue engineering and self-healing research, where the body uses its system, sometimes with the help of biological materials, to rebuild organs and tissues or to regenerate cells.

The stem cell therapies segment is the fastest-growing during the forecast period.Stem cell therapy is also called regenerative medicine. It helps in repairing injured, dysfunctional, and diseased tissue by the use of stem cells and their derivatives. Applications of cell therapies in regenerative medicines include regenerating damaged cartilage in joints, improving weakened immune systems, urinary problems, neurological disorders, autoimmune diseases, spinal cord injury, and treating cancers, which helps in the growth of the segment.

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By Application Type

The musculoskeletal application segment dominated the regenerative medicine market in 2023. Treatment and diagnosis of problems arising from the musculoskeletal systems are treated with the help of regenerative medicine. This includes diseases and injuries affecting the bones, joints of spines, limbs, and muscles. PRP, MSC therapy, and IRAP-induced ACS are regenerative medicines that are used for musculoskeletal injuries.

The oncology application segment is the fastest-growing during the forecast period.Oncology, also known as cancer immunotherapy, is a form of regenerative medicine. Cancer immunotherapy helps in engineering, replacing, regenerating, or activating the immune system to fight against cancer. Cancer immunotherapy is the most commonly used and promoted form of regenerative medicine. Regenerative medicine is used to help cancer patients understand cancer biology and cancer treatment. MSC regenerative medicine may used for the treatment of tumor sites.

Market Dynamics

Driver

Rising senior population

An increased proportion of the senior population is the main driver of the regenerative medicine market. As the senior population increases, degenerative problems and age-related illnesses increase, and this leads to the need for treatments and contributes to the growth of the market. For the treatments of these patients, regenerative medicine is required as age increases. There is a slight decrease in the regenerative properties of many tissues due to age-dependent changes in tissues. Regenerative medicines and anti-aging are involved in the process of reducing harmful elements that cause death or diseases in cells and also modifying these cells to get back to their healthy, normal functions.

Restraint

Reimbursement and manufacturing

The significant challenge for regenerative medicine nowadays is reimbursement and manufacturing, both of which are barriers to the regenerative medicine market. In the fast-moving field of gene therapy and cell therapy, regulation and policy may fail to keep up with scientific innovation. In the manufacturing case, developers and regulators struggle to standardize processes essential for the transition from the making of small-scale batches of therapies to use in clinical trials to the high-scale batches essential by full-scale marketing. The manufacturing processes of gene therapies and cell therapies are more complex than those of other drugs.

Browse More Insights:

AI in Pharmaceutical Market: The global AI in pharmaceutical market size was valued at USD 908 million in 2022 and is expected to reach over USD 11813.56 million by 2032, poised to grow at a compound annual growth rate (CAGR) of 29.30% from 2023 to 2032.

Drug Discovery Services Market: The global drug discovery services market size was valued at USD 21 billion in 2022 and is expected to hit USD 69.72 billion by 2032, poised to grow at a compound annual growth rate (CAGR) of 12.80% from 2023 to 2032.

Small Molecule API Market: The global small molecule API market size was valued at USD 184.8 billion in the year 2023and is expected to hit around USD 299.2 billion by 2032 with an increasing CAGR of 5.5% during the forecast period 2023 to 2032.

Drug Discovery Market: The global drug discovery market size was valued at US$ 55.46 billion in 2022 and is expected to be worth around US$ 133.11 billion by 2032, growing at a CAGR of 9.2% from 2023 to 2032.

Small Molecule Drug Discovery Market: The global small molecule drug discovery market size was exhibited at USD 75.96 billion in 2022 and is projected to hit around USD 163.76 billion by 2032, growing at a CAGR of 7.97% during the forecast period 2023 to 2032.

Small Molecule Immunomodulators Market: The global small molecule immunomodulators market size reached USD 156.2 billion in 2022 and is projected to hit around USD 283.70 billion by 2032, registering a CAGR of 6.20% during the forecast period from 2023 to 2032.

Artificial Intelligence (AI) In Drug Discovery Market: The global artificial intelligence (AI) in drug discovery market size was estimated at USD 1.4 billion in 2022 and is projected to hit around USD 9.7 billion by 2032, registering growth at a CAGR of 21.36% from 2023 to 2032.

Opportunity

Increase in tissue engineering.

Tissue engineering become a transformative field in modern healthcare, providing a creative approach toward replacing, regenerating, and repairing lost or damaged organs or tissues. This helps address the limitations of traditional therapies, revolutionize medical treatments, and improve the quality of life for many individuals. As technological capabilities and scientific understanding increase, tissue engineering development will help and contribute to the growth of the regenerative medicine market. Tissue engineering helps in a combination of biochemical biomaterials and cell factors for creating functional tissues, which are copies of natural tissue functions and properties. At that time, regenerative medicine helps in natural healing mechanisms to replace damaged organs or tissues. These also help to offer personalized therapeutic solutions and overcome the challenges of reducing chronic diseases and organ shortages for transplantation.

Recent Developments

Regenerative Medicine Market Key Players

Market Segmentation

By Product

By Material

By Application

By End User

By Geography

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Regenerative Medicine Market Size Expected to Reach USD 154.05 Bn by 2033 - GlobeNewswire

John Cleese says he’s been spending 17,000 annually on stem cell therapy to ‘buy a few extra years’ – Yahoo News UK

John Cleese has revealed he has been spending 17,000 every 12 months for the past 20 years on stem cell therapy in an attempt to combat the effects of ageing.

The Monty Python star and co-creator, who also opened up about being surprisingly poor despite his five-decade career, said he doesnt look bad for his age after getting stem cells from Switzerland.

Stem cells can act as a repair system for the body and are sometimes used in regenerative therapies for long-term conditions like Crohns disease. The potential benefits of stem cells as an anti-ageing remedy include cell rejuvenation, reduced risk of age-related diseases and improved organ function.

In an interview with Saga Magazine, the comedian said: These cells travel around the body and when they discover a place that needs repair, theyll then change into the cells that you want for repair, so they might become cartilage cells or liver cells.

So I think thats why I dont look bad for 84.

He admitted he spends approximately 17,000 every 12 to 18 months.

But if youre buying yourself a few extra years, I think its worth it, he said.

Cleese also said his wife, jewellery designer Jennifer Wade, 52, keeps me young.

Addressing their 32-year age gap, he said: A lot of people comment and then the moment they actually see us together for two minutes they say oh, I get it and it never arises again.

What I love is that shes 30 years younger than I am, but she keeps me young.

I mean, it is sad to think I shall die some time before she will, but Im in pretty good health.

Im not fit, but the way I put it is the doctors dont yet know what Im going to die of.

In the same interview, Cleese said he is surprisingly poor after his five-decade career.

He joked that his $20m divorce from his ex-wife Alyce Faye Eichelberger resulted in him having to work in his eighties.

Cleese was married to Eichelberger, an American psychotherapist, for 16 years before their split in 2008. Eichelberger received a $20m (16m) divorce settlement, after which Cleese travelled the world with The Alimony Tour to raise the money.

When the interviewer notes Cleeses continued busy work schedule despite his elevated age, he refers to Eichelberger in his response: Well, youre quite right, but theres only one person responsible for that.

He continues: Can you believe when I met her, I had a beautiful house in Holland Park and no mortgage and when I broke up with her, I had a flat in Sloane Square and a full mortgage? How they figured out she was worth $20m, I have no idea.

The interview also mentions that Cleese does not own a car or property, having handed over the short lease of his flat to his current wife, Wade.

Although he states that this decision made a huge difference to Wade, Cleese said: But Im surprisingly poor.

I never thought it was necessary to own a great deal. The most important thing is to have enough money to have some really good food, buy clothes twice a year and have nice holidays.

The May 2024 edition of Saga Magazine will be released next week.

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John Cleese says he's been spending 17,000 annually on stem cell therapy to 'buy a few extra years' - Yahoo News UK