Category Archives: Stem Cells

Published: Oct. 15, 2021 at 8:50 AM EDT|Updated: 18 hours ago

HANGZHOU, China, Oct. 15, 2021 /PRNewswire/ -- On Oct. 11th, 2021, CellOrigin Inc. released data about its second generation of iPSC-CAR-Macrophage which has a genetically integrated secondary signal to confer controlled CAR-iMac polarization, in the 5th International Conference of IGC China, 2021, Beijing.

Recently, CellOrigin Biotech, a company committed to iPSC-derived innate immune cell therapeutics, has announced a new round of investment by Kunlun Capital. The investment will be used for the CMC development for its current pipeline of iPSC-derived innate immune cells such as iPSC-CAR-Macrophage and rationlly designed iPSC-NK cells. Before, CellOrigin have also acquired investment from Shulan Health and Nest. Bio Ventures.

CellOrigin Biotech has a long term focus on iPSC-derived innate immune cells and its applications in new cancer immune cells. Dr. Jin Zhang, the scientific co-founder of CellOrigin used to be trained as a research fellow at the Boston Children's Hospital and Harvard Medical School. Now, his team worked closely with clinicians at the First Affiliated Hospital of Zhejiang University, and for the first time his team reported the induced pluripotent stem cell or iPSC-derived CAR-macrophages (CAR-iMac), and its applications in cancer immunotherapies.

CellOrigin Biotech holds the domestic and global patents for iPSC-derived CAR-Macrophage, and the engineering for polarization. With this proprietary platform, they are collaborating with research groups in genome engineering and synthetic biology worldwide to fully unleash the potential of iPSC-derived immune cells, which are highly editable, expandable and clonal. Eventually, they would like to achieve a goal of bring more effective, universal and safe immune cell products to cancer patients, especially for those with solid tumors. The investigator initiated trials has been initiated at the First Hospital of Zhejiang University. The core proprietary technology platform and the core patents including the engineered macrophages from pluripotent stem cells has been authorized and is in the process of entering different countries worldwide.

To support the CMC of its pipeline products, on Oct 1st, CellOriginhas announced the launch of its 3000 square feet GMP facility at Hangzhou, China.

About Kunlun Capital

Founded in 2015, Kunlun capital is committed to long-term value investment, establishing long-term partnership with entrepreneurs, and focusing on investing in enterprises with high technical barriers, excellent founding team and explosive growth potential. In recent years, Kunlun capital has successively invested in KEYA Medical, EdiGene, Cytek (NASDAQ:CTKB), Hui-Gene Therapeutics, OBiO, Okeanos, Ucell Biotech, CellOrigin, Soonsolid, Inke (HK:03700), Dada (NASDAQ:DADA), Dreame, Bamboocloud, Pony.ai, PingCAP, Leyan Technologies.

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CellOrigin secured a new round of investment for developing its globally proprietary iPSC-CAR-Macrophage technology platform - WWNY

Imagine youre about to go on a cross-country trip, stopping at spots along the way to admire local attractions. Youd probably want to have a road atlas handy, containing maps at different scales, covering both the major highways and the roads of smaller cities and towns or at least a GPS that can access a digital atlas with this information.

Until recently, cancer researchers have been like cross-country travelers with only a few maps of a few popular cities. And because of how fast some cancers grow, the maps quickly go out of date. This situation has hindered doctors ability to understand whats really going on inside tumors and develop effective treatments.

The Human Tumor Atlas Network (HTAN) was created to change that. It aims to develop high-resolution maps of many kinds of cancer so that doctors could have a more-complete view of the textured terrain of tumors including how they change over time to become more deadly. HTAN is funded by the National Cancer Institute and involves a consortium of cancer centers across the United States.

After several years of painstaking research, the first such atlas from investigators at Memorial Sloan Kettering Cancer Center for small cell lung cancer is now ready for viewing, and its full of new insights.

The most exciting thing we found is a rare population of stem-like cells within these tumors that is closely correlated with patient outcomes, explains Charles Rudin, a physician-scientist at MSK who co-led the lung cancer project. The more enriched they are in the tumor, the worse the prognosis.

Not only that, but these stem-like cells have metastatic properties meaning theyre prone to spread and researchers found them across many SCLC tumors that otherwise were very different.

That was a massive surprise, says Dana Peer, a computational biologist at MSK who is a principal investigator of the HTAN and co-led the lung cancer atlas project. It raises the possibility that this tiny fraction of cells could be driving metastatic behavior across tumors.

Small cell lung cancer is one of the deadliest cancers. It tends to spread early and aggressively; two-thirds of cases are already metastatic at diagnosis. Chemotherapy is not very effective. The researchers hope their new atlas, which was published October 14, 2021, in the journal Cancer Cell, will lead to improvements in care for people with the disease.

Building the atlas required years of collaborative work from two groups with very different areas of expertise: clinicians like Dr. Rudin with disease-specific expertise in small cell lung cancer and computational biologists like Dr. Peer and her team.

Dr. Rudin points to the fact that there are four co-first authors on the paper an unusual occurrence as evidence of the diversity of skillsets needed to complete a study like this. The co-first authors are Joseph Chan, lvaro Quintanal-Villalonga, Vianne Ran Gao, and Yubin Xie.

Dr. Peer, Chair of the Computational and Systems Biology Program at the Sloan Kettering Institute, took the lead on the computational side of things. She is an expert in single-cell RNA seq (scRNAseq), a technique that allows scientists to get a detailed picture of which genes are turned on in many hundreds of cells at the same time.

By applying scRNAseq to SCLC tumor specimens obtained from patients at MSK, Dr. Peer and her team were able to find this rare population of stem cell-like cells lurking amidst the cells of the surrounding tumor, like locating a needle in a haystack.

We would never have been able spot these cells with bulk sequencing. We really needed single cell analysis to find them.

We would never have been able spot these cells with bulk sequencing, she says. We really needed single cell analysis to find them. (Bulk sequencing is what researchers would do before scRNAseq was available essentially putting the tumor in a blender and sequencing all the RNA that fell out.)

The single cell technique also allowed the team to go further. Within the cells making up this tiny population, one gene stood out: PLCG2. This gene makes a protein that acts as a second messenger it relays signals from one protein to another.

PLCG2 did not initially strike me as the sort of gene that would be involved in regulating stem cell populations, Dr. Rudin says. It seems like more of a worker bee.

But indeed, PLCG2 does seem to be playing an important role. The gene is most highly expressed in this stem cell-like population, the scientists found. And when they experimentally increased or lowered its activity in cancer cell lines, it altered the ability of the cancer cells to metastasize.

They researchers think that these PLCG2-high cells could be part of the explanation for SCLCs aggressiveness. If so, it could open up new possibilities for treatment.

The thought is that if we can develop strategies to selectively target this cell population, we might be able to suppress metastasis and ultimately improve outcomes for patients with small cell lung cancer, Dr. Rudin says.

What we really want to do is try to stop metastasis in its tracks, Dr. Peer adds. But to do that, we need to better understand these rare cell populations that seem to be driving it. Thats the goal of this atlas.

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Molecular Atlas of Small Cell Lung Cancer Reveals Unusual Cell Type That Could Explain Why Its So Aggressive - On Cancer - Memorial Sloan Kettering

A genetic syndrome that affects bones

Osteogenesis Imperfecta (OI) is a hereditary disorder occurring in 1:10,000 births and characterised by osteopenia (bone loss) and skeletal fragility (fractures). Secondary features include short stature, skeletal deformities, blue sclera and dentinogenesis imperfect. (1) There is a large clinical variability in OI, and severity ranges from mild to lethal, based on radiological characteristics. Genetically, OI is a collagen-related syndrome. Type I collagen is a heterotrimeric helical structure synthesized by bone-forming cells (osteoblasts), and it constitutes the most abundant protein of the skeletal organic matrix. (2) Synthesis of type I collagen is a complex process. (3) Collagen molecules are cross-linked into fibrils (which confer tensile strength to the bones). Those are then mineralised by hydroxy-apatites (which provides compressive strength) and assembled into fibres.

Dominant mutations in either the COL1A1 or the COLA1A2 genes are responsible for up to 90% of all OI cases. These mutations (more than 1,000 of which have been identified) lead to impairment of collagen structure and production, which in either quantitative or qualitative bone extracellular matrix (ECM) defects. Mutations affecting ECM structure have serious health consequences because the skeleton protects visceral organs and the central nervous system and provides structural support. Bones also store fat in the yellow bone marrow found within the medullary cavity, whilst the red marrow located at the end of long bones is the site of haematopoiesis. In addition, the ECM constitutes a reservoir of phosphate, calcium, and growth factors, and is involved in trapping dangerous molecules.

Stem cell therapy for OI aims to improve bone quality by harnessing the ability of mesenchymal stem cells (MSC) to differentiate into osteoblasts, with the rationale that donor cells would engraft into bones, produce normal collagen and function as a cell replacement. Stem cells have, therefore, been proposed for the treatment of OI (4) and, in particular, prenatal foetal stem cell therapy (foetal stem cells injected into a foetus, i.e. foetal-to-foetal) approach, which offers a promising route to effective treatment. (5) Human foetal stem cells are more primitive than stem cells isolated from adult tissues and present advantageous characteristics compared to their adult counterparts, i.e. they possess a higher level of plasticity, differentiate more readily into specific lineages, grow faster, senesce later, express higher levels of adhesion molecules, and are smaller in size. (6,7) Prenatal cell therapy capitalises on the small size of the foetus and its immunological naivete. In addition, stem cells delivered in utero benefit from the expansion of endogenous stem cells and may prevent organ injury before irreversible damage. (8)

However, human foetal stem cells used are isolated from either foetal blood drawn by cardiac puncture, either during termination of pregnancy or during ongoing pregnancy, albeit using an invasive procedure associated with a high risk of morbidity and mortality for both the foetus and the mother (9). Foetal cells can also be isolated from the first-trimester liver (following termination of pregnancy) and such cells are currently used in The Boost Brittle Bones Before Birth (BOOSTB4) clinical trial, which aims to investigate the safety and efficacy of transplanting foetal derived MSCs prenatally and/or in early postnatal life to treat severe Osteogenesis Imperfecta (OI) (10). Alternatively, foetal stem cells can be isolated during ongoing pregnancy from the amniotic fluid, either during mid-trimester amniocentesis or at birth (11,12) or from the chorionic villi of the placenta during first-trimester chorionic villi sampling (13).

We have demonstrated that human fetal stem cells isolated from first trimester blood possess superior osteogenic differentiation potential compared to adult stem cells isolated from bone marrow and to fetal stem cells isolated from first trimester liver. We showed that in utero transplantation of these cells in an experimental model of severe OI resulted in a drastic 75% decrease in fracture rate incidence and skeletal brittleness, and improvement of bone strength and quality.(14) A similar outcome was obtained using placenta-derived foetal stem cells (15) and amniotic fluid stem cells following perinatal transplantation into experimental models. (16,17)

Understanding the mechanisms of action of donor cells will enable the engineering of donor cells with superior efficacy to stimulate bone formation and strengthen the skeleton. Despite their potential to differentiate down the osteogenic lineage, there is little evidence that donor cells contribute to regenerating bones through direct differentiation, due to the very low level of donor cell engraftment reported in all our studies. When placed in an osteogenic microenvironment in vitro, foetal stem cells readily differentiate into osteoblasts and produce wild type collagen molecules. However, there are insufficient proofs that collagen molecules of donor cell origin contribute to the formation of the host bone ECM to confer superior resistance to fracture.

It is now well accepted that stem cells can influence the behaviour of target cells through the release of paracrine factors and, therefore, contribute to tissue regeneration indirectly. We have indeed recently shown that donor stem cells stimulate the differentiation of resident osteoblasts, which were unable to fully mature in the absence of stem cell treatment. (16,17) We are now focusing our efforts on understanding the precise molecular mechanisms by which donor cells improve skeletal health to counteract bone fragility caused by various OI-causative mutations.

References

Please note: This is a commercial profile

2019. This work is licensed under aCC BY 4.0 license.

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Stem cell & gene therapy to treat osteogenesis imperfecta: hype or hope - Open Access Government

Urian B., Tech Times 05 October 2021, 12:10 am

(Photo : Image from Unsplash Website) New Stem Cell Approach Through Using Wavelength Laser Might have Discovered Why Humans Lose Hair

A new stem cell approach through the use of wavelength lasers might have discovered why humans lose their hair. Rui Yi, a professor of pathology at Northwestern University, is now setting out to answer the question.

According to the Straits Times, a generally accepted hypothesis regarding stem cells notes that they replenish tissues and organs, which include hair, but they will then eventually be exhausted and then even die in place. This particular process is seen as quite an integral part of the aging process.

Stem cells reportedly play a huge role when it comes to the growth of human and mice hair. The director of the Black Family Stem Cell Institute at the Icahn School of Medicine located at Mount Sinai, Sarah Millar, gave a statement. Luminate Medicine has been able to find a way to avoid chemotherapy hair loss.

Sarah Millar wasn't reportedly involved in Yi's paper and explained that the cells gave rise to the hair shaft as well as its sheath. After a period of time, which is short for human body hair and still much longer for hair on a person's head, the follicles then become inactive, and its lower part starts to degenerate. Sarah Millar's discovery can be found on Eurekalert.

The hair shaft then stops its growth and starts to shed, which is only to be replaced by a brand new strand of hair while the cycle repeats. While the rest of the follicles then die, a collection of stem cells still remains in the bulge and are ready to start turning into hair cells in order to grow a strand of hair.

Researchers who study aging usually take chunks of tissue from animals at different ages and examine the changes. There are, however, two drawbacks to this approach, according to Yi. There has also been a relation made betweenhair loss and teeth.

First, it was noted that the tissue was already dead. It is also not clear as to what led to the charges that are reportedly observed or what will then come after them. He then decided that the team would use a different approach.

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They reportedly watched the growth of other individual hair follicles in the ears of mice through the use of a long-wavelength laser that will be able to penetrate deep into the tissue. They then start labeling hair follicles along with green fluorescent protein, anesthetizing the animals in order for them to not move.

They then put their ear under the microscope and started to go back and forth to watch what was happening to the exact same hair follicle. The result showed that when the animals got older and grey, they started to lose their hair, their stem cells also started to escape their own small homes in the bulge.

The cells then changed their shapes from around to certain amoeba-like and squeezed out of small holes in the follicles. They then reportedly recovered their normal shapes and started darting away.

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New Stem Cell Approach Through Using Wavelength Laser Might have Discovered Why Humans Lose Hair - Tech Times

In conversation with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., The United States/Japan

To make the trial investments more meaningful and to avoid ambivalence in animal models, medical science is adopting novel in vitro models of specialised human pluripotent cell lines. Pluripotent stem cells(PSCs) have the agility to expand indefinitely and differentiate into almost any organ-specific cell type. iPSC-derived organs andorganoidsare currently being evaluated in multiple medical research arena like drug development, toxicity testing, drug screening, drug repurposing, regenerative therapies, transgenic studies, disease modeling and more across clinical developments. Innovative pharmacovigilance methodologies are preferring induced pluripotent stem cells (iPSCs) for pre-clinical and clinical investigational studies. Global Induced Pluripotent Stem Cell (iPSC) market is expected to reach $2.3 B by 2026. The iPSC market inAsia-Pacificis estimated to witness fast growth due to increasing R&D projects across countries likeAustralia,JapanandSingapore.

I Peace, Inc. a Palo Alto-based global biotech company with its manufacturing base in Japan, has succeeded in developing and mass-producing clinical grade iPS cells through its proprietary iPS cell manufacturing services. The human iPSC (hiPSC) lines at I Peace leverage differentiated cells across clinical research and medical applications. Biopsectrum Asia discovered more about Japan's stem cell manufacturing ecosystem with Dr Koji Tanabe, Founder and CEO, I Peace, Inc., (The United States/Japan). Tanabe earned his doctorate under Dr Shinya Yamanaka, a Kyoto University researcher who received the 2012 Nobel Prize in Physiology or Medicine for discovery of reprogramming adult somatic cells to pluripotent cells. I Peace is focusing on this Nobel Prize-winning iPSCs technology where Tanabe had played a key role in generating the worlds first successful human iPSCs as one of the team members and is currently industrialising it in the US and Japan.

How do you define Japans Stem cell manufacturing dynamics aligning with regional and APAC market potential?

We believe that human cells play a pivotal role in next-generation drug therapy. Clinical trials of iPSC applications are in full swing not only in Japan, but worldwide as well. In the US, the momentum of clinical trial research is astounding. Yet, mass production of GMP compliant cell products remains a challenge. Entry into this venture is no easy task. As a contract development and manufacturing organisation (CDMO), I Peace is geared to tackle that challenge and become the pioneer of mass production technology of clinical grade cell products.

Can you elaborate I Peaces cost-effective proprietary stem cell synthesis solution and its manufacturing scale?

The key advantage of iPSCs is the ability to create pluripotent cells from an individuals own cells. Furthermore, iPSCs can multiply indefinitely and evolve into any type of cell, making iPSCs an ideal tool for transplant and regenerative medicine and drug research. However, clinical applications of iPSCs to date, utilise heterogenic transplantation. It is because manufacturing of just one line of iPSCs requires a cost intensive clean room to be occupied for several months. Manufacturing process complexities also pose a barrier to cost reduction and mass production.

In contrast, I Peace has developed a proprietary, fully automated closed system for iPS manufacturing, enabling cost-effective production of multiple lines of iPSCs from multiple donors in a single room. Within a few years, we expect to manufacture several thousand lines of iPSCs simultaneously in a single room. With this technology, I Peace can efficiently generate an ample supply of various iPSCs for heterogenic transplant, while also fostering a society where everyone can bank their own iPSCs for potential medical use.

How does I-Peace better position its businesses objectives and go-to-market strategies?

I Peaces manufacturing facility and its processes have undergone rigorous audits and are certified to be in compliance with GMP guidelines of the US, Japan, and Europe. We have the capacity to manufacture clinical-grade iPSCs and iPSC-derived cells for clinical use in the global market. Our manufacturing staff have unparalleled expertise in the manufacturing of iPSCs, and their knowledge and experience make it possible to mass produce high quality clinical-grade iPSCs in the shortest possible time. Additionally, we streamlined the iPSC use licensing scheme to expedite collaborative ventures with downstream partners. We believe these strategies position I Peace as a global leader in iPSC technology.

How do you outline the concept of democratising access to iPSC manufacturing?

At I Peace, we envision a world in which everyone would possess their own iPSCs and if needed, receive autologous transplant medication using their own iPSC. We believe in the importance of raising awareness of Nobel Prize winning iPSC technology and we think much more needs to be done. We need to enlighten the public about iPSCs - what they are, how they are created, and how they play a role in next-generation medical therapies. We also need to underscore the benefits of early banking ones own iPSCs, such as autologous transplant and the fact that cells taken in the early stages of life are preferable over cells collected later in life.

To democratise iPSC access, it is also important to expedite application research. We work closely with downstream partners, and support their iPSC-derived drug therapy development efforts by providing iPSCs to meet their needs. We also collaborate with downstream partners in the development of promising therapies including the use of T-cells for cancer therapy, cardiomyocytes for the treatment of heart disease, and neurocytes for neurological disease.

What is your outlook around boosting public-private stakeholders initiatives to encourage awareness on stem-cell-based therapeutics?

iPSC research has advanced tremendously over the past 16 years, and even more so since Dr Shinya Yamanakas Nobel Prize award in 2012. The acceleration of applied research is paving the way for stem cell-based therapeutics to become a common treatment modality in the near future. As human cell manufacturing requires specialised professional skills and knowledge, it is important to promote functional specialisation. These specialisations include donor recruiting, cell manufacturing (where I Peace is the key player), and implementing cell transplant as a medical practice. We believe that creating a systematic industry structure will build awareness and further drive the growth of stem cell-based therapy.

Can you brief Japans licensing key notes to manufacture and process clinical-grade cells in the region?

Japan enacted three laws to promote the use of regenerative medicine as a national policy:

1) The Regenerative Medicine Promotion Act -- representing the country's determination to promote regenerative medicine;

2) The Pharmaceuticals, Medical Devices, and Other Therapeutic Products Act (PMD Act); and

3) The Act on the Safety of Regenerative Medicine (RM Act). The U.S. also has various tracks such as the Regenerative Medicine Advanced Therapy (RMAT) Designation, Breakthrough Therapy designation, and Fast Track designation.

Of significance, the PMD Act enables a fast-track for regulatory approval of regenerative medicalproducts in Japan. In compliance with the RM Act, I Peace was audited by the PMDA and licensed by the Ministry of Health, Labour, and Welfare to manufacture specific cell products.

Because cell product manufacturing regulations are not standardised globally, cell therapy developers are forced to source GMP iPSCs for each market. I Peace however, has overcome this hurdle. We have built in compliance with global GMP regulations, including FDA's cGMP regulations per 21 CFR 210/211 in our operation. As a result, we can provide cells for global use in multiple markets, accelerating both product development and regulatory approval.

Hithaishi C Bhaskar

hithaishi.cb@mmactiv.com

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"Stem cell-based therapeutics poised to become mainstream option - BSA bureau

SACRAMENTO, Calif., Oct. 5, 2021 /PRNewswire/ --StemExpress is proud to announce that they will be the official COVID-19 testing provider for 2021's Meeting on the Mesa, a hybrid event bringing together great minds in the cell and gene biotech sphere. It has partnered with Alliance for Regenerative Medicine to comply with the newly implemented California state COVID-19 vaccination and testing policy regarding gatherings with 1,000 or more attendees. This partnership will allow the vital in-person networking aspect of the event to commence while protecting the health and safety of participants and attendees.

In-person networking commences at the 2021 Cell and Gene Meeting on the Mesa with COVID-19 testing options provided by StemExpress.

As a leading global provider of human biospecimen products, StemExpress understands the incredible impact that Meeting on the Mesa has on the industry and has been a proud participant for many years. For over a decade, StemExpress has provided the cell and gene industry with vital research products and holds valued partnerships with many of this year's participants. As such, it understands the immense value that in-person networking provides and is excited to help bring this element back to the meeting safely and responsibly.

StemExpress has been a trusted provider of widescale COVID-19 testing solutions since early 2020 - providing testing for government agencies, public health departments, private sector organizations, and the public nationwide. For Meeting on the Mesa, StemExpress is offering convenient testing options for unvaccinated attendees and those traveling from outside of the country. Options will include take-home RT-PCR COVID Self-Testing Kits and on-site, rapid PCR testing for the duration of the event. The self-testing kit option allows attendees to test for COVID in the days leading up to the event for a seamless admission and the days following the event to confirm they haven't been exposed. The on-site rapid testing option utilizes the new Thermo Fisher Accula, offering in-person testing at the event with results in around 30 minutes. StemExpress is excited to bring these state-of-the-art COVID testing solutions to the frontlines of the Cell & Gene industry to allow for safe in-person connections.

The StemExpress partnership with Alliance for Regenerative Medicine seeks to empower the entire cell and gene industry with a long-awaited opportunity to return to traditional networking practices. It is well known that innovation doesn't exist in a vacuum - allowing great minds to come together is a sure way to spur scientific growth and advance cutting-edge research, giving hope for future cures.

Cell and Gene Meeting on the Mesa will take place October 12th, 2021, through October 14th, 2021, at Park Hyatt Aviara,7100 Aviara Resort Drive Carlsbad, CA 92011. To learn more about the event, please visit MeetingOnTheMesa.com.

For more information about COVID testing solutions for businesses and events, visit https://www.stemexpress.com/covid-19-testing/.

About StemExpress:

Founded in 2010 and headquartered in Sacramento, California, StemExpress is a leading global biospecimen provider of human primary cells, stem cells, bone marrow, cord blood, peripheral blood, and disease-state products. Its products are used for research and development, clinical trials, and commercial production of cell and gene therapies by academic, biotech, diagnostic, pharmaceutical, and contract research organizations (CRO's).

StemExpress has over a dozen global distribution partners and seven (7) brick-and-mortar cellular clinics in the United States, outfitted with GMP certified laboratories. StemExpress runs its own non-profit supporting STEM initiatives, college and high school internships, and women-led organizations. It is registered with the U.S. Food and Drug Administration (FDA) and is continuously expanding its network of healthcare partnerships, which currently includes over 50 hospitals in Europe and 3 US healthcare systems - encompassing 31 hospitals, 35 outpatient facilities, and over 200 individual practices and clinics.

StemExpress has been ranked by Inc. 500 as one of the fastest-growing companies in the U.S.

About the Alliance for Regenerative Medicine:

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory, reimbursement and manufacturing initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-based therapies. Early products to market have demonstrated profound, durable and potentially curative benefits that are already helping thousands of patients worldwide, many of whom have no other viable treatment options. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing regenerative medicines and advanced therapies. In its 12-year history, ARM has become the voice of the sector, representing the interests of 400+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups. To learn more about ARM or to become a member, visit http://www.alliancerm.org.

Media Contact: Anthony Tucker, atucker@stemexpress.com

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StemExpress Partners with the Alliance for Regenerative Medicine to Provide COVID-19 Testing for the Cell and Gene Meeting on the Mesa - ABC 12 News

On Friday (1), the National Health Surveillance Agency (Anvisa) approved a clinical study for a treatment with stem cells, aimed at patients with viral pneumonia due to covid-. Tests against the SARS-CoV-2 coronavirus should take place in 4 Brazilian states, including Paran, Rio Grande do Sul, Bahia and Rio de Janeiro.

In the Phase1/2 research, the safety and efficacy of potential advanced cell therapy is evaluated solutions based on human cells or genes, such as stem cells. According to Anvisa, the initial study of the treatment is sponsored by the Paran Association of Culture (APC) of the Pontifical Catholic University of Paran (PUC/PR).

Research by PUC Paran tests the efficacy and safety of stem cells against covid-1024 (Image: Reproduction/Andrea Piacquadio/Pexels)

In the study of stem cells against covid-, researchers will be able to recruit up to 60 volunteers. To participate, the person must have a diagnosis of viral pneumonia caused by the Sars-CoV-2 coronavirus, confirmed by RT-PCR tests, in a moderate or severe situation. In addition, you will be required to sign a consent form.

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This is a phase 1/2a clinical trial with a mesenchymal stem cell-based product Allogeneic, with the main objective of evaluating the safety in the treatment of patients with pneumonia caused by SARS-CoV-2, informs Anvisa. In general, these cells are derived from the tissue of the umbilical cord (TCU) of newborns.

The following clinical centers participate in the study:

Hospital Espaol, in Salvador, Bahia;

Porto Alegre Hospital de Clnicas, in Porto Alegre, Rio Grande do Sul;

According to the safety data collected in the clinical trial, an independent committee will evaluate the continuity of the research. In addition, Anvisa highlighted that the aspects related to ethics in research with human beings were the evaluated and the trial was approved by the National Research Ethics Committee of the Ministry of Health (Conep/MS).

So far, Anvisa has not approved any treatment with stem cells for any of the phases of covid-1024. This is because no evidence has been presented to confirm the safety and efficacy, so far. In this sense, the use of such treatments can put people at serious risk and constitutes a sanitary and criminal offence.

For clinical use in the population, it is necessary that there is unequivocal proof of the safety, efficacy and quality of the products. During the development phase and through controlled research, the products are defined the clinical indications, the main adverse reactions observed, the special care with the patient during and after use, as well as the critical attributes of the products quality, completes the agency on the importance of regulation.

Source: Anvisa

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Brazil investigates the use of stem cells in the treatment of covid-19 The Clare People - The Clare People

Myles Glass has spent the past several years living life on the sidelines in a wheelchair, wishing for a better day. That day came in November 2020.

INDIANAPOLIS A 13-year-old boy living with sickle cell disease has been given a second chance at life, thanks to his mother.

Myles Glass has been through more in his young life than most adults. For the past few years, Glass has spent his days in and out of Riley Hospital for Children.

"[I] kind of have to look on the bright side of things. Being in the hospital, I meet new nurses and kids who go through what I go through. It's kind of hard to go through that at my age," Glass said.

He was diagnosed with sickle cell disease as a newborn. According to the Centers for Disease Control and Prevention, African Americans make up the largest number of people with the disease in the U.S.

Sickle cell disease is an inherited condition that impacts red blood cells and causes pain, infections and extreme fatigue. These symptoms keep Glass from doing things he loves.

"For him, it's kind of like we have to have him in a bubble," said his mother, Melissa Sanders.

Glass has spent the past several years living life on the sidelines in a wheelchair, wishing for a better day.

"[I would] hope that one day, I can do what kids do, like playing football and basketball," Glass said.

That day came in November 2020 when his mother donated bone marrow for a stem cell transplant, curing him of sickle cell disease.

"I was able to give him a second life with being a donor so that he can somewhat be a normal kid," Sanders said.

Riley Hospital for Children Dr. Seethal Jacob, who has been working with Glass and his family, said one baby every two minutes is born with sickle cell disease. She also said studies show there is a clear disparity for funding for this disease.

"There's been a lot of neglect when it comes to the disease itself. I think it's important to pay attention to the population it affects. I think that likely tells the story why sickle cell disease has been a neglected disease for so long," Jacob said.

Despite his challenges, Glass is staying positive and making strides in his physical therapy at Riley Hospital for Children.

"He's already been through harder things than most people will ever go through. I think anything else in life is going to be a piece of cake," said his physical therapist, Sarah Johnson.

"This gives me a glimpse of hope that even though you may have been diagnosed with this disease, it's not the end of the world," Sanders said.

For Glass, this is just the beginning. He hopes his story encourages other people living with sickle cell disease to keep moving forward.

"I know it's hard now, but you'll get through it. You'll be able to do what kids do your own age," Glass said.

Click here for more information on sickle cell disease and treatment options.

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Indianapolis mother gives 13-year-old son with sickle cell disease a 2nd chance at life - WTHR

Mini brains grown in a lab from stem cells have spontaneously developed rudimentary eye structures, scientists report in a fascinating new paper.

On tiny, human-derived brain organoids grown in dishes, two bilaterally symmetrical optic cups were seen to grow, mirroring the development of eye structures in human embryos. This incredible result will help us to better understand the process of eye differentiation and development, as well as eye diseases.

"Our work highlights the remarkable ability of brain organoids to generate primitive sensory structures that are light sensitive and harbor cell types similar to those found in the body," said neuroscientist Jay Gopalakrishnan of University Hospital Dusseldorf in Germany.

"These organoids can help to study brain-eye interactions during embryo development, model congenital retinal disorders, and generate patient-specific retinal cell types for personalized drug testing and transplantation therapies."

(Elke Gabriel)

Brain organoids are not true brains, as you might be thinking of them. They are small, three-dimensional structures grown from induced pluripotent stem cells - cells harvested from adult humans and reverse engineered into stem cells, that have the potential to grow into many different types of tissue.

In this case, these stem cells are coaxed to grow into blobs of brain tissue, without anything resembling thoughts, emotions, or consciousness. Such 'mini brains' are used for research purposes where using actual living brains would be impossible, or at the very least, ethically tricky - testing drug responses, for example, or observing cell development under certain adverse conditions.

This time, Gopalakrishnan and his colleagues were seeking to observe eye development.

In previous research, other scientists had used embryonic stem cells to grow optic cups, the structures that develop into almost the entire globe of the eye during embryonic development. And other research had developed optic cup-like structures from induced pluripotent stem cells.

Rather than grow these structures directly, Gopalakrishnan's team wanted to see if they could be grown as an integrated part of brain organoids. This would add the benefit of seeing how the two types of tissue can grow together, rather than just growing optic structures in isolation.

"Eye development is a complex process, and understanding it could allow underpinning the molecular basis of early retinal diseases," the researchers wrote in their paper.

"Thus, it is crucial to study optic vesicles that are the primordium of the eye whose proximal end is attached to the forebrain, essential for proper eye formation."

Previous work in the development of organoids showed evidence of retinal cells, but these did not develop optic structures, so the team changed their protocols. They didn't attempt to force the development of purely neural cells at the early stages of neural differentiation, and added retinol acetate to the culture medium as an aid to eye development.

(Gabriel et al., Cell Stem Cell, 2021)

Their carefully tended baby brains formed optic cups as early as 30 days into development, with the structures clearly visible at 50 days. This is consistent with the timing of eye development in the human embryo, which means these organoids could be useful for studying the intricacies of this process.

There are other implications, too. The optic cups contained different retinal cell types, which organized into neural networks that responded to light, and even contained lens and corneal tissue. Finally, the structures displayed retinal connectivity to regions of the brain tissue.

"In the mammalian brain, nerve fibers of retinal ganglion cells reach out to connect with their brain targets, an aspect that has never before been shown in an in vitro system," Gopalakrishnan said.

And it's reproducible. Of the 314 brain organoids the team grew, 73 percent developed optic cups. The team hopes to develop strategies for keeping these structures viable on longer time-scales for performing more in-depth research with huge potential, the researchers said.

"Optic vesicle-containing brain organoids displaying highly specialized neuronal cell types can be developed, paving the way to generate personalized organoids and retinal pigment epithelial sheets for transplantation," they wrote in their paper.

"We believe that [these] are next-generation organoids helping to model retinopathies that emerge from early neurodevelopmental disorders."

The research has been published in Cell Stem Cell.

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Scientists Grew Stem Cell 'Mini Brains'. Then, The Brains Sort-of Developed Eyes - ScienceAlert

Abstract

Coronavirus disease 2019 (COVID-19) continues to burden society worldwide. Despite most patients having a mild course, severe presentations have limited treatment options. COVID-19 manifestations extend beyond the lungs and may affect the cardiovascular, nervous, and other organ systems. Current treatments are nonspecific and do not address potential long-term consequences such as pulmonary fibrosis, demyelination, and ischemic organ damage. Cell therapies offer great potential in treating severe COVID-19 presentations due to their customizability and regenerative function. This review summarizes COVID-19 pathogenesis, respective areas where cell therapies have potential, and the ongoing 89 cell therapy trials in COVID-19 as of 1 January 2021.

Coronavirus disease 2019 (COVID-19) continues to strain patients, providers, and health care systems worldwide. Since its discovery, the disease has contributed to approximately 200 million infections and 4 million deaths worldwide. The scientific community has focused vast resources on understanding the virus causing COVID-19, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the pathologies associated with the infection. Enormous effort has been placed to shed light on the mechanisms of viral entry and infection, the interaction between the virus and the hosts immune system, and the mechanisms of injury underlying the common manifestations of the disease.

SARS-CoV-2 initially emerged as a pathogen causing mainly viral pneumonias; however, experience in the proceeding months showed that the disease manifests throughout the body, leading to pathologies of the immune, renal, cardiac, and nervous systems, among others. While most patients have a mild course, over 15% develop severe and critical disease (1), leading to a substantial number of patients requiring prolonged hospitalization with intensive care services and potentially facing subsequent chronic manifestations related to pathological injuries from the disease process. In addition, mortality can be as high as 61.5% in critically ill patients with the disease (2).

As we begin to appreciate the subacute and chronic sequela of COVID-19, it is crucial to focus research efforts on finding therapies that not only dampen the acute damage but also can do so in a targeted manner while restoring physiological function and addressing the long-term sequela of the disease. Cell therapies have the potential to regenerate damaged tissue and tackle the immune system and, hence, are a treatment option with great promise. Here, we provide an overview of the COVID-19 pathogenesis in various organ systems, the overall advantages of cell therapies, potential cell targets and strategies within each organ system, and a summary of current cell therapy studies and trials for COVID-19 as of 1 January 2021.

SARS-CoV-2 first interacts with cells via binding of the viral spike protein to angiotensin-converting enzyme 2 (ACE2) on the cell surface (3, 4). After binding to ACE2, the spike protein is processed by the host transmembrane protease serine 2 (TMPRSS2), priming it for membrane fusion. This is considered to be the primary route of infection in vivo. Alternatively, the virus can be taken up into the cell via endocytosis and the spike protein processed by the endosomal proteases cathepsins B and L (3). After fusion with the cell membrane and release into the cytoplasm, the RNA replication machinery encoded in the first open reading frame of the viral genome is translated, followed by RNA replication and viral protein translation. SARS-CoV-2 co-opts and alters numerous cellular proteins and pathways, many of which are yet to be elucidated (5). It has been indicated that neuropilin 1 (NRP1) has a role in potentiating SARS-CoV-2 entry through the ACE2 pathway (6, 7). Studies from other coronaviruses provided evidence for CD147 and the 78-kDa glucose-regulated protein (GRP78) as putative alternative receptors, but more investigations on how the collective tissue distribution of these factors correlate with viral tropism and disease symptoms are under active investigation (8, 9).

Cellular tropism of SARS-CoV-2 is considered to be largely dictated by the distribution of ACE2. Bulk transcriptomic studies found ACE2 primarily expressed in the lungs, intestinal tract, kidneys, gallbladder, and heart; lower levels of expression were observed in the brain, thyroid, adipose tissue, epididymis, ductus deferens, breast, pancreas, rectum, ovary, esophagus, liver, seminal vesicle, salivary gland, placenta, vagina, lung, appendix, and skeletal muscle (1012). In the respiratory tract, ACE2 is most highly expressed in nasal epithelial cells, where SARS-CoV-2 is thought to initially infect followed by propagation into the distal alveoli (13). Many organs that express higher levels of ACE2 are not major sites of viral replication, indicating that expression of other host factors, including TMPRSS2, NRP1, and host restriction factors likely contributes to viral tropism (12).

Although most patients infected with SARS-CoV-2 present with mild symptoms (14), a considerable part of the population, including elderly patients and those with underlying comorbidities, have an increased risk of more severe outcomes, including death (15). Current treatment options for severely ill patients, aimed at reducing inflammation during the acute phase of the infection, have their limitations. Medications may be nonspecific for SARS-CoV-2 targets or are repurposed without a clear mechanism of benefit, while others such as remdesivir and tocilizumab may not be readily accessible because of federal allocations or cost barriers (16). In addition, these treatments have not focused on long-term sequela of the disease such as regeneration of damaged tissue structure and function. Cell therapies may thus be a promising class of therapies that could overcome these challenges through their customizability, targetability, scalable manufacturing, and restoration of function.

Cellular therapies have shown success in treating conditions that have otherwise been challenging to manage with mainstream treatment modalities, including, but not limited to, oncologic, neurodegenerative, and immunologic disorders. Cell therapy approaches including, but not limited to, mesenchymal stromal cells (MSCs), induced pluripotent stem cells (iPSCs), and T cells have been widely studied, and their efficacy has led to several U.S. Food and Drug Administration (FDA) approvals of cell therapies including, most famously, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) (1720). Extensive safety and efficacy data from cell therapies trials in various indications suggest that cell therapies could play a role in treating patients with COVID-19 as well.

Two potential concerns with cell therapies are immune rejection and tumorigenicity. Immune rejection concerns for allogeneic cell therapy have been discussed in the literature, especially as new cell therapies emerge. MSCs, for example, are considered to be immune suppressive and immune evasive, yet, the standard of treatment using allogeneic MSCs is the addition of immunosuppressive regimens alongside the cell therapy (21, 22). While immunosuppressive therapy may be used to protect the graft, it may not always prevent graft rejection and can come with its own adverse effects. Genome engineering can help address the immune system by tackling both the innate and adaptive immune systems. Potential strategies include knocking out genes responsible for immune system activation, such as major histocompatibility complex I and II (23, 24). These modifications could address both the acute and chronic rejection phases, making the cell grafts more resistant to the host immune system.

Tumorigenicity is an important consideration with cell therapies. The risk of tumorigenicity seems to be greater with MSCs, iPSCs, and human embryonic stem cells (hESCs), and it can present in the form of teratoma or as a true tumor (2527). This risk can be reduced by increasing the efficiency of differentiation to the target cell type thereby reducing residual pluripotent cells, such as by transcription factormediated cell programming or by incorporating suicide genes into cell grafts that can be activated in the rare chance a graft becomes malignant (2830). Several suicide mechanisms have been described in the literature, including a recent study by Itakura et al. (31) in which iCaspase9 was inserted as a fail-safe system in iPSC cell lines. If these cell lines become cancerous once transplanted in mice, induction of the iCaspase9 with a small molecule showed the formed tumors to rapidly reduce in size (31). These approaches increase the safety profile of cell therapies for clinical applications in patients with COVID-19 and beyond.

A clear understanding of COVID-19 pathogenesis is necessary to appreciate the potential benefit of cell therapies. Cell therapies provide paramount benefit as potential targeted treatment strategies to address localized damage inflicted by the disease and restore physiological functions (Fig. 1). In 2020, March and April recorded a large initial surge in global COVID-19 cases and deaths, as presented by the World Health Organization. There was a concurrent increase in the numbers of cell therapybased clinical trials initiated during those 2 months (Fig. 2A). As of 1 January 2021, there are 89 cell therapybased clinical trials registered on clinicaltrials.gov (Table 1) targeting COVID-19 pathology. Most of the clinical trials are held in the United States and China, 36% and 16%, respectively, with the rest of the clinical trials spread across the globe (Fig. 1B). MSCs constitute the majority cell type used in the cell therapy clinical trials, around 71%, with the rest using cell types such as natural killer (NK) cells, T cells, early apoptotic cells, and others (Fig. 1C). About 88% of the clinical trials are in phases 1 and 2, with one trial in phase 2/3 and one in phase 3 (Fig. 2D). The enrollment in each clinical trial was most frequently 21 to 30 patients but ranged up to 400 depending on the phase of the trial (Fig. 2E). In addition, the variability of patient enrollment numbers could be due to the varying statuses of each clinical trial (Fig. 2F). It is also worth noting that over half of the cell therapybased clinical trials are sponsored and supported by the industry sector (Fig. 2G), which indicates the pivotal role for industry in accelerating the necessary research to combat COVID-19.

Blue text boxes describe specific pathogenesis for each organ system. Green text boxes describe potential and ongoing cell therapy applications for each organ system. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

(A) Number of COVID-19 targeting cell therapy clinical trials started in each month of the year 2020. (B) World map showing global distribution of the registered cell therapy clinical trials and their numbers per country. (C) Different cell types used in the cell therapybased clinical trials and their respective count. (D) Stages of the 89 cell therapy clinical trials registered as of 1 January 2021. (E) Distribution of patient enrollment numbers across the 89 clinical trials. (F) Breakdown of the 89 cell therapy clinical trial statuses. (G) The percentages of cell therapies sponsored and supported by the industry sector.

Search approach: performed 1 January 2021; Clinicaltrials.gov: advanced search; Condition - OVID; Study Type -Interventinal; Intervention/treatment - Cell; of 157 studies, exclude nonCOVID-19 patients (n = 12) and noncell therapy trials (n = 56); leaving 89 available studies. NCT, national clinical trial.

Pulmonary symptoms are the mainstay of COVID-19 and may include dry cough, dyspnea, pneumonia, and acute respiratory distress syndrome (ARDS) (32). Bilateral pulmonary infiltrates and ground-glass opacities are seen radiographically in over 70% of hospitalized patients (14). Furthermore, ARDS has shown to be present in over 90% of deceased patients (33). ARDS and the associated alveolar damage are thought to be primarily due to immune-related response (3, 34). Other pulmonary complications may include secondary pulmonary hypertension, hypercoagulability-related pulmonary emboli, and long-lasting fibrosis in patients who do recover from the acute infection (35, 36).

Some preclinical data suggest that patients with COVID-19 may benefit from cell therapies, particularly using MSCs in models of viral and inflammatory lung damage (37). For instance, MSCs were found to reduce the impairment of alveolar fluid clearance caused by influenza A H5N1 infection in vitro and mitigate lung injury in vivo (38). Another study showed that MSC treatment reduces influenza H9N2induced acute lung injury in mice and reduces pulmonary inflammation (39). In another study, MSCs were shown to promote macrophages to become anti-inflammatory and take on a phagocytic phenotype through extracellular vesicles, thereby ameliorating lung injury in mice (40).

Several studies have described promising treatment of pneumonia and ARDS in critically ill patients with COVID-19 using cell therapies. In China, Liang et al. (41) reported treatment of one patient with severe COVID-19 unresponsive to steroid medications, after three successive injections of 5 107 human umbilical cord MSCs at days 1, 4, and 7 of treatment initiation. The patients pulmonary lesions had begun to resolve by day 7 after the first MSC injection. Tang et al. (42) reported treatment with allogeneic menstrual bloodderived MSCs of two patients with COVID-19 with ARDS. Treatment involved three successive injections of 1 106 MSCs/kg of body weight at days 1, 2, and 4 of treatment initiation. Both patients were discharged from the hospital. Leng et al. (43) reported a pilot study where they transplanted a single dose of 1 106 MSCs/kg of body weight in seven patients with mild, severe, and critical COVID-19, with three patients on the placebo arm. Results from the study showed overall safety of the treatment, with two severe patients recovering and being discharged within 10 days of treatment. In Spain, Sanchez-Guijo et al. (44) treated 10 patients under mechanical invasive intubation with either one, two, or three doses of 1 106 adipose-derived MSCs/kg of body weight. Seven of the 13 patients were extubated approximately 7 days after initiation of treatment. Furthermore, the authors observed that patients who received cell therapy earlier in their disease course had better outcomes. These open labeluncontrolled administrations are important as they demonstrate apparent safety with no obvious adverse events.

Various MSC-based strategies are assessing treatment of patients with COVID-19 with pulmonary symptoms, especially pneumonia and ARDS. One phase 1/2a randomized double-blind trial (NCT04355728) assessed administration of two infusions of 1 107 umbilical cordderived MSCs for COVID-19 ARDS, showing improved 28-day survival following therapy (91% in treatment group, n = 12 versus 42% in control, n = 12) (45). Another phase 3 study comparing administration of two injections of 2 106 MSCs/kg of body weight and standard of care compared to placebo injection and standard of care in patients with COVID-19 with moderate to severe ARDS failed to meet the primary end point of 43% reduction in mortality in an interim analysis (NCT04371393). Thus, further investigation is necessary to determine whether MSC-based therapy could improve COVID-related lung injury.

COVID-19related lung fibrosis has been characterized by fibroblast proliferation, airspace obliteration, and microhoneycombing, which is thought to persist in patients who survive the acute infection (46). This pattern of fibrotic change may be similar to that of idiopathic pulmonary fibrosis (IPF) (36), and prior cell therapy studies in IPF may shed light on potential avenues for cell therapy applications in patients with COVID-19. IPF is a progressive disease of unknown etiology that leads to fibrosis of the lungs and is the primary cause of more than half of all lung transplants worldwide (47). Cell therapies using type II pneumocytes (PTIIs), which are progenitors of the lung alveolar epithelium, have shown efficacy in preclinical animal models of IPF by regenerating lung epithelium, releasing surfactant, and reversing pulmonary fibrosis (48, 49). A phase 1 clinical study also showed that targeted intratracheal delivery of PTIIs showed safety and clinical stability at 12-month follow-up of 16 patients with moderate to severe IPF (50). In addition to PTIIs, MSCs have also been used in IPF. A recent randomized trial of patients with IPF treated with two doses of 2 108 allogenic bone marrow MSCs every 3 months for 1 year showed safety and improved respiratory function when compared to control participants (51). This suggests that even patients with COVID-19 with residual chronic fibrosis may benefit from cell-based therapies in the future, although further data are necessary to support this conclusion. Ultimately, cell therapies that can reverse fibrotic changes or supplement normal pneumocyte function could address potential chronic pulmonary effects from COVID-19.

The hosts immune response toward SARS-CoV-2 has been studied carefully since the outbreak, with many potential mechanisms of interaction being elucidated on the basis of similarities of the virus to SARS-CoV. Most patients with COVID-19 mount antibody responses to SARS-CoV-2, which vary in magnitude and potency (52). Neutralizing antibodies appear to target the receptor binding domain of the spike proteins (52, 53). Patients with high immunoglobulin M (IgM) and immunoglobulin G (IgG) titers have a worse prognosis (54), which could be correlated with high viral load but could also indicate a harmful robust immune response through antibody-dependent enhancement (ADE). ADE is a phenomenon that has been observed in several viruses, including SARS-CoV, where viral-specific antibodies promote viral entry into immune cells expressing Fc receptors (55), such as monocytes, macrophages, and B cells, leading to enhanced amplification of the virus. Implications of ADE in COVID-19 have been discussed in greater detail by Eroshenko et al. (56). With regard to T cells, several studies have compared leukocyte profiles between patients with mild and severe manifestations of the disease and showed decreased T cell count in both CD4+ and CD8+ populations, more commonly in intensive care unit (ICU) patients but highly prevalent in non-ICU patients as well (57). Lower levels of CD4+ T helper cells and CD8+ cytotoxic T cells likely hinder the ability of the immune system to neutralize and kill viral-infected cells.

In addition, a marked increase of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF-), and interferon- (IFN-) has been observed in patients with severe COVID-19 (57, 58). In these cases, SARS-CoV-2 immune evasion leads to a robust viral replication and a delayed and dysregulated IFN- response, resulting in recruitment and accumulation of inflammatory macrophages and neutrophils (58, 59). Further IFN- activation by these cells leads to additional cytokine and chemokine signals [IFN-, TNF-, C-C motif chemokine ligand (CCL)2, CCL7, and CCL12] that enhance infiltration and activation of monocytes and neutrophils, further exacerbating the inflammatory response and inducing high cytokine levels, a phenomenon referred to as cytokine storm, which has been linked to more severe manifestations of COVID-19 (60).

Several immune-based cell strategies can be proposed for targeting different pathologies of COVID-19. Several NK cell therapies for COVID-19 are under investigation (Table 1). NK cells are activated and recruited at the site of infection in response to IL-12 and IL-18 signals. They control viral replication using perforin and granzyme granules and induce Fas ligand or TNF-arelated apoptosis-inducing ligandmediated apoptosis in infected cells (61). Cell therapies involving NK cells and chimeric antigen receptor (CAR) NK cells have shown clinical safety and efficacy in numerous oncological indications (62), and they may have a role in treating various infectious pathologies as well (63). As NK cells recognize viral infected cells by identifying up-regulated stress markers and down-regulated inhibitory ligands, exogenous administration of NK cellbased therapies could thus assist in identifying SARS-CoV-2infected cells and promote viral clearance (64). A phase 1 study is assessing the efficacy and safety of CYNK-001 cells, which are allogeneic, off-the-shelf, and cryopreserved NK cells derived from CD34+ human placental stem cells, in 14 adult patients with mild to moderate COVID-19 (NCT04365101). In another phase 1 study, FT516 cells, which are allogeneic, off-the-shelf, and cryopreserved NK cells derived from iPSCs, are being tested for efficacy and safety in 12 adult patients with COVID-19 who are hospitalized and fulfill requirements for hypoxia (NCT04363346). With regard to CAR NK cells, a phase 1/2 study in China is using off-the-shelf NKG2D-ACE2 CAR NK cells to target viral infected cells while also secreting IL-15 as a superagonist and granulocyte-macrophage colony-stimulating factor neutralizing single-chain variable fragment to reduce the likelihood of cytokine release syndrome (NCT04324996). Intravenous infusion of 1 108 cells/kg of body weight will be administered weekly in patients with COVID-19, and the study is currently recruiting patients.

Given that immune system overactivation is a significant factor in pathologies of COVID-19, another potential strategy could involve CD4+CD25+Foxp3+ regulatory T cells (Tregs). Tregs function by secreting anti-inflammatory cytokines IL-10 and transforming growth factor (TGF-) as well as by contact-dependent signaling, and have been shown to inhibit the influx of neutrophils to the lung, induce apoptotic cell clearance of activated neutrophils and macrophages, and decrease proinflammatory cytokine levels (65, 66). Moreover, they can inhibit excessive innate immune responses via induction of secondary immunosuppressive neutrophils that generate anti-inflammatory cytokines and via enzymes indoleamine 2,3-dioxygenase and heme oxygenase-1, which further inhibit cellular proliferation (66). The safety and feasibility of Tregs has been clinically evaluated over the past decade, showing tolerability and clinical improvement especially in the setting of solid-organ transplantation and autoimmune disease (67). Hence, the immunosuppressive role of Tregs may be beneficial in quelling the cytokine storm in patients with COVID-19. Potential strategies may include using polyclonal expanded Tregs versus engineered antigen-specific Treg approaches. Polyclonal Tregs offer a more generalized immunosuppressive strategy, which may be similar to current immunosuppressive medications. Polyclonal Tregs have been clinically evaluated with promising results in type 1 diabetes and other autoimmune diseases (68), but they have not been clinically tested in immune overactivation in viral infections. A concern with this therapy would be the exacerbation of acute infection by excessive quelling of the host immune response to SARS-CoV-2. Engineered antigen-specific Tregs could help localize immunosuppressive effects (65), but this could also facilitate enhanced viral replication. Overall, Treg therapies could aid in suppressing the overactive immune system in patients with COVID-19 (69), but generalizing early safety data from clinical trials of autoimmune and transplant patients toward patients with COVID-19 would need careful evaluation. Two phase 1 clinical trials, which are not yet recruiting, are aiming to test the efficacy and safety of allogeneic, off-the-shelf, and cryopreserved Treg cell infusions in patients with COVID-19 with moderate to severe ARDS (NCT04468971) or intubated and mechanically ventilated (NCT04482699).

Besides Tregs, other T cell therapies are being evaluated for COVID-19 (Table 1). Viral-specific T cells are currently under investigation in three trials, and they are using viral-specific T cells from healthy donors who have mounted an appropriate response to the SARS-CoV-2 (NCT04457726, NCT04406064, and NCT04401410). A better understanding of effective targets could aid in the development of engineered T cells from more accessible and scalable sources than previously infected healthy donors. In addition, a phase 1/2 trial evaluating the use of RAPA-501, a hybrid T helper 2/Treg phenotype, aims to suppress immune overactivation in a T cell receptorindependent manner (NCT04482699). Engineered T cells, particularly CAR T therapies, have shown promise in the treatment of immune system overactivation in diseases such as pemphigus vulgaris, type 1 diabetes, and lupus (70), and targeted T cell therapies could play a role in treating COVID-19 immune overactivation and facilitating viral clearance. Recent single-cell sequencing studies of patients with COVID-19 have shown an increase in monocytes, macrophages, and clonally expanded CD8+ T cells, which may contribute to the cytokine storm seen in severe cases (71, 72). This provides a rationale to direct cell therapies such as CAR T/NK cells to target these enriched populations with the goal of reducing the excess cell population, and potentially decreasing the severity of the cytokine storm. In addition, B lymphocytes could theoretically be engineered to recombinantly express humanized monoclonal antibodies with neutralizing antiSARS-CoV-2 activity. However, convalescent plasma or monoclonal antibodies likely have similar benefits without the increased complexity of a cell therapybased modality (73).

In addition to their role in targeting COVID-19related lung damage, MSCs are also an intriguing target for immune-based cell therapy because of their immunomodulatory capacities. In the lung, MSCs mediate immune homeostasis by TNF- and IL-1induced up-regulation of anti-inflammatory cytokines such as protein TNF-stimulated gene 6, IL-10, TGF-, prostaglandin E2, and nitric oxide (74, 75). Moreover, by modulating overactivation of the immune system, MSCs have shown efficacy for the treatment of immune-related conditions such as steroid-refractory graft-versus-host disease and systemic lupus erythematosus (76, 77). Hence, MSC therapy may play a role in suppressing COVID-19associated immune activation and cytokine storm. Several recent studies have reported decreases in inflammatory marker levels after treatment with MSCs that correlated with clinical improvement (4144). Moreover, ongoing clinical trials are assessing the immunomodulatory capabilities of MSCs in patients with COVID-19 (NCT04348435, NCT04377334, and NCT04397796). Another phase 1 clinical trial is assessing the efficacy and safety of allogeneic umbilical cord bloodderived MSCs as adjuvant therapy in patients receiving oseltamivir and azithromycin (NCT04457609). Dosing for MSC trials varies widely between 5 105 and 1 107 cells/kg or 2 107 and 2 108 cells per dose with the number of doses ranging from one to four. Cell sourcing for MSC trials includes the umbilical cord, placenta, adipose tissue, intra-aortic tissue, olfactory mucosa, and the dental pulp (78). More detailed reviews on mechanisms of MSC immunomodulation and potential benefits in COVID-19 have been previously explored (75, 7889).

Neurological manifestations are a significant consideration in patients with COVID-19 and are reported in 57.4% of confirmed cases (90). Presenting symptoms range from headache, anosmia, and ageusia to more serious manifestations such as ischemic stroke, encephalitis, and encephalomyelitis (91). The innate immune response is likely responsible for symptoms such as headache and encephalitis through uncontrolled cytokine release. However, symptoms such as anosmia, encephalomyelitis, and stroke suggest potential viral invasion of the central nervous system (CNS). Proposed mechanisms of CNS viral access include retrograde axonal transport through vagal afferents peripherally (92) or via direct CNS invasion, as studies have shown ACE2 receptors to be expressed in several regions of the brain, especially in oligodendrocytes and astrocytes (93). The symptoms of anosmia and ageusia were initially suggestive of CNS invasion, especially as SARS-COV studies had shown that the virus could enter the brain through the olfactory nerve within days of infection, causing inflammation and demyelination (94). However, analysis of human RNA sequencing and single-cell sequencing data showed that ACE2 and TMPRSS2 are not expressed in olfactory sensory nerves but instead in olfactory epithelium (95). Acute cerebral ischemic events have been reported in patients with COVID-19, especially in younger patients without typical risks of cerebrovascular disease (96, 97). These manifestations are likely due to an overall prothrombotic state, potential down-regulation of ACE2, which causes an overall loss of neuroprotection, and hyperinflammatory cytokine release. In addition, there has been an increasing number of reports of Guillain-Barre syndrome and its variants, transverse myelitis, and other demyelinating conditions in affected patients, some with multifocal lesions in the brain and spine (98). The presence of demyelination has also been present in autopsy studies (98). The etiology of these lesions is likely immune-related, potentially because of a delayed immune reaction.

To date, there have been no reports of cell-based clinical trials addressing neurologic manifestations in patients with COVID-19. However, the high incidence of neurologic manifestations coupled with increasing reports of demyelinating disease and ischemic stroke in affected patients may require treatment options that focus on long-term deficits, which can potentially be addressed via cell therapy. Regarding demyelination, oligodendrocyte precursor cells (OPCs) have been explored in the setting of spinal cord injury and have showed safety, tolerability, cell engraftment, and improved motor function at 12-month follow-up in patients (NCT02302157). In addition, human iPSC (hiPSC)derived OPCs were shown to remyelinate denuded axons in nonhuman primates with experimental autoimmune encephalomyelitis (EAE), a common animal model for multiple sclerosis (99). As COVID-19related demyelination is likely due to immune-mediated myelin damage, successful applications of OPCs in other demyelinating animal models such as EAE suggest a potential benefit of OPCs in COVID-19related refractory demyelination.

Patients with COVID-19 who suffered acute ischemic strokes, especially those with persistent deficits after mechanical thrombectomy or thrombolytic therapy, could also be a target of cell therapy. The long-term outcomes of patients suffering strokes, most of whom are younger and suffer large vessel occlusions, could be devastating. The prospect of stem cell therapies in stroke has expanded, with several concluded and ongoing clinical trials using bone marrowderived stem cells and neural stem cells (100). MASTERS-2 (NCT03545607) and TREASURE (NCT02961504) are ongoing phase 3 clinical trials assessing treatment outcomes after intravenous administration of bone marrowderived adult progenitor stem cells in patients suffering from ischemic stroke in the acute setting. Hence, this subpopulation of patients with COVID-19 may benefit from neuroregenerative cell therapies in the future.

Cardiac manifestations, such as elevated troponin levels and myocardial ischemic infarctions, are commonly seen in patients with COVID-19, particularly in severe presentations (101). Myocardial injury was found in 22% of hospitalized patients and nearly 60% of deceased patients (4, 14). Moreover, cardiac arrhythmias were shown to be present in 44% of patients with COVID-19 in the ICU (102). Although cardiac cells express high levels of ACE2 (11), it remains unclear whether these cases constitute direct or indirect injury. One study on hiPSC-derived cardiomyocytes from patients with COVID-19 suggests viral invasion and cytopathic features in cardiac tissue (103). As cell therapies are designed, one potential way to mitigate the risk of SARS-CoV-2 viral entry of the treatment may be to genetically modulate viral entry proteins within the cell therapy itself. Indirect injury could be due to systemic hypoxia, secondary pulmonary hypertension, arrhythmia due to metabolic derangements, and cytokine storm damage (104).

Early cell therapy trials in acute myocardial infarct have largely focused on bone marrow mononuclear cells (BMMNCs), and early studies such as BOOST (105) and TOPCARE-MI (106) showed improvements in infarct size and left ventricular ejection fraction. Subsequent trials such as BOOST-2 (107) and TIME (108) showed no clinical benefit, however, questioning the role of BMMNCs in acute myocardial infarction. Preclinical data using a combination of cardiopoietic stem cells and MSCs have been promising and are under investigation in human trials (NCT02501811) (109). Further, Menasch et al. (110) showed that hESC-derived cardiac progenitors given to six patients with ischemic left ventricular dysfunction showed clinical improvement in systolic function without new tumors or arrhythmias. Clinical applications of iPSC-derived cardiomyocytes are also being explored (111). These advances in cell-based cardiac therapy can potentially be exploited for patients suffering from COVID-19related cardiac ischemia. In addition, a recent clinical study used cardiosphere-derived cells, which are cardiac progenitor cells, to assess treatment of severe pulmonary manifestations in six patients with COVID-19. Four of the six patients were discharged from the hospital, while the remaining two were in stable conditions at the time the study was published (112). A phase 2 trial further assessing the efficacy of these cardiosphere-derived cells is currently under investigation (NCT04623671).

Gastrointestinal manifestations occur in 5 to 10% of COVID-19 cases; however, symptoms have been mild and self-limited to nausea, diarrhea, and vomiting, despite ACE2 and TMPRSS2 being coexpressed in the small and large intestines and SARS-CoV-2 being detected in fecal samples of infected patients, suggesting direct viral invasion of enterocytes (113). This suggests that chronic intestinal sequela is unlikely to occur, negating the need for advanced treatments such as cell therapy. Hepatic involvement also appears to be frequent. Elevations in alanine aminotransferase and aspartate aminotransferase have been reported in up to a third of patients (114). ACE2 expression has been identified in cholangiocytes (115, 116); however, histopathological examinations have yet to show direct viral inclusions in the liver (117). Other possibilities for hepatic injury may include immune-mediated damage, systemic hypoxia secondary to lung damage, and drug-induced liver injury (118). Stem cellderived hepatic cells have been studied in the setting of acute and chronic liver failure. Patients have received cell therapies through the portal vein or splenic artery with improvement in serological markers such as prothrombin time or severity of hepatic encephalopathy (119). Although hepatocyte-based therapies have largely been considered a bridge to transplantation rather than a curative therapy itself, rare cases of patients with COVID-19 with acute liver failure may benefit from hepatocyte-based therapies (120).

Renal manifestations are frequent and range from mild proteinuria to severe injury requiring renal replacement therapy (121). Pei et al. (122) showed that 75% of patients with COVID-19 presenting with pneumonia were found to have an abnormal urine dipstick. Moreover, the presence of acute kidney injury (AKI) was associated with increased mortality, and only 46% of those patients who developed an AKI showed complete resolution after 12 days of follow-up. Over 80% of AKIs were intrinsic, with the remainder being secondary to rhabdomyolysis; there were no cases of prerenal AKI (122). Pathological studies have demonstrated acute tubular necrosis, presence of microthrombi, and mild interstitial fibrosis; however, no evidence of lymphocytic infiltrate in affected patients was found (123). While direct viral invasion is possible as ACE2 expression is present in tubular epithelium and podocytes, secondary mechanisms appear more relevant in inducing renal damage, which may include systemic hypoxia, rhabdomyolysis, cytokine-mediated damage, microemboli due to hypercoagulability, and cardiorenal congestion from right heart strain (121).

Cellular therapies for kidney disease are currently being explored and may benefit patients with COVID-19 suffering from permanent kidney injury. For example, preclinical studies using iPSC-derived renal precursor cells have shown the ability for these cells to engraft into damaged tubules and improve renal function (124). In addition, Swaminathan et al. (125) conducted a phase 2 trial using intra-aortic allogenic MSCs in the setting of postcardiac surgeryrelated AKI. However, the results showed no significant improvement in time to recover from AKI, dialysis use, or 30-day mortality. A phase 1 clinical trial, which is not yet recruiting, is aiming to assess the efficacy and safety of allogeneic MSCs infused via continuous renal replacement therapy (CRRT) in patients with COVID-19 with AKI undergoing CRRT (NCT04445220). Patients will be divided into three arms: low dose (2.5 107 cells), high dose (7.5 107 cells), and control. These studies could shed light on a possible role for cell therapies for the treatment of COVID-related renal damage.

Hematological and vascular sequela, especially hypercoagulability and disseminated intravascular coagulation (DIC), are serious manifestations of SARS-CoV-2 (126). The hypercoagulable state increases the risk of venous thromboembolism, which can lead to ischemic stroke and multisystem organ failure via microemboli (127). Rates of venous thromboembolism in critically ill patients with COVID-19 have been estimated to be as high as 31% (128). Moreover, Tang et al. (129) reported that 70% of deceased patients met criteria for DIC. The hypercoagulable state may be related to stimulated production of antiphospholipid antibodies and complement activation, vascular endothelial damage, and prolonged immobility in the ICU (130). Although the hypercoagulable state is likely due to a variety of factors, endothelial disruption is one potential cause that may contribute to multisystem end-organ damage in COVID-19 (131). CD34+ cells, hematopoietic stem cells that can give rise to endothelial progenitors and restore vasculature, have been approved for an investigational new drug by the FDA to assess their efficacy and safety for lung damage repair. CD34+ cells are thought to promote vascular regeneration to counter ischemic damage and have shown efficacy and safety in trials evaluating their potential in cardiac and critical limb ischemia (132). Cord blood CD34+ cells also showed protective effects on acute lung injury induced by lipopolysaccharide challenge in mice, similar to another study that showed that peripheral blood CD34+ cells attenuated acute lung injury induced by oleic acid in rats (133, 134). Hence, therapy with CD34+ cells could prove feasible for promoting vascular growth in the lungs of patients with COVID-19 suffering from significant pulmonary damage (NCT04522817).

Overall, cell therapies show great promise in several diseases, and data from other studies suggest that certain cell therapies may be applicable in particular pathogenesis aspects of COVID-19. Specific factors such as dosing of the cells, route of administration, allogenic versus autologous cells, role of immunosuppressive therapy, tolerance of treatment in elderly patients, role of extracellular vesicles, and readouts of effectiveness need to be better delineated. As an example, risk for severe illness with COVID-19 increases with age. There are lessons to be learned about recipient age from studies using hematopoietic stem cell transplantation (HSCT) or MSCs. For instance, HSCT studies have shown that patient age is correlated with transplant-related morbidity and mortality, but improvements such as the use of cytokines and less toxic or reduced conditioning have allowed older patients to receive these therapies. In the context of MSCs, a study conducted to evaluate patient age on the efficacy of MSC cell therapy in ischemic cardiomyopathy showed that older patients did not have an impaired response. Although these studies are not directly translatable to other cell types or patients with COVID-19, they nevertheless represent a starting point for future investigation (135140). Cell dosing and number of injections should be tailored to patient-specific responses and tolerance of treatment. Route of administration should be localized as much as possible to reduce the risk of unintentional side effects in distant organs while maximizing efficacy at the infected organ system. Disseminated coronavirus involving multiple organ systems, for example, may benefit from intravenous infusion of cell therapy to allow treatment to reach multiple infected organs. Various routes of administration have been previously explored for respiratory and pulmonary diseases including intravenous, intratracheal instillation, inhalation, aerosolization, and nebulizers. Intratracheal instillation could be advantageous, as it provides highly precise, local delivery to the respiratory tract using a small dose; however, instillation is highly nonphysiological and may result in inconsistent and heterogeneous deposition focused on the upper airways (141). Five clinical trials for lung cell therapies have used aerosolization as the route of administration (NCT04313647, NCT04473170, NCT04389385, NCT04491240, and NCT04276987). This route of administration may be preferred because of the potentially broader distribution of cells in the lung while reducing the probability of cell damage and loss (141).

Another interesting avenue to consider is the use of a combination of various cell therapies. MSCs, for example, have been studied for their synergistic effects with other cell types, including pulmonary endothelial cells and epithelial cells (142). For instance, MSCs were shown to stimulate endothelial progenitors in patients with heart failure and preserve endothelial integrity after hemorrhagic shock (143, 144). These findings could support investigation of both cell types as a combination cell therapy.

From a scalability standpoint, allogenic or off-the-shelfbased therapies that are either human leukocyte antigen (HLA)matched or do not have HLAs present would be favored over autologous cells. HLA matching or depletion may also reduce the need for immunosuppression. Clinical trial readouts should include COVID-19related outcomes and organ function related to the cell therapy being administered. Last, the idea of leveraging the field of synthetic biology to further adapt engineered cell lines should also be considered. For example, cell therapies that modulate expression of viral entry proteins, decrease residual potentially tumorigenic pluripotent cells, or adopt genome-scale mammalian translational recoding to confer viral resistance could be of keen advantage (145, 146).

B. Diao, C. Wang, R. Wang, Z. Feng, J. Zhang, H. Yang, Y. Tan, H. Wang, C. Wang, L. Liu, Y. Liu, Y. Liu, G. Wang, Z. Yuan, X. Hou, L. Ren, Y. Wu, Y. Chen, Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection. 12, 2506 (2020).

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Cell therapy strategies for COVID-19: Current approaches and potential applications - Science Advances