Stem Cells Special Report: Hope over hype

Unveiling the true promise of stem cell therapy, not the empty promises

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Special Report on Stem Cells: Hope over hype
Unveiling the true promise of stem cell therapy, not the empty promises
By Randall C Willis
In July, AXIS Stem Cell Institute announced its arrival in Seattle, offering help with autoimmune diseases, neurodegenerative conditions, musculoskeletal injuries and chronic metabolic conditions using adipose- and bone marrow-derived stem cells, platelet-rich plasma and other cell sources to promote healing and rejuvenation.
On Sept. 20 and 21, R3 Stem Cell offers a two-day stem cell training session in Tijuana, Mexico, where attendees will get a basic understanding of regenerative therapies and comprehensive training for aesthetics, musculoskeletal, neurologic, autoimmune, urologic and other specialities. Paid attendees will also receive a free stem cell procedure and facial rejuvenation treatment.
And in the time that it takes you to consider this news, there is every chance that yet another clinic will start offering reportedly life-transforming stem cell therapies.
But based on what?
Unproven ground
In August, Emma Frow and colleagues at Arizona State University described their analysis of direct-to-consumer (DTC) stem cell clinics in the southwestern United States.
Of the 170 clinics they examined, they noted that the most commonly treated conditions were orthopedic and inflammatory disorders, followed by pain, cosmetic and neurodegenerative conditions. This was consistent with previous studies looking farther afield.
“Further examination is under way of the specific evidence that these businesses present to support their use of a given cell type or cell source for the treatment of a particular condition, but preliminary analysis suggests that these applications are largely ‘unproven’ as defined by scientific norms and professional academic societies,” the authors wrote.
Further complicating matters is uncertainty in exactly what types of cells the clinics are injecting into patients, with adipose and bone marrow described most often.
“The majority of stem cell businesses use adult stem cells, using varied terminology including ‘adult,’ ‘mesenchymal’ and ‘hematopoietic’ stem cells,” the authors explained. “We report the terms used by the businesses themselves, acknowledging that the type of cell being advertised is not necessarily consistent with current scientific terminology.”
Sowmya Viswanathan of Toronto’s University Health Network (UHN) suggests that although stem cell therapies have largely proven safe in orthopedics, questions of efficacy remain open.
“There are mixed results,” she says, “and many of these were not done in controlled trials, so it is difficult to assess their efficacy compared to anything else.”
Her bigger concern is for DTC clinics that are dealing with more complex indications, like neurodegeneration or diabetes, and the injections of untested stem cell preparations.
“The cells that we use in clinical trials are very well characterized,” Viswanathan explains. “They’re highly regulated, and the regulators require you to do a bunch of testing before you can show that these cells are safe to be injected into patients.”
“The stem cell clinics do no such characterization or at very limited levels, and they don’t really assure the quality of those cells,” she presses. “In many cases, they really don’t know what they’re injecting. It’s some kind of mixture, which may or may not contain stem cells.”
When major adverse events occur, the whole field has to pause, and everything—legitimate and unproven—comes under tighter scrutiny and distrust.
“If the outcomes are poor, [consumers] may all just turn their back on cell and gene therapy,” adds Stacey Johnson, director of communications and marketing at the Centre for Commercialization of Regenerative Medicine (CCRM). “They’ll just remember that this is dangerous and bad.”
“That could do a lot of harm to the industry,” she continues, adding that although it has not yet happened, it remains a risk for the future that the industry needs to manage.
Part of that management strategy involves educational campaigns for both clinicians and prospective patients.
Liz Csaszar, CCRM development manager, points to recent efforts by the International Society for Stem Cell Research (ISSCR) to help people better understand the differences between proven and unproven therapies. The trick, adds Johnson, is to find the balance between information and scare-mongering.
And several organizations, including ISSCR and the International Society for Cell and Gene Therapy, have issued strongly worded position statements highlighting the potential hazards of unproven stem cell therapies and offered advice on topics such as informed consent.
As with any medical therapy, the final control comes down to regulatory.
“I’m happy to see that the regulators—Health Canada and the FDA—have come on board and are providing letters to these clinics, telling them to cease and desist in their activities, and are hopefully going to enforce this implementation,” says Viswanathan.
Even here, however, there is a numbers game at play.
“That 70-80 percent of stem cell businesses are operating outside of franchises may limit the effectiveness of pursuing regulatory action by targeting franchises,” wrote Frow and colleagues.
As with education, the trick to moving forward will be finding a balance between policing and incentives.
“I think there’s this yin-yang,” offers Viswanathan. “You have to stop those unproven therapies or curtail them as much as is possible, but at the same time, it is important to accelerate research either by funding more research and/or by providing more regulatory pathways to bring this into the clinic, and frankly, incentivizing the companies that are investing in doing this research properly and following those pathways.”
“Help them meet with success, that they have a good translational and commercial pathway so that patients have access to these products, as well,” she concludes.
So, what might that success look like?
MSC on the knee
Viswanathan’s efforts to develop stem cell-based therapies for knee osteoarthritis (OA), she says, is the result of conversations with orthopedic surgeons, who told her of the paucity of options for OA patients.
In early-stage OA, she recounts, patients are told to lose weight, stop smoking, get some exercise and maybe try some over-the-counter creams and ointments. When the condition progresses to late stage, the options are largely limited to knee replacement. In between, the surgeons told her, are years of hell with few or no options.
Viswanathan immediately thought of mesenchymal stromal cells (MSCs). She points specifically to the inflammatory and fibrotic components of the condition, both of which are congruent with the biology of the cells.
And there were other factors that made MSCs appealing.
“I think OA is one of those indications that makes sense for MSC for a number of reasons: one, we can inject locally, which means you need lower doses of cells,” she explains. “Two, there is really nothing out there, so there is a lot of headroom for making some kind of improvements that are longer-lasting.”
Third, she adds, there is something of a safety net with end-stage patients, at least, in that if something goes wrong—and assuming the cells stay local—surgeons can replace the joint.
Earlier this year, Viswanathan and colleagues described their efforts to treat knee OA with bone marrow-derived MSCs in a clinical trial of 12 patients.
At 12 months, they saw significant improvements in reported pain and symptoms relative to baseline, as well as improvements in quality of life and stiffness. Over the same period, however, there were no signs of improvement in either knee cartilage or synovitis.
These results were largely consistent with other studies published earlier in the year also using MSCs, but from umbilical cord and adipose tissue.
In a controlled Phase 1/2 trial, Francisco Espinoza and colleagues at Universidad de los Andes divided knee OA patients into three treatment groups receiving: hyaluronic acid at baseline and six months; UC-MSC at baseline; and UC-MSC at baseline and six months. They then monitored the patients’ clinical and structural outcomes for 12 months.
Over the first nine months, both MSC groups saw larger pain and function improvements from baseline than the control group. These improvements continued to 12 months for the double-dose group. Again, there was no significant improvement in MRI scores.
Kang-Il Kim and colleagues at Yonsei University and Kyung Hee University, meanwhile, performed a six-month Phase 2b study with adipose-derived MSCs versus saline control and effectively found the same results as the other two studies: a variety of symptomatic, functional and pain improvements, yet no improvement in cartilage.
Although none of these studies found structural changes in MSC treatment, says Viswanathan, other studies have. One of the complicating factors, she suggests, is a disconnect between structure and symptoms.
“People can have horrible MRIs and X-ray images, but they are very non-symptomatic; they don’t feel bad,” she explains. “Others have really great MRI and X-ray images, but they feel terrible.”
Other challenges to comparing studies is the lack of standardization in protocols—e.g., MSC source, dosing, preparation—and an absence of head-to-head trials.
“There are some differences in how people isolate the cells—whether they use enzymes, the kind of medium that they use, how they culture the cells, how they grow them,” Viswanathan continues. “All of that contributes to the potency of these cells.”
Even developing a consensus definition of potency is a challenge, as Viswanathan explained in a recent review of MSC manufacturing with colleagues from UHN and Ireland’s Regenerative Medicine Institute.
“MSC potency assay development has proven challenging due to issues such as limited cell numbers available for testing (for example in autologous therapies), limited long-term stability, and inherent variability between MSC donors,” the authors wrote. “There is also a substantial need for appropriate reference standards for MSCs that can be used to determine potency assay consistency as well as the ‘relative’ potency of different MSC batches.”
Further complicating matters, they continued, was a poor understanding of the mechanism(s) by which MSCs perform their function. The likelihood of the mechanism being multifactorial, they argued, makes “it difficult to select a single potency assay that remains relevant to the functionality of the MSCs clinically.”
Among the many possible directions for such assays—e.g., immune assays, angiogenic assays, extracellular vesicles—the authors offered the example of efforts at Osiris Therapeutics to monitor TNF receptor-1 as a surrogate biomarker to perform lot-release tests for Prochymal (now Mesoblast’s TEMCELL HS). They also highlighted data correlating cellular morphology and immunomodulatory activity, opening the door to a system like Cleveland Clinic’s CellX colony selection tool.
Viswanathan suggests that although many groups have shown efficacy with MSCs derived from a variety of tissues, a significant consideration of source material choice may be commercial. A company that has invested hundreds of thousands of dollars to advance an adipose tissue platform, she says, isn’t likely to simply abandon it because research might suggest that umbilical cord is better.
She also recognizes that other stem cell sources, such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs), may prove more efficacious than MSCs.
“One of the advantages of MSCs is that they are adult cells and they’re senescent,” Viswanathan explains. “You can grow them up for a certain period of time and then, no matter what you do, they stop growing.”
For a field that is always concerned about the risk of tumorigenesis, this is a definite plus.
“[Senescence is] also a disadvantage because there is a very narrow window in which you can grow up these cells and get them to have an effect,” she admits. “So, you have to do this very early on; otherwise, the cells start fatiguing and they are not as potent.”
Pluripotent stem cells (PSCs), on the other hand, are very potent and can be grown in very large quantities, allowing you to dose a lot of patients.
“But then, because they keep their proliferative capacity, it creates a safety concern that if you have one of these cells left, is that going to cause a tumor; maybe not right away, but maybe 10 years down the road,” Viswanathan points out. “So, the safety that you have to show for these cells is much higher.”
She is quick to note, however, that these concerns have not dissuaded researchers in Japan, California or in Toronto’s BlueRock Therapeutics—groups that have invested in PSC technology and believe the safety concerns can and will be addressed.
She sees room for both approaches.
“I don’t think there is anything wrong with having multiple approaches and multiple types of cells to solve a problem,” Viswanathan offers. “There is room for different cell therapies to be on the market, and different patients will respond to different cell therapies.”
One segment may respond to MSCs, she suggests, while another segment needs the more sophisticated but also more complicated biology of the PSCs.
There is still so much left to understand about these therapies, including when to intervene in knee OA’s natural history—earlier may be better for efficacy, but will patients be more risk-averse—and what the precise mechanism of action is for these cells.
It’s a process, according to Viswanathan, and her work is just step one of 100.
“The kinds of therapies we’re doing now will set the stage for maybe more sophisticated and maybe more efficacious—but maybe more high-risk—therapies down the road,” she notes. “We need to accumulate the data in a stepwise manner.”
Not all therapeutic indications are starting so close to scratch, however.
A diabetic sweet spot
Twenty years ago, Canadian teacher Byron Best became the first recipient of the pancreatic islet transplantation by what became known as the Edmonton Protocol, developed by James Shapiro and colleagues at the University of Alberta.
Within a week, the diabetes patient was insulin-independent and able to maintain a steady glucose count. Others quickly followed, and for many late-stage type 1 diabetes patients, unmanageable disease became more manageable.
Also working at the University of Alberta at that time was Tim Kieffer, now at the University of British Columbia, who recalls the impact of Shapiro’s efforts.
“This remarkable work solidified in my mind that a cell-based approach is a superior form of insulin replacement which has the potential to cure diabetes,” he recalls.
Like many others, his group seeks to use stem cells as the source of insulin-producing cells, at least in part, because transplants presently rely on tissues taken from cadavers, which can be in significantly short supply.
“The key advantage we envision is that the procedure will re-establish automatic control of blood sugar regulation, so patients are finally free from thinking about diabetes on a daily basis,” Kieffer continues. “Moreover, with the restoration of normal blood sugar levels, we anticipate the progressive damage to nerves and blood vessels will cease, so there will be no further progression of diabetic complications.”
In many ways, these complications are what drive interest in cell-based therapies, as even with insulin injections to maintain blood glucose levels, patients can still struggle with problems like retinopathy, neuropathy, nephropathy and cardiovascular disease.
In January 2018, Kieffer and colleagues described their study of insulin replacement versus islet cell transplantation in insulin-deficient mice.
“After two months of insulin therapy by injections, we found islet cell hyperplasia and obvious islet fibrosis by trichrome staining in insulin-deficient islets,” the authors reported. As well, injections facilitated only partial maturation of islet β-cells.
In sharp contrast, mice receiving transplants showed no signs of fibrosis, their islets appearing much as those of insulin-producing mice.
“Because the primary deficit of Ins1-/-Ins2-/- mice is a loss of insulin, it is surprising that replacing insulin by injections alone or islet transplantation resulted in dramatically divergent outcomes for the endogenous β-cells,” the authors wrote. “We proposed three variables that could contribute to the differences in β-cell phenotype between Ins1-/-Ins2-/- mice treated with islet transplantation and those treated with insulin injection: glycemic control was superior in mice treated with islet transplantation relative to those treated with insulin injections, native mouse insulin produced by transplanted islets may signal in β-cells with higher bioactivity than recombinant insulin, or insulin-deficient islets may fail to produce other essential factors that are replaced by transplanted islets.”
Aside from tissue availability concerns, another rationale for using stem cell-derived islets and pancreatic progenitor cells may be efforts to reduce the variability inherent in different donor islets and in the processes used to liberate the desired cells from the surrounding tissue.
“In contrast, laboratory-grown β-cells or their progenitors can be cultivated under optimal standardized conditions to purity and in vast quantities as a readily available cell source,” wrote Kieffer and colleagues from UBC and Kyoto University in a 2018 review.
“Efforts to differentiate pluripotent stem cells, whether embryonic stem cells or induced pluripotent stem cells, into β-cells have been guided by decades of studies unraveling the processes by which islet cells normally develop,” they continued. “A great deal of effort has been required to optimize the culture conditions, particularly the concentrations of media constituents and timing of the activation or inhibition of key signaling pathways to obtain stepwise differentiation of the cells through normal developmental pathways.”
Unlike cadaver tissue, which involves transplanting mature endocrine cells, ESCs and iPSCs offer researchers the opportunity to test transplantation of cells at different levels of maturation. Research to understand what cell stage is optimal is ongoing.
“Currently, it is easier to get cells to pancreatic progenitors than it is to mature endocrine cells,” Kieffer explains. “Moreover, it is faster and cheaper to produce large numbers of pancreatic progenitors than mature endocrine cells.”
Which cells offer the best product, he notes, may depend upon variables such as where the cells are implanted and whether they are encapsulated to protect them from immune attack.
“Ultimately, it is possible that there could be multiple product candidates, each with unique strengths and weaknesses,” he continues.
Kieffer says that factors to consider beyond how well the product regulates blood sugar are:
  • Costs;
  • Time it takes following implant before normal glucose homeostasis is restored;
  • Procedure(s) required to treat the patient;
  • Whether any accompanying drugs are required; and
  • How long the product will last.
In February, Jeffrey Millman and colleagues at Washington University in St. Louis described a six-stage differentiation protocol to improve glucose responses in ESC-derived β-cells.
Using a STZ-induced diabetic mouse model, the researchers showed that their Stage 6 cells not only offered greater glucose tolerance than in sham-treated mice, but the treated mice also had glucose clearance similar to non-STZ mice. And by 10 weeks post-transplantation, the STZ-mice demonstrated improved insulin secretion in response to high glucose challenge.
“Proper dynamic insulin release is an important feature of β-cell metabolism that is commonly lost in diabetes,” the authors concluded. “We have established a renewable resource of [stem cell-] β-cells with dynamic insulin release that can be used to better study the mechanism of β-cell failure in diabetes and demonstrated their response to several secretagogues.”
Another reason islet transplantation was largely left to late-stage patient populations was the concomitant need for lifelong immune suppression to prevent, or at least slow, the patient’s rejection of the transplant tissue. This challenge, and the general desire to intervene earlier in the disease course, if possible, made the case for encapsulation.
In the bag
“Cell encapsulation is a promising approach to contain the implanted cells, thereby enhancing safety, particularly if in a retrievable device, while also ideally shielding cells from the immune system,” Kieffer says. “However, that same barrier can also impede the exchange of nutrients and oxygen, and delay insulin release, thereby compromising the graft function.”
Hitting the perfect balance between these two poles has been the mission of companies like Sernova, Sigilon Therapeutics and ViaCyte, each of which are developing islet cell encapsulation devices.
“The strategy here is as long as you can eliminate cell-cell contacts—between the host tissues and your graft cells—you will protect against the adaptive immune destruction, allograft rejection or autoimmunity,” explains ViaCyte’s CSO Kevin D’Amour. “So, the materials we use are blocking cells, but they’re wide open from a molecular perspective, so even large molecules and antibodies can flow through.”
Interestingly, he continues, a bigger problem is not so much maintaining appropriate device porosity, but rather what he describes as progressive biofouling once the device is implanted.
“This is what we call the Achilles heel of the whole encapsulation field,” D'Amour adds. “It’s not coming up with encapsulation to prevent rejection; lots of materials can do that. It’s coming up with something that avoids the biofouling.”
CEO Paul Laikind points to data presented at the 2018 American Diabetes Association meeting from a Phase 1/2 clinical trial that showed solid protection of stem cell-derived pancreatic progenitor cells (PEC-01) against allogeneic and autoimmune rejection and sensitization. Furthermore, the PEC-01 cells differentiated into endocrine islet cells where there was good host tissue integration and vascularization.
ViaCyte is exploring three approaches to cell encapsulation, Laikind explains.
PEC-Direct uses an open device, meaning that patients still require concomitant immune suppression. The second approach, PEC-Encap, uses full encapsulation, removing the need for immune suppression. The third approach, PEC-QT, is discussed further below and involves collaboration with CRISPR Therapeutics.
In each case, the PEC-01 cells are transplanted inside the Encaptra drug delivery system, which is bound by a porous membrane made of polytetrafluoroethylene, also known as Gore-Tex.
“We are really excited and enthusiastic about the collaboration we have with them,” Laikind enthuses. “Not only is Gore an expert in the material science aspects of the membrane that we use, they are also one of the leading experts in implantable medical devices.”
The collaboration has been vital to finding membranes that boast all the right performance characteristics and yet avoid the biofouling issues.
“We just started implanting patients with that new encapsulation technology about a month or so ago,” Laikind says. “We expect to have data around the end of the year that, based on what we’ve seen, we believe will show that we have overcome that foreign body response—and we’ll now have an effective way of delivering the cells in a fully encapsulated mode.”
So why invest in PEC-Direct if PEC-Encap is improving?
“The disadvantage of the open device—PEC-Direct—is of course the need for immune suppression,” Laikind offers. “The advantages are we believe it can give very good dosing capability.”
He also says the open system may offer extended lifetimes for the treatments.
“The fully encapsulated version that we use for PEC-Encap has the big advantage of not needing immune suppression,” he continues, “but it does have some limitations on dosing and probably will have to be replaced every several years.”
Thus, like the Edmonton protocol, PEC-Direct may find itself limited to late-stage type 1 diabetes patients, whereas PEC-Encap could find it being used much earlier in disease progression, before many of those comorbidities become entrenched.
Trying to offer the best of both worlds is PEC-QT, which takes advantages of CRISPR Therapeutics’ gene-editing capabilities.
Still at the preclinical stage, the project involves altering PEC-01 so they are immune-evasive and thus could be used in the open device without the need for immune suppression.
“We believe it will give us a very important and exciting product going forward that could treat not only type 1 but also type 2 patients,” Laikind speculates.
At this month’s European Association for the Study of Diabetes meeting, CRISPR researchers will present their efforts to apply immune-evasive gene-editing to the stem cell library at the heart of PEC-01: CyT49. Success would open the door to a wider array of potential stem cell-derived cell therapies.
“Genetic engineering provides tremendous potential to endow cells with designer features that can enhance survival, function and safety,” offers Kieffer, more broadly. “However, we are potentially playing with fire—for instance, when cloaking cells from immune detection—so we better know how to snuff it out when needed.”
Again, this is the safety benefit of encapsulating cells within a device: there is always the option of removing the cell delivery device should something go wrong, either with the cells themselves or in a patient’s response to treatment.
“That actually has been a significant advantage for us in our discussions with the regulators,” Laikind recounts. “Regulators at some points in time have struggled a bit with cell therapies and such where you’re putting cells into a patient, but the fact that we are putting them into a device that could be removed at any time was a big safety advantage.”
Other companies are pursuing similar efforts to encapsulate islet cells.
In July, Sernova reported initial results from a Phase 1/2 clinical trial of its Cell Pouch encapsulated islet cells at the International Pancreas and Islet Transplantation Association congress.
In the initial type 1 diabetes patient, the cell pouch was well vascularized, enabling transplantation of purified islet cells. The researchers also noted an 87-percent reduction in hypoglycemic events and improvements in glycemic control.
“The first dose of islets transplanted into the Cell Pouch has shown safety and early indicators of potential efficacy,” said principal investigator Piotr Witkowski from University of Chicago in a study announcement. “We found some glucose-stimulated C-peptide and insulin present in the bloodstream, which are the gold standard indicators of islet function.”
A little further back in the development pipeline are encapsulation technologies from Sigilon, Semma Therapeutics and Novo Nordisk.
At July’s ISSCR conference, Semma Therapeutics presented its preclinical efforts to encapsulate and transplant stem cell-derived islet cells into pigs. The device protected cells from immune response while showing that the cells rapidly secreted insulin in response to C-peptide stimulation.
The company is looking to move free cells into clinic early in 2020 and encapsulated cells in late 2020.
In April 2018, Lilly signed a collaborative agreement with Sigilon to use its Afibromer technology to encapsulate iPSC-derived β-cells. Unlike the above devices, Sigilon’s approach relies on chemically modified alginates that form millimeter-sized hydrogel beads. Preclinical studies show that the beads are sufficiently permeable for an influx of nutrients and efflux of insulin, and do not trigger fibrosis.
For its part, Novo Nordisk is also following the alginate stream in collaboration with Cornell University’s Minglin Ma. Rather than simply release microbeads into the body where they might be impossible to retrieve, however, Ma has attached their beads to long polymer threads that can be removed when desired.
They described their platform—which they have dubbed TRAFFIC—in late 2017, where they showed that not only could they return glucose homeostasis in STZ-induced diabetic mice with encapsulated rat islets, but also that retrieval of the devices was straightforward in both mice and dogs.
“We believe this encapsulation design will minimize the risks and discomfort associated with transplantation, make repeated transplantation a more acceptable option, and therefore likely accelerate and contribute to the translation of cell encapsulation for [type 1 diabetes] and potentially many other diseases,” the authors concluded. “Furthermore, our modified thread device could be available to researchers or clinicians as an off-the-shelf, ready-to-use product, and cell encapsulation may be performed at site via a one-step in-situ cross-linking.”
Doing the work
As Frow and colleagues discussed, the development of stem cell-based cell therapeutics extends well beyond orthopedics and diabetes.
MSCs are being studied for their ability to reverse the effects of acute myocardial infarction (AMI) and ischemic heart failure by research groups like Ottawa Hospital Research Institute’s Duncan Stewart and colleagues, and University of Washington’s Charles Murry and colleagues.
Kadimastem is exploring ESC-derived astrocytes in the treatment of amyotrophic lateral sclerosis, with preclinical animal models showing improvements in motor function and life expectancy.
Athersys, meanwhile, continues its development of Multistem for conditions such as stroke, acute respiratory distress syndrome and AMI.
In each of these cases, there are bound to be setbacks alongside the successes, but everyone will do the work rather than simply offer empty promises.
Viswanathan singles out Athersys, in particular, for its dedication on the heels of poor initial results in a Phase 2 trial versus stroke.
“They didn’t meet endpoints, but they went back and they looked at their data,” she recalls. “They said okay, but it did work in a cohort of patients when we gave them the treatment within a 36-hour window of the stroke. It worked really well, so maybe that’s what we need to do.”
She congratulates the company on sticking with the program and finding the money to move forward with further clinical trials using the revised protocol. And, she adds, they are now getting good results.
“Doing clinical trials is not easy,” she acknowledges. “There is a lot on the line, there is a lot of pressure to get it right.”
CCRM’s Jana Machen remains hopeful.
“I think some of these [DTC] clinics are led by physicians who truly believe that they are seeing clinical results,” she says. “The challenge is now on them to design the clinical trial to bring forward the data.”
There really isn’t any other way forward.

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