Special Report on regenerative medicine: Outside, looking in

Regenerative medicine turns its focus on the eye

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John was one of those fortunate few who managed to retire early from his job as an editor, looking forward to spending more time with his grandkids and diving headlong into his hobby of landscape painting. But shortly after retiring, something seemed wrong.
Colors that used to be quite distinct on his palette became muddy and started to lose their luster. He found it difficult to discern the details of a scene. And he began to develop headaches after even the shortest period of reading.
Noticing that he’d avoided his canvases for a couple weeks, his wife finally prodded him and convinced him to see the family doctor…who sent him to an ophthalmologist…who sent him for a battery of tests.
John had age-related macular degeneration (AMD). He was quickly losing his sight in one eye, and was showing early signs of AMD in the other.
Under the scope
AMD is just one of a handful of eye disorders that are seeing increasingly prevalence in the Western world (see sidebar In their eyes below). Although drug therapy and surgery are viable options in some cases, few of these treatments get to the underlying pathology of the diseases. For this reason, researchers are looking more and more to the application of regenerative medicine using stem cells to either bolster the failing ocular tissues or simply replace them with fully functional cells.
“Cellular regenerative medicine for the retina may be the best therapeutic approach when multiple disease processes are causing the degeneration and death of one particular type of cell that is critical for vision,” explains Charles Irving, CEO of Cell Cure Neurosciences. “Multiple disease processes can be difficult to target using a single drug or biologic therapeutic agent.”
Irving’s company is exploring the use of human embryonic stem cells (hESCs) in AMD, differentiating the pluripotent cells into retinal pigment epithelial (RPE) cells to repair the damaged tissues.
“The challenges of this type of ophthalmologic regenerative medicine are to deliver the cells to the proper anatomical site without damaging the cells and the patient’s surrounding tissues, and to have assurance that the cells will survive, engraft and take over the functions of the patient’s own degenerating cells,” he continues.
One key to the use of regenerative medicine in the eye is the fact that the organ is largely immunoprivileged, adds Nianzhen Li, lead scientist for Fluidigm. Effectively an extension of the nervous system, the eye essentially sits behind the ocular equivalent of the blood-brain barrier.
Thus, Li continues, when stem cell-derived tissues are introduced to the eye, there is little risk of rejection.
Immunoprivilege makes the eye more amenable to off-the-shelf allogeneic cell therapy. Such an approach should reduce the costs of treatment as therapeutic tissues can be produced in larger quantities and stored. This, in turn, should facilitate reproducibility from at least the product’s perspective.
And nicely, because the eyes occur on the surface of the body and are largely fronted by small windows—whether to the retina or soul—they also provide an accessibility advantage when it comes to tissue replacement efforts.
This was noted recently by Kapil Bharti of the National Eye Institute (NEI) and colleagues, who reported on the proceedings of a 2014 meeting convened by the NEI and the National Institutes of Health (NIH) Center for Regenerative Medicine to promote cell-based therapies for degenerative retinal diseases.
“[NEI Director Paul Sieving] pointed out that the eye is an ideal organ in which to begin trial therapies using stem cells because of the optical and surgical accessibility of its internal structures and the broad and growing spectrum of noninvasive procedures that allow us to closely monitor clinical procedures,” recounted the authors in Investigative Ophthalmology and Visual Science.
Combined, these advantages make for “attractive first-in-human applications for this technology,” opined Steven Schwartz and colleagues at the University of California, Los Angeles, in a 2014 Lancet paper.
At the same time, one could ask, why go to the extreme of using stem cell-derived tissues with their complex differentiation protocols and inherent risks?
Seeing stem cell benefits
“Macular degeneration retinal specialists have long dreamed of treating dry AMD by replacing degenerating RPE cells with functioning RPE cells,” says Irving.
“Pioneering surgical approaches tried to transfer within the same eye RPE cells from less-diseased areas onto the macular area,” he continues. “Unfortunately, this proved to be a very complex procedure with a high rate of surgical complications.”
“Due to its high metabolic activity, the RPE represents an ideal tissue for transplantation in AMD,” said Elisa Buschini and colleagues at the University of Turin in a recent Clinical Ophthalmology review. “Several strategies, either allogeneic or autologous, have been tried to transplant RPE cells in degenerated areas, without great success due to graft rejection, poor viability of cells and complex attachment to the Bruch’s membrane.”
Thus, although the technical ability to transplant RPE cells was available, clinicians needed a more viable source of tissue.
“There are important advantages to using cells derived from pluripotent stem cell sources, including the ability to have a virtually unlimited supply of cells and to control their differentiation to ensure optimum safety and potency before transplantation,” suggested Schwartz and colleagues.
According to Irving, the first major breakthrough occurred when stem cell researchers noticed clusters of pigmented cells in their cell cultures. The clusters had arisen from the spontaneous differentiation of hESCs into RPE cells.
“However, the real breakthrough came when investigators at Hadassah University Hospital Medical Center in Jerusalem discovered a way to direct the differentiation of hESCs to RPE cells using a particular sequence of differentiation signals,” he recounts.
It was this work that led Cell Cure Neurosciences to initiate a lab-to-bedside translational development program for RPE cells, which the company calls OpRegen.
“OpRegen represents an extension of the early RPE transplantation efforts, but utilizes an external source of RPE cells,” Irving explains.
In September, the company received Fast-Track Designation for OpRegen in AMD and announced it was enrolling patients in a Phase 1/2a dose-escalation and safety study. The trial is currently recruiting patients at the Hadassah University Hospital Medical Center, and Irving expects to announce preliminary results in a few months.
Like OpRegen, most efforts to replace damaged ocular tissue rely on hESCs rather than induced pluripotent stem cells (iPSCs) that are often used in the stem cell arena. From Li’s perspective, this has more to do with history than any other factor.
“hESCs were discovered earlier, so people already have lots of experience with it, know how to grow them and how to differentiate them,” she says. She also, however, acknowledges the totipotent nature of hESCs as a factor, something to which Irving nods.
“If we are going to replace degenerating cells, we might as well replace them with youngest and most robust cells that are available,” he says. “These are usually obtained by differentiating ‘the mother of all cells,’ the hESC, which remains the gold-standard cell source for regenerative medicine.”
Similar to Cell Cure Neurosciences, Ocata Therapeutics has an early-stage clinical program that is developing hESC-derived RPE cells for the treatment of AMD. Late last year, the company announced the enrollment of the first patient in its Phase 2 trial that would see three cohorts of up to 20 subjects receive immune suppressive treatment followed by RPE cell transplantation.
“A key goal of this study is to more fully explore the efficacy signal that we reported in the Lancet in October [2014], with comparison to a control group of untreated patients rather than using the fellow eye for comparison,” announced Ocata CMO Eddy Anglade. “We believe that the data developed in this Phase 2 study will allow us to optimize the addressable patient population using well controlled data while assessing potential endpoints for efficacy.”
In the previous Phase 1/2 study, Schwartz and colleagues noted that hESC-derived cells were well tolerated for up to 37 months post-transplantation in patients with atrophic AMD or the related Stargardt’s macular dystrophy, without any major signs of adverse proliferation, rejection or adverse events. As well, many patients noted improvements in visual acuity in the treated eye versus its untreated counterpart.
At the same time that the company was announcing progress in its AMD study, it also announced the awarding of an Small Business Innovation Research grant from the NEI and NIH for preclinical development of its photoreceptor progenitor cells for use in other retinal degenerative diseases, such as retinitis pigmentosa and photoreceptor dystrophies.
“Our studies in multiple animal models have shown that these cells can integrate into damaged retina, promote survival of host photoreceptors and restore vision in completely blind animals, using either ESCs or iPSCs as source material,” offered Ocata’s chief scientific officer, Robert Lanza.
Beyond embryonic cells
Human ESCs are hardly the only source of tissues for regenerative ophthalmology, however.
In late 2015, RIKEN’s Masayo Takahashi reported on the progress of their patient who had received iPSC-derived RPE cells for the treatment of wet AMD, a more advanced form of the disease with an otherwise very bad prognosis. The results come from a clinical trial that was terminated in November.
Takahashi reported the RPE graft was performing well, with no signs of tumorigenesis or recurring neovascularization, and the patient’s showed signs of vision stabilization as well as improvements in visual acuity quality of life.
Last July, meanwhile, StemCells Inc. announced it completed transplantation of the first subject participating in its RADIANT study. This is a Phase 2 trial to evaluate the company’s human neural stem cell platform (HuCNS-SC) in the treatment of geographic atrophy, an advanced form of dry AMD.
The trial, designed as a “fellow-eye” controlled study, will see 63 patients aged 50 to 90 years receive subretinal transplantation of HuCNS-SC into the eye with inferior best-corrected visual acuity. Patients will be followed for 12 months and monitored for safety as well as structural and functional improvements.
And just a couple months earlier, Henry Klassen and colleagues at the University of California, Irvine, initiated a Phase 1 clinical trial of their retinal progenitor cells (RPCs) in the treatment of retinitis pigmentosa, relying on support from the California Institute for Regenerative Medicine (CIRM). The hope is that the RPCs will protect the photoreceptor cells that have not yet been damaged by the disease and work to replace lost cells.
The work also served as the basis of Klassen’s co-founding of jCyte.
“This milestone is a very important one for our project,” said Klassen in announcing the trial, suggesting the group was very excited “to be moving into the clinic after many years of bench research.”
Following a similar pathway to jCyte, U.K.-based ReNeuron announced in May that it had received FDA approval to commence a Phase 1/2 clinical program to test its RPC platform in retinitis pigmentosa. The open-label dose-escalation study will involve up to 15 patients of the Massachusetts Eye and Ear treatment center in Boston.
Within weeks, the company also announced the same program had received FDA Fast-Track Designation.
“This, together with the Orphan Drug Designation already granted for the program in both the United States and Europe, provides accelerated clinical development and marketing authorization processes for our RP treatment candidate, as well as the potential for a significant period of market exclusivity once approved in these major territories,” said ReNeuron CEO Olav Hellebø in the second announcement.
In a nod to ESCs but without the potential ethical baggage, International Stem Cell Corp. (ISCO) has gone a completely different route. The company pioneered an alternative source of pluripotent stem cells derived from unfertilized ova, calling the resulting cells human parthenogenetic stem cells.
Using this approach, ISCO has developed methods to generate not only RPE cells for treatment of AMD, but also corneal cells and whole tissues (CytoCor) for use in the treatment of conditions such as corneal blindness. Both programs are in preclinical phases.
Delivering those benefits
In many of the situations described above, cells are injected as a suspension. But there may be times when the cells need to be better organized on a supportive mesh or sheet to deliver optimal efficacy.
“Until recently, no one knew if cells administered as a suspension were capable on settling down and forming the monolayer of cells required for their normal function,” explains Irving. “In that case, some companies decided to skip a cell suspension product and develop a product in which the RPE cells are layered on a prosthetic membrane prior to implantation. We termed such a product OpRegen Plus.”
According to Bharti and colleagues, the choice between cell suspensions and cells in a sheet may come down to a question of how advanced and extensive the disease is.
“In the case of stem cell-derived RPE, cells in a suspension probably function by providing nonpolarized trophic support or nonspecific phagocytosis,” they noted in Investigative Ophthalmology and Visual Science. “They may provide beneficial effects through the secretion of neuroprotective cytokines or neurotrophic factors and the ability to clear out debris in the subretinal space.”
Thus, even if the new cells don’t integrate into the existing tissues and instead die, they might give the host a sufficient boost in activity to repair itself.
In contrast, cells in a sheet may be required when the tissue damage is more extensive and the host is less likely to self-regenerate.
“Cells in a sheet provide polarized trophic support, specific receptor-mediated phagocytosis and vectorial fluid absorption from the apical to basal side. Of course, the cell sheet will have to integrate into the host layer for cells to function over longer periods,” note the authors, who are quick to caution, however, that cells in a sheet come with a significant challenge when it comes to delivery.
Unlike cell suspensions, which can be injected into the subretinal space through cannulas, with no concern for cell orientation, sheet transplantation is much more complicated.
“The graft needs to be transplanted in the subretinal space in the correct apical-basal orientation, and a relatively large retinal opening is required, which may increase the risk of complications.”
Cell Cure Neurosciences has found success with both applications.
“Happily, during our preclinical animal studies, we obtained histological data clearly showing that OpRegen cells had organized themselves into monolayers,” Irving enthuses. “Moreover, we expect to obtain imaging data from our clinical studies that indicate that OpRegen cells also do this in dry AMD patients. Additionally, RPE cells on membranes may find application in patients whose underlying Bruch’s membrane may have been damaged and cannot readily support RPE cells.”
At the 2015 meeting of the Association for Research in Vision and Ophthalmology (ARVO), Vladimir Khristov and colleagues at the NEI reported on their efforts to apply iPSC-derived RPE to biodegradable electrospun PLGA scaffolds of various designs, generating autologous RPE sheets. Using gene expression, immunostaining and electron microscopy, they noted the RPE cells resembled native cells in morphology and molecular properties. As well, electrophysiological experiments suggested the cells maintained tight contact with neighboring cells. (For other ARVO presentations, see sidebar On the brink below)
Not all applications of stem cell technologies to eye disease require injection or surgery, however. In the case of dry eye syndrome (DES), preliminary results in animal models suggest that topical application may be sufficient.
Working in a chemically induced rat model of DES, Emrullah Beyazyildiz and colleagues in Turkey topically applied mesenchymal stem cells (MSCs) to one eye of each test subject. They then monitored the rats for physiological and symptomatic changes.
“Recently, studies have shown that MSCs could play a significant role in corneal epithelial regeneration and transdifferentiate into the corneal epithelial or stromal cells in different types of corneal injury models,” the authors wrote in their Stem Cells International paper.
The researchers noted that MSCs quickly integrated into the host tissues and that signs of inflammation diminished rapidly.
“Topically applied MSCs effectively treated DES in rats by reducing inflammation and increasing epithelial recovery that was confirmed by histological and ultrastructural analysis,” they reported.
How, precisely, these cells are functioning to repair and reverse the damage, however, is still open for speculation.
“Topically applied MSCs can penetrate into conjunctival epithelium and meibomian glands and could decrease inflammation by their anti-inflammatory effects,” they suggested. “This may be mediated by paracrine effects, differentiation or transdifferentiation of topically transferred MSCs to goblet cells or glandular cells, immunomodulatory effects of transferred MSCs or stimulation of repair mechanisms of damaged goblet cells of conjunctiva.
“Further studies with larger sample sizes and on different types of DES models are needed to clarify the exact mechanism of how topically applied MSCs show therapeutic effects on DES.”
Bench to bedside
Despite so many cellular platforms entering clinical trials, there are many more programs sitting at the preclinical stage and hurdles remain in making the transition to the clinic.
As you move out of research and into the therapeutic space, suggests Howard High, corporate communications fellow for Fluidigm, the need for ultrapure samples that can be easily developed and offer predictable outcomes is increasingly important. Clinicians and clinical technicians have different skills than their research counterparts, so it is vital—as with any therapeutic modality—that the regenerative medicine system be as technically foolproof as possible.
As StemCells Inc. board member Alan Trounson told attendees at ISSCR 2014, stem cell researchers and organizations need to shift from a “cottage industry” mindset and be prepared to gear their efforts up to industrial strength. Effectively, he challenged them to move from a bench headspace to a manufacturing mindset (see also Taking stem cells from bench to business, July 2014 DDNews).
Fluidigm is focused on ensuring that transition is as smooth as possible, designing a series of platforms to help optimize and analyze stem cell systems. High cites the example of the automated, multiwell Callisto cell culturing platform that he suggests bridges the single-cell and multicell worlds. Such systems, he suggests, add a layer of automated, repeatable control to experiments that helps researchers differentiate between real results and serendipity.
Ensuring the resilience of such therapeutic platforms may be critical to determining whether someone like John picks up the brush again.

In their eyes
Although most regenerative ophthalmology efforts target age-related macular degeneration (AMD), researchers are turning their gaze upon a variety of ocular conditions.
Age-related macular degeneration (AMD): The leading cause of vision loss in people 50 and over, AMD is the result of damage to the macula, a spot near the center of the retina crucial to sharp, central vision. In dry AMD, retinal pigment epithelial (RPE) cells degenerate and can no longer support the overlying photoreceptor cells. In wet AMD, the membrane underlying the retina thickens and breaks, triggering angiogenesis. The newly formed blood vessels are easily damaged and exude fluid, which further reduces vision.
Stargardt’s macular dystrophy: Similar to AMD, Stargardt’s is more prevalent in children and teenagers. Triggered by genetic mutations, the disease leads to a build-up of the fatty yellow pigment lipofuscin that leads to RPE degeneration.
Retinitis pigmentosa: Unlike AMD, which primarily impacts central vision, retinitis pigmentosa initially reduces peripheral vision. Here a variety of genetic mutations can lead to abnormal apoptosis of rod photoreceptors, which may be initially experienced as diminished night vision.
Dry eye syndrome (DES): Moving to the front of the eye, DES is a disorder of the tear film and ocular surface that leads to eye discomfort, visual difficulties and, in some cases, ocular surface damage. As the condition can result from several triggers, treatment has typically been aimed at symptomatic relief.

On the brink
In May 2015, several research groups presented their efforts in regenerative medicine at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). The science ranged from efforts to use stem cells for modeling disease pathology to cell-free cell therapy.
Generating iPSC-derived retinal pigment epithelial (RPE) cells from cadavers, Janmeet Saini and colleagues at Rensselaer and University of Albany developed a model system for studying AMD. Gene expression studies showed that when compared to controls, RPE derived from former AMD patients exhibited significantly higher expression of many markers associated with AMD pathology, including Aß precursor and VEGF-A. Increased Aß42 and VEGF-A secretion was also noted by ELISA.
Also working in AMD, Daniel Feitelberg and colleagues at Scripps Research Institute and the University of California, San Diego, monitored the longevity and behavior of iPSC-derived RPE in a rat model. Following rats for more than two years post-RPE injection, the scientists detected no increased risk of neoplasms. As well, both immunohistochemistry and flow-cytometry-based phagocytosis assays suggested that iPSC-derived cells that integrated successfully both thrived and functioned normally for up to 2.5 years, while cells that did not integrate were quickly consumed by host macrophages.
Beyond AMD
Taking a cue from the work done in AMD, Laura Montals and colleagues at Vall d’Hebron Research Institute differentiated RPE cells and photoreceptors from hESCs and iPSCs. They then transplanted the RPE cells with or without the photoreceptors into the subretinal space of model rats with retinitis pigmentosa. Monitoring expression markers and using electron microscopy, they noted that the human RPE cells not only survived in the rat eye, but also improved photoreceptor survival and reduced glial stress.
Moving away from pluripotent stem cells, Rui Zhang and colleagues at University Hospitals Eye Institute in Cleveland described their efforts to apply human mesenchymal stem cells (hMSCs) to corneal damage resulting from physical scarring and infection. Working in mice, the researchers treated their subjects with antibiotic alone, hMSCs alone or both together.
Within days, the corneas of mice receiving combination therapy demonstrated less edema, infiltration and clinical disease than those receiving antibiotics alone, and immunohistochemistry of the same group showed reduced neutrophil recruitment and disruption of the overall structure.
Other researchers demonstrated that it was also possible to receive the benefits of stem cell therapy without the risks associated with the cells themselves. Thomas Ritter and colleagues from National University of Ireland, Galway, for example, used ultracentrifugation and filtration to isolate extracellular vesicles (EVs) from MSCs and examined their efficacy in corneal wound repair.
In the presence of MSC-EVs, both corneal epithelial and endothelial cells were observed to migrate to and close scratch wounds in vitro. As well, the treated corneal endothelia demonstrated increased capacity for angiogenesis.
Moving from plastic to animal models, Xiaomin Zhang and colleagues at Tianjin Med University Eye Hospital and University of Louisville applied similarly isolated exosomes from human umbilical cord MSCs to experimental autoimmune uveitis in rats. Treatment significantly reduced the signs of inflammation. Flow cytometry and immunochemistry demonstrated similar reductions in the infiltration of T-cells and macrophages.
(For more information on EVs and exosomes, see Non-invasion of the body snatchers in the October 2015 issue of DDNews)

ISCO receives authorization to initiate Phase 1 trial of stem cells for treatment of Parkinson’s disease
CARLSBAD, Calif.—Moving outside the arena of ophthalmology in regenerative medicine, International Stem Cell Corp. (ISCO), one of the sources for this special report, announced in December that the Therapeutics Goods Administration of Australia cleared a regulatory submission of ISCO's wholly owned subsidiary, Cyto Therapeutics, to initiate a Phase 1 clinical trial, a dose escalation trial of human parthenogenetic stem cells-derived neural stem cells (ISC-hpNSC) in patients with moderate to severe Parkinson’s disease (PD). Currently, there is no cure for PD, which is the second most common neurodegenerative disease and affects over 7 million people worldwide.
“We are very pleased to start the first human study of ISC-hpNSC’s for the treatment of this debilitating disease. There is a large unmet medical need for new treatments that may halt or reverse the progression of Parkinson's disease and we believe our human neural stem cells may fill this need for the millions of people with this disease” said Dr. Andrey Semechkin, ISCO’s CEO.
The company announced the previous year positive results from its preclinical studies for its ISC-hpNSC therapeutic candidate. In those preclinical studies, the cells demonstrated an improvement in Parkinson’s disease symptoms and increase in brain dopamine levels following the intracranial administration of ISC-hpNSC. The studies further noted that the ISC-hpNSCs provided neurotrophic support and cell replacement to dying dopaminergic neurons.
The open-label, single center, uncontrolled clinical trial will evaluate three different dose regimens of 30,000,000 to 70,000,000 neural cells. A total of 12 participants with moderate to severe Parkinson’s disease will be treated. Following transplantation, the patients will be monitored for 12 months at specified intervals,to evaluate the safety and biologic activity of ISC-hpNSC. PET scans will be performed at baseline, as part of the screening assessment and at six and 12 months after surgical intervention. Clinical responses compared to baseline after the administration of ISC-hpNSC will be evaluated using various neurological assessments.
The study will be performed at Royal Melbourne Hospital in Melbourne, Australia.
StemCells announces strategic realignment
NEWARK, Calif.—In late December, StemCells Inc., one of the sources for this special report, announced a strategic realignment to fully focus the company’s resources on its proprietary HuCNS-SC platform technology for the treatment of chronic spinal cord injury (SCI).
According to the company, evidence of efficacy from its ongoing clinical trials in chronic SCI offers therapeutic promise to restore lost function previously considered unrecoverable. StemCells recently reported a pattern of improvements in both strength and motor function, six months post-transplant of its proprietary HuCNS-SC cells, in the first cohort of its Phase 2 Pathway study in cervical spinal cord injury. These interim findings are especially compelling given that all patients were treated between 10 to 23 months post-injury. Spontaneous motor recovery is not expected in SCI at this late stage after injury. Moreover, the emerging Phase 2 data are consistent with the evolution of positive outcomes seen in the company’s previous Phase 1/2 study in thoracic SCI, in which measurable sensory gains were reported in the majority of patients and two of the seven patients enrolled with complete injuries converted to incomplete injuries.
“The decision to prioritize our spinal cord injury program required some difficult choices, including the suspension of the Company’s Phase 2 Radiant study in geographic atrophy of age-related macular degeneration (AMD) while we seek a partner to fund continued development in retinal disorders,” said StemCells CEO Martin McGlynn. “Given the strength of our clinical findings for the safety and preliminary efficacy of our HuCNS-SC platform technology in treating chronic spinal cord injury, we have decided that now is the time to narrow our focus. Our overall mission remains the same: to realize the full potential of cell-based therapeutics as a one-time intervention yielding a long-term benefit for millions of patients affected by intractable diseases and disorders of the central nervous system. While our programs addressing neurodegenerative diseases and retinal disorders have also shown great promise, we have concluded that the most effective way to accomplish our objective is by concentrating our limited corporate resources on the program with which we are making the most rapid progress—chronic spinal cord injury.”
The plan is estimated to yield a cost reduction of approximately $20 million over the next two years, allowing the company to expedite completion of its ongoing Phase 2 Pathway study and commencement of a pivotal Phase 3 clinical trial in chronic spinal cord injury.
The immediate suspension of the Radiant study will entail curtailing further patient enrollment and service agreements related to the AMD program; the restructuring will also involve the reduction of StemCells staff by about 25 percent.

Regenerative medicine roundup
A quick look at several other companies involved in various therapeutic applications of cell therapies
New funding for cell-based hemophilia therapy
LONDON, Ontario—A new research grant of $8.5 million (Canadian dollars) awarded by the European commission via its Horizon 2020 program aims to address patients affected by hemophilia A, also called factor VIII deficiency. The funds are earmarked to the HemAcure consortium, consisting of Canadian-based Sernova Corp. and five European academic and private partners, who will be working jointly to advance development of a GMP clinical-grade factor VIII-releasing therapeutic cell product via Sernova's signature technology, called the Cell Pouch, for the treatment of severe hemophilia A.
The therapy being developed by the HemAcure consortium is expected to be highly disruptive to the current standard-of-care treatments for hemophilia A. The therapeutic uses the patient's own cells, which have been corrected for the factor VIII gene. Central to the therapy is Sernova’s Cell Pouch System, a novel implantable and scalable medical device that would release factor VIII on a continual basis at a rate that would be expected to significantly reduce disease-associated hemorrhaging and joint damage. The constant delivery of factor VIII is also expected to reduce or eliminate the need for multiple weekly infusions which is the current standard of care using plasma-derived or recombinant, genetically engineered factor VIII for the prophylactic treatment of hemophilia A.
Pluristem reaches agreement with Japan's PMDA
HAIFA, Israel—Pluristem Therapeutics Inc., a developer of placenta-based cell therapy products, announced in mid-December that it has reached an agreement with Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) on the design of the final trial needed to apply for conditional approval of PLX-PAD cells in the treatment of critical limb ischemia (CLI). The approval of the protocol for the 75-patient trial was part of a larger agreement on the development of PLX-PAD via Japan’s new accelerated regulatory pathway for regenerative medicine.
“With this achievement we have advanced our strategy to expedite commercialization of our cell products. Pluristem is now positioned favorably to accelerate negotiations with those Japanese pharma companies interested in becoming dominant players in the expanding regenerative medicine market in Japan,” stated Pluristem Chairman and CEO Zami Aberman.
Patients will be randomized into three groups of 25. Group one will receive an initial 150-million PLX-PAD cell dose followed eight weeks later by a second 150-million cell dose, group two will be treated with an initial 300-million PLX-PAD cells followed eight weeks later by a second dose of 300 million cells and group three will receive two doses of placebo. The primary efficacy endpoint will be a CLI-free diagnosis of a patient for 60 days.
Ground-state stem cells hold promise for genetic therapy, study finds
DURHAM, N.C.—A new study appearing in STEM CELLS Translational Medicine shows that ground-state, patient-specific induced pluripotent stem cells show significant promise for disease modeling, gene editing and future clinical therapy.
Ultimately, the discovery by a Chinese research team could lead to improved treatment for genetic diseases such as beta thalassemia, an inherited blood disorder caused by flawed or missing genes.
Scientists conducting the study derived induced pluripotent stem cells (iPSCs) in a ground, or naive, state of pluripotency from non-reproductive cells of patients with beta thalassemia and injected them into mice embryos. They then examined how well those stem cells performed compared to non-naive stem cells derived from the same non-reproductive cells. They learned that the naive cells functioned just as well as the others in terms of proliferation, gene expression and the ability to change into progenitor cells, and did an even better job of correcting damaged genes.
“The single-cell cloning efficiency of the naive iPSCs reached up to 88 percent, far higher than the efficiency of the primed iPSCs,” they wrote. “These results indicate that naive iPSC lines can be successfully generated from beta thalassemia fibroblasts under defined culture conditions.”
So far, there has been no effective treatment for beta thalassemia, a disorder also known as Cooley’s anemia. People with the condition often must undergo frequent blood transfusions, a therapy that causes iron to build up in the body over time and can bring about heart failure as early as the teens or early 20s.
Besides generating naive iPSCs from human non-reproductive cells, the Chinese scientists also generated the cells from human urine samples, a step that could not only lead to a better, less-invasive treatment for beta thalassemia but perhaps also give researchers an improved way to obtain stem cells for future studies, they said.
“The emergence of iPSC technologies and the development of gene-targeting strategies bring new hope for treating genetic diseases,” they added. “Our findings demonstrate the feasibility and superiority of using patient-specific iPSCs in the naive state, which has important implications for clinical use of human iPSCs in the future.”
A dozen researchers at Tongji University in Shanghai and Guangzhou Medical University collaborated on the study, supported by China’s National Natural Science Foundation and Ministry of Science and Technology, Shanghai’s Science and Technology and Education.

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