Stem cell-based implants successfully secrete insulin in patients with typediabetes

Date:
December 2, 2021
Source:
Cell Press
Summary:
Interim results from a multicenter clinical trial demonstrate
insulin secretion from engrafted cells in patients with type 1
diabetes. The safety, tolerability, and efficacy of the implants,
which consisted of pancreatic endoderm cells derived from human
pluripotent stem cells (PSCs), were tested in 26 patients. While
the insulin secreted by the implants did not have clinical effects
in the patients, the data are the first reported evidence of
meal-regulated insulin secretion by differentiated stem cells in
human patients.



FULL STORY ========================================================================== Interim results from a multicenter clinical trial demonstrate insulin
secretion from engrafted cells in patients with type 1 diabetes. The
safety, tolerability, and efficacy of the implants, which consisted
of pancreatic endoderm cells derived from human pluripotent stem cells
(PSCs), were tested in 26 patients. While the insulin secreted by the
implants did not have clinical effects in the patients, the data are
the first reported evidence of meal- regulated insulin secretion by differentiated stem cells in human patients. The results appear December
2 in the journals Cell Stem Cell and Cell Reports Medicine.


==========================================================================
"A landmark has been set. The possibility of an unlimited supply
of insulin- producing cells gives hope to people living with type 1
diabetes," says Eelco de Koning of Leiden University Medical Center,
a co-author of an accompanying commentary published in Cell Stem
Cell. "Despite the absence of relevant clinical effects, this study will
remain an important milestone for the field of human PSC-derived cell replacement therapies as it is one of the first to report cell survival
and functionality one year after transplantation." Approximately 100
years following the discovery of the hormone insulin, type 1 diabetes
remains a life-altering and sometimes life-threatening diagnosis. The
disease is characterized by the destruction of insulin-producing ?-cells
in the Islets of Langerhans of the pancreas, leading to high levels of
the blood sugar glucose.

Insulin treatment lowers glucose concentrations but does not completely normalize them. Moreover, modern insulin delivery systems can be
burdensome to wear for long periods, sometimes malfunction, and often
lead to long-term complications. While islet replacement therapy
could offer a cure because it restores insulin secretion in the body,
this procedure has not been widely adopted because donor organs are
scarce. These challenges underscore the need for an abundant alternate
supply of insulin-producing cells.

The use of human PSCs has made significant progress toward becoming a
viable clinical option for the mass production of insulin-producing
cells. In 2006, scientists at Novocell (now ViaCyte) reported a
multi-stage protocol directing the differentiation of human embryonic
stem cells into immature pancreatic endoderm cells. This stepwise protocol manipulating key signaling pathways was based on embryonic development of
the pancreas. Follow-up studies showed that these pancreatic endoderm
cells were able to mature further and become fully functional when
implanted in animal models. Based on these results, clinical trials were started using these pancreatic endoderm cells.

Now two groups report on a phase I/II clinical trial in which
pancreatic endoderm cells were placed in non-immunoprotective ("open") macroencapsulation devices, which allowed for direct vascularization
of the cells, and implanted under the skin in patients with type 1
diabetes. The use of third-party off- the-shelf cells in this stem
cell-based islet replacement strategy required immunosuppressive
agents, which protect against graft rejection but can cause major side
effects, such as cancer and infections. The participants underwent an immunosuppressive treatment regimen that is commonly used in donor islet transplantation procedures.



==========================================================================
In Cell Stem Cell, Timothy Kieffer of the University of British
Columbia and his collaborators provided compelling evidence of functional insulin-secreting cells after implantation. PEC-01s -- the drug candidate pancreatic endoderm cells produced by ViaCyte -- survived and matured
into glucose-responsive, insulin-secreting cells within 26 weeks after implantation. Over the up to one year of follow-up, patients had 20%
reduced insulin requirements, and spent 13% more time in target blood
glucose range. Overall, the implants were well tolerated with no severe graft-related adverse events.

"For the first time, we provide evidence that stem cell-derived PEC-01s
can mature into glucose-responsive, insulin-producing mature ?-cells
in vivo in patients with type 1 diabetes," Kieffer says. "These early
findings support future investment and investigation into optimizing
cell therapies for diabetes." However, two patients experienced serious adverse events associated with the immunosuppression protocol. Moreover,
there was no control group and the interventions were not blinded,
limiting causal conclusions, and outcomes were highly variable among
the small number of participants. In addition, further studies need to determine the dose of pancreatic endoderm cells necessary to achieve
clinically relevant benefits for patients.

In Cell Reports Medicine, Howard Foyt of ViaCyte and his collaborators
reported engraftment and insulin expression in 63% of devices
explanted from trial subjects at time periods ranging from 3 to 12
months after implantation. The progressive accumulation of functional, insulin-secreting cells occurred over a period of approximately 6-9
months from the time of implant.

The majority of reported adverse events were related to surgical implant
or explant procedures or to immunosuppressive side effects. Despite
potent systemic immune suppression, multiple surgical implantation sites,
and the presence of foreign materials, the risk of local infection
was exceedingly low, suggesting that this approach is well tolerated in subjects who are at risk for a poor healing response. The researchers are currently working on ways to promote graft vascularization and survival.



==========================================================================
"The present study demonstrates definitively for the first time to our knowledge, in a small number of human subjects with type 1 diabetes, that
PSC- derived pancreatic progenitor cells have the capacity to survive,
engraft, differentiate, and mature into human islet-like cells when
implanted subcutaneously," Foyt says.

Both reports showed that the grafts were vascularized and that cells in
the device can survive up to 59 weeks after implantation. Analyses of
the grafts revealed that the main islet cell types, including ?-cells,
are present.

Moreover, there was no formation of tumors called teratomas. However,
the ratio of different endocrine cell types was atypical compared to
mature pancreatic islets, and the total percentage of insulin-positive
cells in the device was relatively low.

Regarding safety, most severe adverse events were associated with the
use of immunosuppressive agents, emphasizing the life-long use of these
drugs as a major hurdle for wider implementation of these types of cell replacement therapies. "An ideal and sunny possible future scenario would
be the wide availability of a safe and efficacious stem cell-based islet replacement therapy without the need for these immunosuppressive agents
or invasive, high- risk transplantation procedures," says Franc,oise
Carlotti of Leiden University Medical Center, a co-author of the related commentary.

According to de Koning and Carlotti, many questions remain to be
answered. For example, researchers need to determine the differentiation
stage at which the cells are most optimal for transplantation, and the
best transplantation site.

It is also not clear whether the effectiveness and safety of the cells
can be maintained over time, and whether it is possible to eliminate
the need for immunosuppressive therapy.

"The clinical road to wide implementation of stem cell-derived
islet replacement therapy for type 1 diabetes is likely to be
long and winding. Until that time, donor pancreas and islet
transplantation will remain important therapeutic options
for a small group of patients," de Koning says. "But an era
of clinical application of innovative stem-cell based islet
replacement therapy for the treatment of diabetes has finally begun." ========================================================================== Story Source: Materials provided by Cell_Press. Note: Content may be
edited for style and length.


========================================================================== Journal References:
1. Adam Ramzy, David M. Thompson, Kirsten A. Ward-Hartstonge,
Sabine Ivison,
Laura Cook, Rosa V. Garcia, Jackson Loyal, Peter T.W. Kim, Garth L.

Warnock, Megan K. Levings, Timothy J. Kieffer. Implanted
pluripotent stem-cell-derived pancreatic endoderm cells secrete
glucose-responsive C- peptide in patients with type 1 diabetes. Cell
Stem Cell, 2021; 28 (12): 2047 DOI: 10.1016/j.stem.2021.10.003
2. A.M. James Shapiro, David Thompson, Thomas W. Donner, Melena
D. Bellin,
Willa Hsueh, Jeremy Pettus, Jon Wilensky, Mark Daniels, Richard
M. Wang, Eugene P. Brandon, Manasi S. Jaiman, Evert J. Kroon, Kevin
A. D'Amour, Howard L. Foyt. Insulin expression and C-peptide in type
1 diabetes subjects implanted with stem cell-derived pancreatic
endoderm cells in an encapsulation device. Cell Reports Medicine,
2021; 100466 DOI: 10.1016/ j.xcrm.2021.100466 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211202113432.htm

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