Category Archives: Stem Cell Therapy

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Harnessing the potential of hydrogels for advanced therapeutic applications: current achievements and future ... - Nature.com

Stem cell therapy could be used to treat sufferers of a rare bowel disease, a new study led by researchers at the University of Sheffield and University College London (UCL), has demonstrated.

Hirschsprung disease is a rare condition where some nerve cells are missing in the large intestine. This means the intestine cannot contract or move stool and therefore can become blocked. This can cause constipation and sometimes lead to a serious bowel infection called enterocolitis.

Around 1 in 5,000 babies are born with Hirschsprung disease. The condition is usually picked up soon after birth and treated with surgery as soon as possible; however patients frequently suffer debilitating, lifelong symptoms, with multiple surgical procedures often required.

For the first time, researchers have now used stem cell therapy in human tissue from people with Hirschsprung disease to generate nerve cell precursors, which then produce the missing nerves in the intestine after transplantation. This in turn should improve the intestine's functionality. It is hoped the discovery could lead to improved symptoms and better outcomes for individuals with the disease.

Dr Anestis Tsakiridis, Principal Investigator at University of Sheffield said: "Our findings have laid the foundations for the future development of a cell therapy against Hirschsprung disease and we will continue our efforts to bring this to the clinic in the next few years.

"This has been a fantastic collaboration, led by two talented early career scientists, Dr Ben Jevans and Fay Cooper."

The research, published in Gut and funded by the Medical Research Council, is a collaborative effort between researchers at the University of Sheffield and UCL which began in 2017.

Researchers at the University of Sheffield focused on the production and analysis of nerve precursors from stem cells. These were then shipped to the UCL team, who prepared the patient gut tissue, undertook the transplantation and maintenance of the tissue and then tested the function of the tissue segments.

The study involved taking tissue samples donated by GOSH patients with Hirschsprung disease as a part of their routine treatment, which were then cultured in the lab. The samples were transplanted with stem cell-derived nerve cell precursors which then developed into the crucial nerve cells within the gut tissue.

Importantly, the transplanted gut samples showed increased ability to contract compared to control tissue, suggesting improved functionality of the gut in those with the disease.

Principal Investigator, Dr Conor McCann from UCL Great Ormond Street Institute of Child Health, added: "This study is a real breakthrough in our cell therapy work for Hirschsprung disease. It really shows the benefit of bringing the expertise of different groups together which will hopefully benefit children and adults living with Hirschsprung disease in the future."

Researchers will now be applying for further funding for clinical trials to develop this treatment.

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Sheffield Univ. Advances in Rare Bowel Disease Stem Cell Therapy - Mirage News

Both bone marrow transplant and treatment with stem cells derived from bone marrow may help ease symptoms in some people with epidermolysis bullosa (EB), although a bone marrow transplant carries substantial greater safety risks.

Thats according to the review study Bone marrow transplantation and bone marrow-derived mesenchymal stem cell therapy in epidermolysis bullosa: A systematic review, which was published in Pediatric Dermatology.

EB is a group of rare diseases marked by fragile skin that easily blisters. It is caused by mutations that most commonly affect the formation of skin layers.

Supportive care has been the mainstay of therapy for all forms of EB to prevent or respond to disease progression, the researchers wrote.

But bone marrow transplants and stem cell therapies have been explored in EB treatment, with the idea being that providing healthy stem cells may promote healthy skin layers to develop.

Stem cells are specialized cells that can grow into other types of cells and help coordinate biological activities like inflammation and tissue repair.

Different types of stem cells can be found in bone marrow, including hematopoietic stem cells, which are responsible for making new blood cells, and mesenchymal stem cells, which can grow into several types of cells, including those that make up the skin.

Specific stem cell procedures used in EB are bone marrow transplant (BMT) and bone marrow-derived mesenchymal stem cell (BM-MSC) therapy. BMT is a highly invasive process that involves collecting healthy bone marrow stem cells and administering them into a patients bloodstream after treatment with chemotherapy and/or radiation to wipe out existing bone marrow stem cells. BM-MSC therapy is a less invasive procedure where mesenchymal stem cells are infused into a patients bloodstream or administered directly into the skin.

Here, scientists in Indonesia systematically reviewed published studies up to June 2023 that report the outcomes of BMT and BM-MSC therapy in people with EB. Twelve studies that covered 55 patients were included in the final analyses. Almost all the patients had dystrophic EB, while two had junctional EB. Most (63.6%) had BM-MSC therapy, but eight (14.5%) had BMT. Twelve patients (21.8%) had both procedures.

Patients tended to see reductions in disease symptoms after BMT and/or BM-MSC, results showed. However, the rates of recovery and ultimate outcomes varied from person to person, with some seeing better outcomes than others for reasons that arent fully clear.

Although efficacy results were generally positive, the researchers noted that BMT was associated with side effects. BMT, alone or combined with BM-MSC therapy, resulted in graft failure, meaning the transplanted cells were unable to take root, in five patients. There also were five cases of graft-versus-host disease, an immune complication wherein the transplanted cells attack the patients own cells, and five cases of sepsis, a severe blood infection, with BMT.

Pre-BMT chemotherapy or radiotherapy to kill existing bone marrow stem cells weakens the bodys immune system and increases the risk of infections. Among those who had BMT, two patients died of sepsis and another died of cardiac arrest due to pulmonary infections in the setting of chronic lung disease.

Compared with BMT, BM-MSC therapy was much more well tolerated, with no serious side effects reported. No deaths were reported in the BM-MSC therapy group. Two patients developed a temporary abnormal odor linked to the procedure and two developed squamous cell carcinoma, a common type of skin cancer. Its unclear if the treatment caused or expedited the cancer to develop.

Despite its potential advantages for severe forms of EB, bone marrow transplantation is a high-risk therapeutic modality with various adverse events; however, BM-MSCs showed promising results and improved safety of EB cell-based therapy treatment, wrote the researchers, who noted their review was limited by the small number of studies and that there was little data on the treatments affect on patients quality of life. Further study is needed regarding cost, access, and long-term risks of these therapies.

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Stem cell therapies show promise as epidermolysis bullosa treatment - Epidermolysis Bullosa News

MIAMI, June 03, 2024 (GLOBE NEWSWIRE) -- Longeveron Inc. (NASDAQ: LGVN), a clinical stage regenerative medicine biotechnology company developing cellular therapies for life-threatening and chronic aging-related conditions, today announced the launch of its contract development and manufacturing business at the Companys 15,000 square feet state-of-the-art Good Manufacturing Practice (GMP) facility. This facility contains 3,000 square feet of cleanroom space, including eight ISO 7 cleanrooms and ancillary areas, as well as 1,150 square feet of process development, quality control and warehousing space. The Company also announced the initiation of work under its first manufacturing services contract with Secretome Therapeutics, a biotechnology company developing first-in-class therapeutics from neonatal mesenchymal stem cells (nMSC).

We are delighted to partner with Secretome Therapeutics to advance their portfolio of therapeutics in this, our first contract manufacturing agreement in a new, revenue generating business line, said Wael Hashad, Chief Executive Officer of Longeveron. With cellular therapy manufacturing expertise and capabilities in high demand, and Longeverons strength in both, we see a significant opportunity to employ currently unused capacity in our state-of-the-art GMP facility. We have assembled a team of experts and proprietary technologies that enable us to take a systematic approach to rapidly develop improved cell therapies. Longeverons manufacturing expertise, capabilities and facility provide other pharmaceutical organizations the ability to advance their development programs without building their own manufacturing facility. We believe this contract manufacturing opportunity can expand our teams experience and has the potential to generate approximately $4-5 million in annual revenues once it is up and running fully.

Our platform of neonatal stem cell-based therapeutics has the potential to revolutionize treatment for a wide range of chronic, inflammatory diseases, said Vinny Jindal, President and Chief Executive Officer of Secretome Therapeutics. As we move our lead product, STM-01, into clinical studies for HFpEF and dilated cardiomyopathy this year, we look forward to tapping into Longeverons extensive cellular therapy knowledge and manufacturing expertise, which has supported the launch of multiple clinical studies.

Longeveron is primarily focused on advancing development of its lead investigational therapeutic candidate, Lomecel-BTM, a proprietary, scalable, allogeneic cellular therapy, across multiple indications, including hypoplastic left heart syndrome (HLHS) (Phase 2 on-going), Alzheimers disease (Phase 2 completed), and Aging-related Frailty (Phase 2 completed).

About Longeveron Inc.

Longeveron is a clinical stage biotechnology company developing regenerative medicines to address unmet medical needs. The Companys lead investigational product is Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapy product isolated from the bone marrow of young, healthy adult donors. Lomecel-B has multiple potential mechanisms of action encompassing pro-vascular, pro-regenerative, anti-inflammatory, and tissue repair and healing effects with broad potential applications across a spectrum of disease areas. Longeveron is currently pursuing three pipeline indications: hypoplastic left heart syndrome (HLHS), Alzheimers disease, and Aging-related Frailty. For more information, visit http://www.longeveron.com or follow Longeveron on LinkedIn, X, and Instagram.

Forward-Looking Statements

Certain statements in this press release that are not historical facts are forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, which reflect managements current expectations, assumptions, and estimates of future operations, performance and economic conditions, and involve risks and uncertainties that could cause actual results to differ materially from those anticipated by the statements made herein. Forward-looking statements are generally identifiable by the use of forward-looking terminology such as believe, expects, may, looks to, will, should, plan, intend, on condition, target, see, potential, estimates, preliminary, or anticipates or the negative thereof or comparable terminology, or by discussion of strategy or goals or other future events, circumstances, or effects and include, but are not limited to, the potential demand for Longeverons contract manufacturing services and its ability to enter into additional service agreements. Factors that could cause actual results to differ materially from those expressed or implied in any forward-looking statements in this release include, but are not limited to, adverse global conditions, including macroeconomic uncertainty; inability to raise additional capital necessary to continue as a going concern; our history of losses and inability to achieve profitability going forward; the absence of FDA-approved allogenic, cell-based therapies for HLHS or other cardiac-related indications; ethical and other concerns surrounding the use of stem cell therapy or human tissue; our exposure to product liability claims arising from the use of our product candidates or future products in individuals, for which we may not be able to obtain adequate product liability insurance; the adequacy of our trade secret and patent position to protect our product candidates and their uses: others could compete against us more directly, which could harm our business and have a material adverse effect on our business, financial condition, and results of operations; if certain license agreements are terminated, our ability to continue clinical trials and commercially market products could be adversely affected; the inability to protect the confidentiality of our proprietary information, trade secrets, and know-how; third-party claims of intellectual property infringement may prevent or delay our product development efforts; the inability to successfully develop and commercialize our product candidates and obtain the necessary regulatory approvals; we cannot market and sell our product candidates in the U.S. or in other countries if we fail to obtain the necessary regulatory approvals; final marketing approval of our product candidates by the FDA or other regulatory authorities for commercial use may be delayed, limited, or denied, any of which could adversely affect our ability to generate operating revenues; we may not be able to secure and maintain research institutions to conduct our clinical trials; ongoing healthcare legislative and regulatory reform measures may have a material adverse effect on our business and results of operations; if we receive regulatory approval of Lomecel-B or any of our other product candidates, we will be subject to ongoing regulatory requirements and continued regulatory review, which may result in significant additional expense; being subject to penalties if we fail to comply with regulatory requirements or experience unanticipated problems with our therapeutic candidates; reliance on third parties to conduct certain aspects of our preclinical studies and clinical trials; interim, topline and preliminary data from our clinical trials that we announce or publish from time to time may change as more data become available and are subject to audit and verification procedures that could result in material changes in the final data; provisions in our certificate of incorporation and bylaws and Delaware law might discourage, delay or prevent a change in control of our company or changes in our management and, therefore, depress the market price of our Class A common stock; we have never commercialized a product candidate before and may lack the necessary expertise, personnel and resources to successfully commercialize any products on our own or together with suitable collaborators; and in order to successfully implement our plans and strategies, we will need to grow our organization, and we may experience difficulties in managing this growth. Further information relating to factors that may impact the Companys results and forward-looking statements are disclosed in the Companys filings with the Securities and Exchange Commission, including Longeverons Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Securities and Exchange Commission on February 27, 2024, as amended by the Annual Report on Form 10-K/A filed March 11, 2024, its Quarterly Reports on Form 10-Q, and its Current Reports on Form 8-K. The forward-looking statements contained in this press release are made as of the date of this press release, and the Company disclaims any intention or obligation, other than imposed by law, to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise.

Investor Contact: Derek Cole Investor Relations Advisory Solutions derek.cole@iradvisory.com

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Longeveron Announces Contract Development and Manufacturing Business and First Contract - GlobeNewswire

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Cell-based therapies can potentially restore normal immune function and treat organ failure in sepsis. Medical researchers have embarked on clinical trials and pre-clinical studies to investigate the efficacy and safety of such therapies, signaling a promising new avenue in sepsis treatment.

Credit: Professor Xiangming Fang of Zhejiang University, China

Imagine the human body mounting an excessively heightened reaction to an infection, causing multiple organ failures and posing a risk of death. This condition, recognized as sepsis, affects approximately 49 million individuals worldwide annually. To thus reduce the mortality rate and the global burden of sepsis, the World Health Organization has classified it as a priority research area. When coupled with surgical trauma, anesthetic drugs, and various invasive procedures, the impact intensifies, resulting in additional impairment to vital organ functions such as respiration and circulation, making the situation even more perilous and complex. How to improve the perioperative prognosis of patients with concurrent sepsis constitutes a formidable challenge for anesthesiologists.

Bundled therapies form the crux of current sepsis management and treatments that focus on patient revival through fluid administration, timely administration of antibiotics, stabilization of cardiovascular function and blood flow, and supportive care to prevent organ failure. Nevertheless, the constrained efficacy of bundled therapies, especially in treating multiple organ failures over the past two decades, encourages medical researchers to discover novel sepsis therapies.

With the advent of cell-based therapies, there is now the potential to restore normal immune function and protect against multiple organ failures. Medical researchers worldwide are exploring the impact of cell-based therapies on sepsis management and treatment. Advancing the understanding on this front, a research group led by Professor Xiangming Fang from the Department of Anesthesiology and Intensive Care, The First Affiliated Hospital, School of Medicine, Zhejiang University, China, reviewed the existing literature on such cell-based therapies.

When asked about the scope of the review, Prof. Fang says, "This review provides a concise overview of immune cell therapy, its current status, and the strides made in the context of sepsis research, discussing potential strategies for the management of patients with sepsis during perioperative stages." Their findings were published online in theChinese Medical Journalin April 2024.

The research group found that mesenchymal stem cell (MSC)-based therapies are emerging as a promising approach for treating sepsis. MSCs have progressed to phase II clinical trials, reflecting the growing interest in the therapeutic potential of these MSCs. They also highlighted that future investigations could concentrate on determining the ideal dosage, administration routes, and storage methods to maximize the efficacy and safety of the treatment.

Importantly, the researchers found that innate immune cells called macrophages, particularly those expressing high levels of triggering receptor expressed on myeloid cells 2 (TREM2high), have shown significant promise in pre-clinical studies addressing surgical sepsis. The phagocytic function (engulfment and digestion of the infectious agents) of these cells, along with debris clearance, tissue repair, and organ perfusion abilities, may ultimately modulate outcomes in surgical sepsis cases. Moreover, latest studies show that targeted administration of these macrophages may facilitate organ function recovery, like heart function, enhancing postoperative outcomes in patients with sepsis.

Furthermore, the researchers highlighted that various immune cell subsets, including neutrophils, natural killer (NK) cells, dendritic cells (DCs), T cells, and B cells, exhibit therapeutic potential in sepsis management. Although neutrophils are essential players in the immune defense against infection, they can behave abnormally during sepsis, contributing to immune dysregulation and organ dysfunction. Similarly, NK cells help fight viral infections but ambiguously affect the body during sepsis. DCs help initiate immune responses, but their numbers decrease and function diminishes during sepsis, making them a potential target for treatment. Various subsets of T cells help regulate immune responses but undergo suppression during sepsis. B cells have been conventionally associated with antibody production but also play complex roles in sepsis, with some evidence suggesting they may have a protective function.

Moving forward, the researchers also emphasize the need for further studies on the behaviors of these immune cells to uncover potential applications as therapeutic targets.The review also discussed the distinctive challenges in the clinical implementation of cell-based immunotherapies for managing and treating sepsis, including precise cell modification, safety, delivery routes, and cost-effectiveness. Prof. Fang adds, Future studies should delve deeper into aspects such as optimal dosage, administration route, and storage methods.

Overall, the advent of cell-based immunotherapies for managing and treating sepsis provides hope to millions of patients and their caregivers. We certainly hope that these research endeavors lead to a new era of better sepsis management.

***

Reference

Titles of original papers: Advancing cell-based therapy in sepsis: An anesthesia outlook

Journal: Chinese Medical Journal

DOI: https://doi.org/10.1097/CM9.0000000000003097

Chinese Medical Journal

Literature review

Not applicable

Advancing cell-based therapy in sepsis: An anesthesia outlook

1-Apr-2024

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Chinese Medical Journal review explores cell-based immunotherapies for sepsis - EurekAlert

Key points

This page provides information on people who have been cured of HIV or appear able to control the virus without treatment. These cases have all been reported by scientists in medical journals or at scientific conferences. Sometimes, people are described as having long-term viral control without antiretroviral therapy (ART) or being in remission. This reflects uncertainty about whether HIV levels might eventually rebound.

While these cases are unusual, a major focus of HIV cure research involves finding out how these people manage to control their HIV, and developing therapies to help more people do the same thing.

Several cases of HIV cure or long-term viral control have been reported in people who received stem cell transplants to treat life-threatening leukaemia or lymphoma. Stem cells are cells produced bybone marrow (aspongytissue found in the centre of some bones) that can turn into new blood cells.

In all but one of the cases, people with HIV received stem cells from a person who had natural resistance to HIV infection due to the presence of the double CCR5-delta-32 mutation. People with this rare genetic mutation do not have CCR5 receptors on their immune system cells, so HIV is unable to gain entry to cells.

The first person cured of HIV was Timothy Ray Brown, an American then living in Berlin, who received two stem cell transplants to treat leukaemia in 2006. The donor had double copies of a rare gene mutation known as CCR5-delta-32 that results in missing CCR5 co-receptors on T cells, the gateway most types of HIV use to infect cells. He underwent intensive conditioning chemotherapy and whole-body radiotherapy to kill off his cancerous immune cells, allowing the donor stem cells to rebuild a new HIV-resistant immune system.

Brown stopped ART at the time of his first transplant but his viral load did not rebound. Researchers extensively tested his blood, gut, brain and other tissues, finding no evidence of replication-competent HIV anywhere in his body. In December 2010, Brown, known as the Berlin patient, began speaking to the press and at this point researchers started using the word cure for him. It was revealed that Browns cure for HIV had been far from easy. Despite this, Brown survived for 14 years from the date of his bone marrow transplant without any sign of HIV returning. He moved back to the US and became an ambassador for HIV cure research. He died in September 2020 at the age of 54, of the leukaemia that first prompted his treatment.

Browns case led researchers to look for similar donors in subsequent situations where people with HIV needed stem cell transplants.

A second case was reported in 2019. Adam Castillejo, the London patient, received a stem cell transplant from a donor with natural resistance to infection as part of treatment for Hodgkin lymphoma. He stopped antiretroviral treatment 16 months after the transplant, by which time all his CD4 cells lacked CCR5 receptors. Still controlling the virus without ART a year later, Castillejo went public. The COVID pandemic prevented him and Timothy Ray Brown ever meeting, but they did talk on the phone before Browns death. He has now been off ART for five years with no trace of HIV.

Marc Franke, the Dsseldorf patient, received a stem cell transplant to treat leukaemia from a donor immune to HIV in 2013. More cautious than Castillejo, he did not stop taking ART until November 2018. His remission from HIV was first announced at the same time as Castillejos in 2019, although it attracted little attention at the time. In February 2023, after more than four years of extensive testing, his doctors declared him cured of HIV. Later that year, Franke told POZ magazine that he has met his donor and also keeps in contact with other people cured of HIV.

The New York patient was described in February 2022. She was notable as being the first female case, and as of that date had been 14 months off ART without her HIV returning. She received a haplo-cord blood transplant to treat leukaemia in 2017. This is a different kind of stem cell transplant, used in circumstances where it is difficult to find a close genetic match, using cells from more than one donor. In this case, umbilical cord blood from a donor with the double CCR5-delta-32 mutation were supplemented by cells from a relative without the CCR5-delta-32 mutation. This procedure was necessary because the woman was mixed-race and the mutation that confers immunity to HIV is found almost solely in people of White European ancestry.

Paul Edmonds, the City of Hope patient, is a Californian named after the cancer centre where he was treated. As reported in July 2022, he received a stem cell transplant to treat leukaemia from a donor with a double CCR5-delta-32 mutation. He is the oldest person so far to experience viral control without treatment (63 years), has been living with HIV the longest (31years), and has the lowest CD4 nadir (below 100). He stopped ART two years after his transplant and has shown no trace of HIV in the 17 months since, with his leukaemia also in remission. Edmonds went public to the newspaper USA Today in April 2023.

Most recently, Romuald, a French-Swiss man initially known as the Geneva patient became the first person to experience HIV remission after a stem cell transplant in 2018 containing cells that did not have the double CCR5-delta-32 mutation. Based on the results of some previous transplants, scientists had assumed that HIV remission after a stem cell transplant was possible only after a transplant from a donor with the double CCR5-delta-32 mutation.

Romuald was diagnosed with HIV in 1990 at the age of 18and had been taking antiretroviral treatment which fully suppressed HIV since 2005. He received the transplant after chemotherapy and radiotherapy to treat leukaemia. Host CD4 cells were completely replaced within a month of the transplant, but he had graft-versus-host disease, which occurs when donor immune cells attack the recipients body. This required treatment with ruxolitinib, a JAK 1/2 inhibitor, which has also been shown to reduce the size of the HIV reservoir. Ultrasensitive viral load testing could not detect HIV after the transplant and the man undertook a planned treatment interruption. No viral rebound had occurred 54 months after transplantation and HIV DNA levels continued to decline off treatment.

Speaking to French-language media in November 2023, Romuald explained that the treatment for his leukaemia was much more difficult than his treatment for HIV. Isolation unit, heavy treatments, chemotherapy, radiotherapy, he said. It was the most difficult period of my life.

He knew that stopping his HIV treatment would be risky, but chose to do so both for himself and to advance scientific research. His intriguing case raises new questions about potential mechanisms that could lead to HIV remission.

Researchers stress that these are unusual cases and attempts to replicate them in other people undergoing cancer treatment have failed in some cases. Stem cell transplants are far too risky for people who do not need them to treat life-threatening cancer, and the intensive and costly procedure is far from feasible for the vast majority of people living with HIV worldwide.

Several cases of HIV control after discontinuing treatment have been reported. These individuals are known as post-treatment controllers.

In many but not all of these cases, the post-treatment controllers had received very early antiretroviral treatment within the first few weeks after infection which sometimes allows the immune system to get ahead of HIVs ability to evade the bodys natural response to it, producing broadly neutralising antibodies and other immune responses that stop more HIV being produced. This results in a much smaller than usual reservoir of cells containing intact proviral DNA. This strategy usually only works if people are treated very early, and it only produces long-term viral control in a fraction, such as a number of patients in France, the US and Germany.

In 2022, the latest report on the French VISCONTI cohort identified six men and four women who started a course of ART within three months of infection, subsequently stopped it, have remained undetectable and have not re-started treatment. Viral loads before treatment were generally high and ART was taken for at least one year. Seven of the ten have now remained undetectable for more than ten years, including one man who stopped treatment 17 years ago.

Acronym for antiretroviral therapy. Antiretroviral therapy usually includes at least two antiretroviral drugs.

Cells from which all blood cells derive. Bone marrow is rich in stem cells.

A level of viral load that is too low to be picked up by the particular viral load test being used or below an agreed threshold (such as 50 copies/ml or 200 copies/ml). An undetectable viral load is the first goal of antiretroviral therapy.

A substance that acts against retroviruses such as HIV. There are several classes of antiretrovirals, which are defined by what step of viral replication they target: nucleoside reverse transcriptase inhibitors; non-nucleoside reverse transcriptase inhibitors; protease inhibitors; entry inhibitors; integrase (strand transfer) inhibitors.

However, there were an additional nine people in the cohort who had periods of low but detectable viral load during follow-up, and a further three people who needed to re-start ART due to raised viral loads.

Its possible that cases of post-treatment control are not more commonly identified simply because, once having started ART, few people stop. A review of several studies suggests that around one person in nine treated very soon after infection may be able to control HIV for at least a year without treatment, while another suggested the proportion might be less than one in 20.

Children started early on ART are thought to be especially good candidates for post-treatment control as they can be started on ART very soon after infection, and they have fewer effector-memory T-cells, which are the type that become latent and hide HIV.

A South African childs case was first presented in 2017. Born with HIV, he was started on ART when he was two months old and taken off it, as part of a clinical trial of early-treated children, when he was one year old. He was still undetectable off ART in 2022 at the age of 13. He had a very weak immune response to HIV but strong activity in a gene that codes for PD-1, an immune checkpoint cell-surface protein that forces immune cells into latency in other words, to force HIV to hide inside the reservoir cells and not come out.

A study of 281 mother-infant pairs identified five South African boys who had controlled HIV despite non-adherence to postnatal antiretroviral treatment. All infants in the study who had acquired HIV received antiretroviral treatment after delivery and 92% were also exposed to the medication in the womb. Infants had been off antiretroviral treatment for between three and 19 months at the time the study reported its findings. HIV control off treatment was associated with HIV that remained sensitive to type 1 interferon and virus with higher replicative capacity. The study suggests that there may be a gender difference in HIV control in infants, as girls are less likely to have HIV sensitive to type 1 interferon because they produce higher levels of type 1 interferon during gestation.

Another case of HIV control after discontinuing treatment in a child treated soon after birth was reported in 2020. A child in Texas started treatment within two days of birth, had a positive HIV DNA test two weeks after birth and discontinued treatment at the age of 13 months. Three years later the child had undetectable HIV RNA and HIV DNA was detectable at extremely low levels intermittently during the follow-up period.

However, there have been a number of reported cases in which HIV DNA was not detectable on any tests, but HIV subsequently rebounded. In 2013, details of a Mississippi baby who received antiretroviral treatment from very soon after birth were reported. Treatment stopped after 18 months as the mother and baby stopped attending the clinic. HIV DNA was undetectable five months later when the mother and baby returned to the clinic and HIV remained undetectable for 27 months before viral load rebound occurred.

One remarkable case of post-treatment control is an Argentinian woman described as the Buenos Aires patient. She had not received treatment in early infection and there was nothing particularly advantageous in her medical history such as a consistently low viral load. On the contrary, when diagnosed in 1996, she had a low CD4 count (160) and at least one AIDS-related illness (toxoplasmosis). Her viral load, initially 2200, rose to 36,000 a year later due to adherence difficulties but after switching her ART regimen she never had a detectable viral load again despite stopping ART in 2007 due to side effects.

When her case was reported in 2021, she had been off ART with an undetectable viral load for at least 12 years. Investigations in 2015 and 2017 could not find any replication-competent HIV DNA in 2.5 billion white blood cells and an upper limit of one unit of intact viral DNA in 390 million CD4 cells. Though her CD4 cells retained immune responses to HIV, her CD8 cells had very weak responses. Unusually, even for HIV controllers, she is now HIV negative, having lost her antibodies to the virus.

This woman does have HLA B*57, a genetic variant associated with lower viral loads and slow progression, but it does not seem to have stopped her developing a severe HIV infection in the first place. Exactly how she has managed to control her HIV so profoundly remains a mystery but her seroreversion disappearance of antibodies and her sluggish CD8 response do seem to be extreme examples of processes seen in some other post-treatment controllers.

A Barcelona woman has controlled HIV for more than 15 years without treatment. Diagnosed with HIV during acute infection, she received four different immune-modulating drugs in addition to her normal antiretroviral treatment as part ofa clinical trial. However, she was the only person out of 20 participants in the trial to maintain long-term viral control off ART, so it is difficult to know whether to ascribe her control to the extra treatment or not.

Like the Buenos Aires patient, she had had typical or even severe initial HIV infection. Her CD4 T-cells were receptive to HIV and her viral DNA turned out to produce replication-competent virus. But the CD8 T-cells of her cellular immune system and the natural-killer (NK) cells of her innate immune system both proved to have particularly strong activity against HIV. Even if her control was achieved only with extra therapy, the immune signatures of these controllers are interesting because they point the way towards how viral control might be induced in other people.

The reasons for viral control off treatment are still not fully understood. Learning how to reproduce this state in a much larger proportion of people, and in those who didnt start treatment soon after infection, is a major goal of cure research.

Few people with HIV can control viraemia without HIV medication. People that can maintain viral loads between 50-2000 copies without treatment are known as viraemic controllers. In the US and UK, less than 4% of people with HIV are considered viraemic controllers. Surprisingly, a recent study identified that 13% of people in the South African and Zambian PopART cohort were viraemic controllers. This is higher than in the US and UK studies, and most of the viraemic controllers identified in the PopART cohort were women. Some studies suggest that women might be more likely to control HIV without medication compared to other groups, but these studies are limited and require further investigation. Understanding how sex differences, and other factors, may contribute to viraemic control has the potential to inform cure strategies.

While viraemic controllers maintain low but detectable levels of HIV, some people can control virus to below 50 copies. Elite controllers control HIV to undetectable levels in the blood, but viral material is still present elsewhere in the body. On the other hand, exceptional elite controllers maintain undetectable viral loads because their immune system seems to have eliminated all intact viral material from their bodies.

Loreen Willenbergisa Californian woman considered to be an exceptional elite controller. She was diagnosed with HIV in 1992 at the age of 37. From the start she maintained a high CD4 count and undetectable viral load since diagnosis (except for one viral blip). She volunteered for studies of long-term non-progressors (people who maintain intact immune systems without treatment) and in 2011 learned that scientists could find no replication-competent HIV in her immune cells. Loreen went public about her story in 2019 and was featured in The New York Times in 2020.

It appears that Willenbergs immune response to HIV is characterised by CD8 cells that have a strong and specific response to the parts of HIV that are most conserved. This means that they are the parts that change least, because to do so would impair viral fitness. They are therefore less likely to mutate away from the attention of the immune system.

In elite controllers this highly selective immune attack has led to the only replication-competent DNA they have being located in so-called gene deserts parts of the host DNA that lack the necessary conformation to allow viral genes to activate. In Willenbergs case, and in a few others, this process has gone further. Although some of her immune cells do contain junk HIV DNA proof that she once did have an active HIV infection no replication-competent DNA can be found.

The scientists who investigated Loreens response to HIV and some other researchers, notably in Spain, have found a few other patients who appear to have achieved self cures. No more than nine of these exceptional elite controllers have yet been documented.

The Esperanza patient is another example of an exceptional elite controller.This woman is named after her home town in Argentina. Diagnosed at the age of 21 in 2013, she took one six-month course of ART during pregnancy in 2020 to safeguard her baby but has never otherwise been on ART and has never had a detectable viral load test in nine years. As with Loreen Willenberg, researchers could find no replication-competent HIV DNA in 1.2 billion white blood cells, and also in 500 million placental cells sampled when she gave birth. In the case of this patient, doctors know that the likely source partner had a high HIV viral load, so her apparent self-cure is not due to viral factors.

There is also the case of an Australian man who appears to have cleared his own infection. This case was published in 2019 but attracted little attention, partly because the subject had an unusual combination of factors (a defective virus, one of his two CCR5 co-receptor genes missing and a response to HIV characteristic of slow progressors) that most people with HIV would not share. However, these factors did appear to have given his body more time than usual to mount a strong CD8 response, and a very specific CD4 response, to HIV. This is the kind of immune response researchers would like to replicate in other people.

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Cases of HIV cure | aidsmap - aidsmap

I never received compliments on my skin until beginning exosome therapy last fall. A few months prior, at the recommendation of Chioma Nnadiformer editor of Vogue.com and current head of editorial content at British VogueI took a consultation visit with practitioner Dr. Akis Ntonos, FNP, ND.

At the time, tackling hyperpigmentation was my main concern, so Ntonos emphasized that our course of action would include alleviating breakouts, balancing my skin's oil production, and reducing pore size. It all started with an in-office chemical peel, then a stem cell microneedling treatment. A few days after our first visit, he called to check in and ask a question: Would I like to participate in an exclusive skin study on skincare's next big ingredient, exosomes?

I didn't really know what exosomes were or how it could help me achieve my skin goals. I had so many questions. Exosomes, Ntonos tells me, are small vehicles released by all cells, including stem cells. In simple terms, exosomes are messengers that carry essential information and factors from one cell to another. By delivering these nanoparticles directly to the skin, one could receive better results. Per Ntonos, exosomes are preferred over actual stem cell applications because they are less contentious as they do not involve whole cells, mitigating the concerns of potential rejection or other complications.

Ntonos explains that exosomes are desirable in the aesthetic would because they enhance the skin's regenerative processes, which results in a more youthful appearance and better outcomes post-treatment. This improves skin quality and appearance, making them ideal for anti-aging and skin rejuvenation treatments. Wrinkles, skin laxity, uneven skin tone, and textural irregularities are all concerns exosomes target; it may also help prevent scarring, improve the appearance of old scars, and potentially treat inflammatory skin conditions. There are even ongoing studies that exosomes can improve hair restoration.

In 2020, Resilille discovered how to harvest many exosomes from a single umbilical cord per batch. Or Age Zero exosomes, as they call them, are derived from Wharton Jelly stem cells which are known for their therapeutic qualities; and, thus primed to achieve an improvement in skin texture, firmness, pore size, and radiance per Resilille CEO Erin Crowley. This innovation helps the ingredients be readily available for aesthetic treatments.

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How Exosome Therapy Gave Me the Skin of My Younger Self - Vogue

November 16, 2022

Karen M. Wai, MD, Theodore Leng, MD, MS, and Jeffrey Goldberg, MD, PhD, Byers Eye Institute at Stanford, Stanford University School of Medicine, Palo Alto, CA

In recent years, the potential of stem cell-based therapies to treat a wide range of medical conditions has given hope to patients in search of novel treatments or cures. At the same time, thousands of rogue clinics have sprung up across the U.S and around the world, offering stem cell-based therapies before being tested for safety and efficacy. When communicating to the public about stem cell-based therapies, it is important to put any treatment claims in context.

Stem cell-based therapies include any treatment that uses human stem cells. These cellshave the potential to develop into many different types of cells in the body. They offer a theoretically unlimited source of repair cells and/or tissues. (For more about stem cells, seehttps://stemcells.nih.gov.)

Over the past three decades, the Food and Drug Administration (FDA) has approved several stem cell-based products. These include bone marrow transplants, which have been transformational for many cancer patients, and therapies for blood and immune system disorders.1 Other approved treatments include dental uses for gum and tissue growth and in skin for burns. Since the early 2000s, stem cell-based therapies have been explored in many eye diseases, including age-related macular degeneration and glaucoma.2 Stem cell-based therapies are also being explored for neurodegenerative diseases such as stroke and Alzheimers disease, and for countless other conditions.

Over time, we expect that breakthroughs will continue with stem cell-based therapies for many conditions. However, at this time, rogue clinics, driven by profits, are taking advantage of patients desperate for cures and are claiming dramatic results, often exaggerated in sensational media testimonials. The clinics may mimic legitimate practices. They may extract a patients own stem cells, concentrate or modify the cells, and then re-inject them. Some manufacturers offer stem cell-based derived products, such as biologic eye drops made with placenta extract or amniotic fluid to treat dry eye. Clinics may provide misleading information and advertise their practice as running clinical trials. However, these clinics almost always work without FDA regulatory approval and outside of legitimate clinical trial approaches.

These unproven, unregulated stem cell treatments carry significant risk. The risks range from administration site reactions to dangerous adverse events. For example, injected cells can multiply into inappropriate cell types or even dangerous tumors. A 2017 report described one Florida clinic that blinded patients with stem cell eye injections.3

The Pew Charitable Trusts gathered 360 reports of adverse events related to unapproved stem cell therapies, including 20 cases that caused death.4 Further, adverse events are likely underreported because these products are not FDA approved or regulated. Many unproven stem cell-based therapies cost thousands of dollars to patients and are not covered by insurance. Further, even if patients avoid adverse events from these therapies, they may suffer consequences from delaying evidence-based treatments.

The FDA has made substantial progress toward regulation of stem cell-based therapies. In 2017, it released guidance under the 21st Century Cures Act that clarifies which stem-cell based therapies fall under FDA regulation. It also better defined how the agency will act against unsafe or unregulated products.5 As of May 2021, the FDA has more strongly enforced compliance for clinics that continue to market unproven treatments.6

Despite this increased regulation, rogue clinics are still relatively commonplace. A 2021 study estimated that there are over 2,500 U.S. clinics selling unproven stem cell treatments.7Patients at these clinics are often led to believe that treatments are either approved by the FDA, registered with the FDA, or do not require FDA approval. It is important to recognize that there are limits to the FDAs expanded reach, especially when it is targeting hundreds of clinics at once. Our clinic at Stanford recently cared for a patient who had received stem cell injections behind his eyes, where he developed tumors that ultimately ruined vision in both eyes.

Progress in stem cell science is rapidly translating to the clinic, but it is not yet the miracle answer we envision. With time, stem cell-based therapies will likely expand treatment options. People considering a stem-cell based therapy should find out if a treatment is FDA-approved or being studied under an FDA-approved clinical investigation plan. This is called an Investigational New Drug Application. Importantly, being registered with ClinicalTrials.gov does not mean that a therapy or clinical study has been authorized or reviewed by the FDA. For more information about stem cell therapies, visit http://www.closerlookatstemcells.org, a resource from the International Society for Stem Cell Research.

As we look hopefully to the future, we need greater awareness of the current limitations of stem cell therapy and the dangers posed by unregulated stem cell clinics. Strong FDA regulation and oversight are important for ensuring that stem cell-based therapies are safe and effective for patients. Accurate communication to the public, careful advocacy by physicians, and education of patients all continue to be crucial.

References:

1 U.S. Food and Drug Administration, Approved Cellular and Gene Therapy Products, Sept. 9, 2022,https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

2 Stern JH, Tian Y, Funderburgh J, Pellegrini G, Zhang K, Goldberg JL, Ali RR, Young M, Xie Y, Temple S. Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell. 2018 Sep 6;23(3):453. doi: 10.1016/j.stem.2018.08.014. Erratum for: Cell Stem Cell. 2018 Jun 1;22(6):834-849. PMID: 30193132.

3 Kuriyan AE, Albini TA, Townsend JH, Rodriguez M, Pandya HK, Leonard RE 2nd, Parrott MB, Rosenfeld PJ, Flynn HW Jr, Goldberg JL. Vision Loss after Intravitreal Injection of Autologous "Stem Cells" for AMD. N Engl J Med. 2017 Mar 16;376(11):1047-1053. doi: 10.1056/NEJMoa1609583. PMID: 28296617; PMCID: PMC5551890.

4 The Pew Charitable Trusts, Harms Linked to Unapproved Stem Cell Interventions Highlight Need for Greater FDA Enforcement, June 1, 2021,https://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2021/06/harms-linked-to-unapproved-stem-cell-interventions-highlight-need-for-greater-fda-enforcement.

5 U.S. Food and Drug Administration, FDA announces comprehensive regenerative medicine policy framework, Feb. 2, 2022,https://www.fda.gov/news-events/press-announcements/fda-announces-comprehensive-regenerative-medicine-policy-framework.

6 U.S. Food and Drug Administration, FDA Extends Enforcement Discretion Policy for Certain Regenerative Medicine Products, July 7, 2020,https://www.fda.gov/news-events/press-announcements/fda-extends-enforcement-discretion-policy-certain-regenerative-medicine-products.

7Turner L. The American stem cell sell in 2021: U.S. businesses selling unlicensed and unproven stem cell interventions. Cell Stem Cell. 2021 Nov 4;28(11):1891-1895. doi: 10.1016/j.stem.2021.10.008. PMID: 34739831.

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Putting Stem Cell-Based Therapies in Context - National Institutes of ...

There's no shortage of opportunity for consumers like John Rodolf to encounter the promise and peril of experimental stem cell treatments. They are being studied by blue-chip medical centers like the Mayo Clinic, offered in the exam rooms of dermatologists and orthopedists, and advertised in newspapers and online by more than 500 stem cell specialty clinics.

The level of scientific vetting these treatments have been subjected to runs the gamut. Some have been carefully developed and sanctioned by the FDA; others haven't been formally studied but have some evidence to support their use. Others still are untested and dangerously unscientific.

It can be difficult to tell which of those categories any given stem cell therapy falls into, in part because websites and advertisements that promote bogus treatments can look just as professional and trustworthy as the ones that discuss legitimate clinical trials. "I found out about the Lung Institute in a magazine advertisement in my doctor's office," says Maureen Rosen, a 75-year-old resident of Ocala, Fla., who, like John Rodolf, paid the Lung Institute thousands of dollars for COPD treatments she says didn't work at all. "And it looked impressive to me. And when I went online, the website looked like any other website that you'd see for a hospital."

Another problem is that questionable treatments are sometimes advertised alongside promising ones. For example, according to court documents and a case study published in the New England Journal of Medicine, three women suffered serious vision impairment (one went completely blind) after participating in a study they found listed at clinicaltrials.gov, a website maintained by the National Institutes of Health (NIH).

The site lists more than 1,000 stem cell-related clinical trials. Some of them have secured investigative new drug (IND) approval from the FDA, a process that can take years of research and involves careful vetting of protocols for safety and close monitoring of patients, as a rule. But other trials listed on the site haven't completed those steps, and there's no easy way to tell the two groups apart.

The clinical trial that allegedly cost the three women their vision was administered at U.S. Stem Cell Clinic (USSCC) in Sunrise, Fla. It involved extracting stem cells from the women's belly fat and injecting them into their eyes to treat their macular degeneration. Researchers say the protocol violated basic safety principlessuch as treating only one eye so that the other would be spared in the event of complicationsand that it used a type of stem cell that hasn't demonstrated any potential for treating macular degeneration. "Fat stem cells can only turn into fat," says Temple of the Neural Stem Cell Institute. "There's no reason to think they would do anything for diseases of the eye." U.S. Stem Cell Clinic declined to be interviewed for this article.

The NIH recently added a disclaimer to its clinical trials home page, warning that not all of the listed studies have been vetted by a federal agency. But critics say that notice isn't enough to protect consumers, many of whom are desperate for miracle cures. "Some clinics effectively use this site as a marketing tool," says Leigh Turner, Ph.D., a bioethicist at the University of Minnesota who has studied the stem cell industry. "They post studies there because it gives them an air of legitimacy, which in turn helps them attract patients."

An NIH spokeswoman told Consumer Reports that the government agency is considering additional measures to help consumers navigate the site better, but she didn't mention specifics.

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The Trouble With Stem Cell Therapy - Consumer Reports

The stem cell therapy project Blue4Therapy brought to a highly successful close  Marketscreener.com

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The stem cell therapy project Blue4Therapy brought to a highly successful close - Marketscreener.com