Surprising culprit in nerve cell damage identified – Washington University in St. Louis Newsroom

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Findings suggest ways to block nerve cell damage in neurodegenerative diseases

Nerve axons (left) serve as the electrical wiring of the nervous system. Scientists have implicated a specific molecule in triggering a self-destruct program in axons that leads to their degeneration (right). Since axonal degeneration is a common thread in many neurodegenerative diseases, including peripheral neuropathy, researchers are seeking ways to block it. Both images show mouse axons. Yellow and green color added for clarity.

In many neurodegenerative conditions Parkinsons disease, amyotrophic lateral sclerosis (ALS) and peripheral neuropathy among them an early defect is the loss of axons, the wiring of the nervous system. When axons are lost, nerve cells cant communicate as they should, and nervous system function is impaired. In peripheral neuropathy in particular, and perhaps other diseases, sick axons trigger a self-destruct program.

In new research, scientists at Washington University School of Medicine in St. Louis have implicated a specific molecule in the self-destruction of axons. Understanding just how that damage occurs may help researchers find a way to halt it.

The study is published March 22 in the journal Neuron.

Axons break down in a lot of neurodegenerative diseases, said senior author Jeffrey D. Milbrandt, MD, PhD, the James S. McDonnell Professor and head of the Department of Genetics. Despite the fact these diseases have different causes, they are all likely rooted in the same pathway that triggers axon degeneration. If we could find a way to block the pathway, it could be beneficial for many different kinds of patients.

Since the molecular pathway that leads to loss of axons appears to do more harm than good, its not clear what role this self-destruct mechanism plays in normal life. But scientists suspect that if the pathway that destroys axons could be paused or halted, it would slow or prevent the gradual loss of nervous system function and the debilitating symptoms that result. One such condition, peripheral neuropathy, affects about 20 million people in the United States. It often develops following chemotherapy or from nerve damage associated with diabetes, and can cause persistent pain, burning, stinging, itching, numbness and muscle weakness.

Peripheral neuropathy is by far the most common neurodegenerative disease, said co-author Aaron DiAntonio, MD, PhD, the Alan A. and Edith L. Wolff Professor of Developmental Biology. Patients dont die from it, but it has a huge impact on quality of life.

In previous studies, Stefanie Geisler, MD, an assistant professor of neurology, working with DiAntonio and Milbrandt, showed that blocking this axon self-destruction pathway prevented the development of peripheral neuropathy in mice treated with the chemotherapy agent vincristine. The hope is that if methods are developed to block this pathway in people, then it might be possible to slow or prevent the development of neuropathy in patients.

Toward that end, the Milbrandt and DiAntonio labs showed that a molecule called SARM1 is a central player in the self-destruct pathway of axons. In healthy neurons, SARM1 is present but inactive. For reasons that are unclear, injury or disease activate SARM1, which sets off a series of events that drains a key cellular fuel called nicotinamide adenine dinucleotide (NAD) and leads to destruction of the axon. Though the researchers previously had shown SARM1 was required for this chain of events to play out, the details of the process were unknown.

SARM1 and similar molecules those containing what are called TIR domains most often are studied in the context of immunity, where these domains serve as scaffolds. Essentially, TIR domains provide a haven for the assembly of molecules or proteins to perform their work.

The researchers had assumed that SARM1 acted as a scaffold to provide support for the work of destroying axons, beginning with the rapid loss of cellular fuel that occurs minutes after SARM1 becomes active. The scientists set about searching for the demolition crew the active molecule or molecules that use the SARM1 scaffold to carry out the demolition. The studys first author, Kow A. Essuman, a Howard Hughes Medical Institute Medical Research Fellow and an MD/PhD student in Milbrandts lab, performed a litany of cellular and biochemical experiments searching for the demolition crew and came up empty.

We performed multiple experiments but could not identify molecules that are traditionally known to consume NAD, Essuman said.

But as a last resort, the investigators tested SARM1 itself. To their great surprise, they found it was doing more than simply providing a passive platform. Specifically, the researchers showed SARM1s TIR domain acts as an enzyme, a molecule that carries out biochemical reactions, in this case destroying axons by first burning all their NAD cellular fuel.

There are more than 1,000 papers describing the function of proteins containing TIR domains, DiAntonio said. No one had ever shown that this type of molecule could be an enzyme. So we went into our experiments assuming SARM1 was only a scaffold and that there must be some other enzyme responsible for demolition of the axon. We essentially searched for a demolition crew, only to discover that the scaffold itself is destroying the structure. Its the last thing you would expect.

The findings suggest molecules similar to SARM1 those with TIR domains and known to serve as scaffolds in the immune system may prove to have additional functions that go beyond their structural roles. The research also invites a search for drugs that block the SARM1 enzyme from triggering axonal destruction.

This work was supported by the National Institutes of Health (NIH), grant numbers RO1NS065053, RO1AG013730, RO1NS087632, NCATS UL1 TR000448, NIGMS P41 GM103422 and NCI P30 CA091842; a Howard Hughes Medical Institute Medical Research Fellowship; and the Muscular Dystrophy Association, grant numbers MDA349925 and MDA344513. Washington University, Milbrandt and co-author Yo Sasaki may derive income from licensing of technology to ChromaDex.

Essuman K, Summers DW, Sasaki Y, Mao X, DiAntonio A, Milbrandt J. The SARM1 Toll/Interleukin-1 Receptor (TIR) Domain Possesses Intrinsic NAD+ Cleavage Activity that Promotes Pathological Axonal Degeneration. Neuron. March 22, 2017.

Washington University School of Medicines 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Surprising culprit in nerve cell damage identified - Washington University in St. Louis Newsroom

Life Extension and Insilico Medicine Use Artificial Intelligence to Develop Ageless Cell – WholeFoods Magazine

Fort Lauderdale, FL Life Extension has partnered with Insilico Medicine to introduce Ageless Cell, the first supplement in its GEROPROTECT line to promote healthy aging by inhibiting cellular senescence.

Cellular senescence is a natural part of the aging process where cells no longer function optimally, affecting organ function, cellular metabolism, and the inflammation response. The accumulation of these senescent cells contributes to the process of aging. The Ageless Cell supplements inhibit the effects of cellular senescence by acting as geroprotectors, or interventions aimed to increase longevity and impede the onset of age-related diseases by targeting and inhibiting senescence-inducing pathways and inhibiting the development of senescent cells.

The partnership with Insilico Medicine allowed researchers to use deep learning algorithms to comb through hundreds of studies and thousands of data points a process that could have taken decades to identify four key anti-aging nutrients: N-Acetyl-L-Cysteine (NAC), myricetin, gamma-tocotrienol, and EGCG. These compounds target pathways that are known to contribute to or protect against the development of senescent cells.

Specifically, NAC upregulates signaling pathways that protect cells against oxidative stress, which promotes cellular senescence. It also reduces pathways that promote inflammation. Myricetin regulates a family of stress-responsive signaling molecules known to regulate aging in many tissues. It also promotes cell differentiation and self-repair. Gamma tocotrienol modulates the mevalonate pathway that controls cholesterol production, cancer promotion, and bone formation. And EGCG regulates the Wnt pathway that determines the fate of developing cells and also prevents sugar-induced damage to tissues, helping to suppress their pro-aging effects.

Clinical aging studies are extremely difficult, if not impossible, to perform at this time. Our collaboration with Insilico Medicine has allowed us to develop geroprotective formulations by using artificial intelligence to study very large data sets, said Andrew G. Swick, Ph.D., senior vice president of product development and scientific affairs for Life Extension.

Scientists found these four nutrients have various complementary and reinforcing properties to influence key anti-aging pathways and combat aging factors by modulating specific biological pathways. By rejuvenating near-senescent cells and encouraging the bodys healthy process for dealing with senescent cells, Ageless Cell turns back the clock at the cellular level, said Michael A. Smith, M.D., senior health scientist for Life Extension.

Alex Zhavoronkov, Ph.D., CEO of Insilico Medicine said, Together, these four natural compounds represent the beginning of the future anti-aging cocktails identified using artificial intelligence under expert human supervision.

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Life Extension and Insilico Medicine Use Artificial Intelligence to Develop Ageless Cell - WholeFoods Magazine

How randomness helps cancer cells thrive – Medical Xpress – Medical Xpress

March 27, 2017 Killer T cells surround a cancer cell. Credit: NIH

In a research effort that merged genetics, physics and information theory, a team at the schools of medicine and engineering at The Johns Hopkins University has added significantly to evidence that large regions of the human genome have built-in variability in reversible epigenetic modifications made to their DNA.

In a report on the research published March 27 in Nature Genetics, the team says the findings also suggest that such epigenetic variability is a major factor in the ability of cancer cells to proliferate, adapt and metastasize.

"These results suggest that biology is not as deterministic as many scientists think," says Andrew Feinberg, M.D., M.P.H., the King Fahd Professor of Medicine, Oncology, and Molecular Biology and Genetics at the Johns Hopkins University School of Medicine and director of the Center for Epigenetics in the Institute for Basic Biomedical Sciences. "If so, they could have major implications for how we treat cancer and other aging-related diseases."

Epigenetic modifications, achieved along the genome by the chemical attachment of methyl molecules, or tags, to DNA, are reversible changes that alter which genes are turned on or off in a given cell without actually altering the DNA sequence of the cell. Such changes enable a complex organism, like a human, to have a wide range of different tissues that all still have the exact same genetic template.

However, in some studies with laboratory mice, Feinberg had observed that these epigenetic tags varied considerably among the mice even when comparing the same type of tissue in animals that have been living in the exact same conditions. "These weren't minor differences, and some very important genes were involved," Feinberg says.

Feinberg, who is also a Bloomberg Distinguished Professor of Engineering and Public Health at The Johns Hopkins University, suspected that this variation might be an adaptive feature by which built-in epigenetic randomness would give some cells an advantage in rapidly changing environments.

To find out if that was the case, he teamed up with John Goutsias, Ph.D., professor of electrical and computer engineering at the Johns Hopkins Whiting School of Engineering, to find a way to measure this controlled type of randomness, scientifically termed epigenetic stochasticity, by using the information-theoretic concept of Shannon entropy.

Using a mathematical model known as the Ising model, invented to describe phase transitions in statistical physics, such as how a substance changes from liquid to gas, the Johns Hopkins researchers calculated the probability distribution of methylation along the genome in several different human cell types, including normal and cancerous colon, lung and liver cells, as well as brain, skin, blood and embryonic stem cells.

As Goutsias explains, this distribution reflects the chance that a particular region of a genome will be methylated in a population of similar cells. In areas of low randomness, this probability would mostly be 0 or 100 percent, but in areas of high randomness, the numbers would be 50-50 or thereabouts.

The analysis revealed that the human genome is organized into large pieces of low or high epigenetic stochasticity, and that these regions correspond to areas of chromosomes that are structurally different in the cell nucleus. Feinberg thinks that a main function of a cell's nucleus might be to partition the genome to make sure that regions of low or high stochasticity are well-defined.

The other significant finding of the study, says Garrett Jenkinson, Ph.D., assistant research scientist at the Johns Hopkins Whiting School of Engineering who carried out much of the analyses, was that this variability goes haywire in cancer cells, which may display significant regional differences in methylation stochasticity compared to normal cells. Based on the evolutionary idea that targeted epigenetic stochasticity can improve adaptation, these observations could explain how cancer cells are good at evading chemotherapy treatments and spreading from one part of the body to another, he adds.

"Researchers have understood the importance of epigenetics in driving cancer growth, but the focus has been trying to reverse epigenetic changes to specific genes," Feinberg says. "We need to readjust and think more broadly about the epigenetic process as a whole." Looking at ways to reverse aberrant changes in variability to make cancer cells more epigenetically controlled should be a target for therapy, he adds.

Earlier this year, Feinberg led a study that considered this view of epigenetics in metastatic pancreatic cancer cells. Using an experimental drug called 6-aminonicotinamide, his group reversed the large-scale epigenetic changes that enabled the tumor cells in mice to metastasize and slow the growth of further tumors.

Explore further: Potentially reversible changes in gene control 'prime' pancreatic cancer cells to spread

More information: Potential energy landscapes identify the information-theoretic nature of the epigenome, Nature Genetics, nature.com/articles/doi:10.1038/ng.3811

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How randomness helps cancer cells thrive - Medical Xpress - Medical Xpress

Scientists discover mechanism that causes cancer cells to self-destruct – Medical Xpress

March 27, 2017

Many cancer patients struggle with the adverse effects of chemotherapy, still the most prescribed cancer treatment. For patients with pancreatic cancer and other aggressive cancers, the forecast is more grim: there is no known effective therapy.

A new Tel Aviv University study published last month in Oncotarget discloses the role of three proteins in killing fast-duplicating cancer cells while they're dividing. The research, led by Prof. Malka Cohen-Armon of TAU's Sackler School of Medicine, finds that these proteins can be specifically modified during the division processmitosisto unleash an inherent "death mechanism" that self-eradicates duplicating cancer cells.

"The discovery of an exclusive mechanism that kills cancer cells without impairing healthy cells, and the fact that this mechanism works on a variety of rapidly proliferating human cancer cells, is very exciting," Prof. Cohen-Armon said. "According to the mechanism we discovered, the faster cancer cells proliferate, the faster and more efficiently they will be eradicated. The mechanism unleashed during mitosis may be suitable for treating aggressive cancers that are unaffected by traditional chemotherapy.

"Our experiments in cell cultures tested a variety of incurable human cancer typesbreast, lung, ovary, colon, pancreas, blood, brain," Prof. Cohen-Armon continued. "This discovery impacts existing cancer research by identifying a new specific target mechanism that exclusively and rapidly eradicates cancer cells without damaging normally proliferating human cells."

The research was conducted in collaboration with Prof. Shai Izraeli and Dr. Talia Golan of the Cancer Research Center at Sheba Medical Center, Tel Hashomer, and Prof. Tamar Peretz, head of the Sharett Institute of Oncology at Hadassah Medical Center, Ein Kerem.

A new target for cancer research

The newly-discovered mechanism involves the modification of specific proteins that affect the construction and stability of the spindle, the microtubular structure that prepares duplicated chromosomes for segregation into "daughter" cells during cell division.

The researchers found that certain compounds called Phenanthridine derivatives were able to impair the activity of these proteins, which can distort the spindle structure and prevent the segregation of chromosomes. Once the proteins were modified, the cell was prevented from splitting, and this induced the cell's rapid self-destruction.

"The mechanism we identified during the mitosis of cancer cells is specifically targeted by the Phenanthridine derivatives we tested," Prof. Cohen-Armon said. "However, a variety of additional drugs that also modify these specific proteins may now be developed for cancer cell self-destruction during cell division. The faster the cancer cells proliferate, the more quickly they are expected to die."

Research was conducted using both cancer cell cultures and mice transplanted with human cancer cells. The scientists harnessed biochemical, molecular biology and imaging technologies to observe the mechanism in real time. In addition, mice transplanted with triple negative breast cancer cells, currently resistant to available therapies, revealed the arrest of tumor growth.

"Identifying the mechanism and showing its relevance in treating developed tumors opens new avenues for the eradication of rapidly developing aggressive cancers without damaging healthy tissues," said Prof. Cohen-Armon.

The researchers are currently investigating the potential of one of the Phenanthridine derivatives to treat two aggressive cancers known to be unresponsive to current chemotherapy: pancreatic cancer and triple negative breast cancer.

Explore further: Nanoparticle paves the way for new triple negative breast cancer drug

More information: Leonid Visochek et al, Exclusive destruction of mitotic spindles in human cancer cells, Oncotarget (2017). DOI: 10.18632/oncotarget.15343

Journal reference: Oncotarget

Provided by: Tel Aviv University

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Scientists discover mechanism that causes cancer cells to self-destruct - Medical Xpress

Cell Therapy Manufacturing Market, 2017-2027 – PR Newswire (press release)

Several players, including cell therapy developers, research institutes, contract manufacturing organizations, and government and non-profit organizations, are playing a critical role in the development and manufacturing of these cell therapies. In fact, a number of these players have made heavy investments to expand their existing capabilities and establish new facilities for cell therapy products in order to meet the increasing demand.

Additionally, stakeholders have received significant support from governments worldwide, in terms of funding and establishment of consortiums to accelerate the transition of these therapies from laboratories to clinics. It is important to highlight that companies that offer logistics and operational services have developed systems / tools for safer and quicker delivery of therapies from manufacturing sites to patients; this has been identified as one of the key challenges in the overall development process.

During the course of our study, we identified over 110 organizations that are actively involved in the manufacturing of cell therapies.

In addition to other elements, the study provides information on:

The current status of the market with respect to key players along with information on the location of their manufacturing facilities, scale of production, type of cells manufactured, purpose of production (fulfilling in-house requirements / as a contract service provider) and the type of organization (industry / non-industry).

Most active regions in terms of cell therapy manufacturing with schematic representations of world maps that clearly highlight the global cell therapy manufacturing hubs.

Roadmaps published by different agencies across the globe to provide strategies to advance cell therapy manufacturing.

Elaborate profiles of key players that offer contract manufacturing services (industry and non-industry) or manufacture cell therapies in-house; each profile covers an overview of the company, information on its manufacturing facilities, and recent collaborations.

Partnerships that have taken place in the recent past covering manufacturing and services agreements, agreements specific to technology / instruments / process developments, and mergers and acquisitions.

A discussion on the key enablers of the market and challenges associated with the cell therapy manufacturing process.

Potential future growth of the cell therapy manufacturing market segmented by the type of cell therapy, source of cells (autologous and allogeneic) and purpose of manufacturing (in-house and contract services). For the purposes of our analysis, we took into consideration several parameters that are likely to impact the growth of this market over the next decade; these include the likely increase in number of clinical studies, patient population, anticipated adoption of commercial cell-therapies and expected variation in manufacturing costs.

We have provided an estimate of the size of the market in the short to mid-term and long term for the period 2017 to 2027. The base year for the report is 2016. To account for the uncertainties associated with the development of novel therapeutics and to add robustness to our model, we have provided three forecast scenarios portraying the conservative, base, and optimistic tracks of the market's evolution.

The research, analysis and insights presented in this report are backed by a deep understanding of key insights gathered from both secondary and primary research. Actual figures have been sourced and analyzed from publicly available data. For the purpose of the study, we invited over 100 stakeholders to participate in a survey to solicit their opinions on upcoming opportunities and challenges that must be considered for a more inclusive growth.

Our opinions and insights presented in this study were influenced by discussions conducted with several key players in this domain. The report features detailed transcripts of interviews held with Tim Oldham (CEO, Cell Therapies), Brian Dattilo (Manager of Business Development, Waisman Biomanufacturing) and Mathilde Girard (Department Leader, Cell Therapy Innovation and Development, YposKesi), Dr. Gerard J Bos (CEO, CiMaas).

Example Highlights

Overall, we identified over 60 industry players and 50 academic institutes / non-profit organizations that are actively contributing in the field of cell-therapy manufacturing. We came across 68 players that are involved in manufacturing of immunotherapies and 66 players that possess capabilities for manufacturing adult stem cell therapies. Further, 28 organizations have facilities for both immunotherapies and adult stem cell therapies. Within the stem cell therapy market, we identified 15 and 17 organizations that are involved in the manufacturing of ESCs and iPSCs, respectively.

As majority of cell therapy products are in early phase of development, several manufacturers have facilities that meet the clinical scale production requirements. However, some players (31, as per our research) have developed / are developing commercial scale capacity for cell therapy production. Examples include (in alphabetical order) apceth Biopharma, Brammer Bio, Cell and Gene Therapy Catapult, CELLforCURE, Cognate BioServices, EUFETS, Guy's and St Thomas' Facility, Lonza, MaSTherCell, PharmaCell and WuXi AppTec.

Although the current market landscape is dominated by contract manufacturers, some well-established cell therapy developers have set up in-house manufacturing capabilities to support their requirements of cGMP grade cells. Examples include (in alphabetical order) Adaptimmune, Argos Therapeutics, Cell Medica, Cellular Biomedicine Group, Juno Therapeutics, Kite Pharma and SOTIO. In addition, we identified over 10 organizations that manufacture cell-based therapies for their own clinical research as well as offer contract services to other organizations Examples include (in alphabetical order) Amsterdam BioTherapeutics Unit (AmBTU), apceth Biopharma, Children's GMP / GMP facility (St. Jude Children's Research Hospital), Cook Myosite, John Goldmann Centre for Cellular Therapy (Imperial College London), MolMed, and PCT (a Caladrius Company).

North America has the maximum number of cell therapy manufacturing facilities (~ 43%), followed by the EU where ~40% of the global cell therapy manufacturing facilities are located. Specifically, in the EU, maximum number of manufacturing facilities are located in the UK (~44%). Other emerging pockets for cell therapy manufacturing include Australia, China, Japan, Singapore, South Korea and Israel; facilities in these regions primarily cater to the Asia-Pacific markets.

Over 140 collaborations have been inked between cell therapy developers, cell therapy manufacturers and other stakeholders of the industry. The motive behind the partnerships varies; they have been signed for obtaining manufacturing services, gaining access to services related to data management, reagent supply and logistics, upgrading technologies for manufacturing processes, and acquisition of manufacturing facilities.

The near-term demand for manufacturing of cell-based therapies will primarily be driven by clinical candidates. In the longer term, the currently approved therapies and late-stage therapies (that are likely to get commercialized in future) will act as key drivers of the market. Our outlook is highly promising; we expect the market for cell therapy manufacturing to grow at an annualized growth rate of ~42% over the course of next ten years and be worth over USD 4 billion in 2027.

Research MethodologyThe data presented in this report has been gathered via secondary and primary research. For all our projects, we conduct interviews with experts in the area (academia, industry, medical practice and other associations) to solicit their opinions on emerging trends in the market. This is primarily useful for us to draw out our own opinion on how the market may evolve across different regions and technology segments. Wherever possible, the available data has been checked for accuracy from multiple sources of information.

The secondary sources of information include:- Annual reports - Investor presentations - SEC filings - Industry databases - News releases from company websites - Government policy documents - Industry analysts' views

While the focus has been on forecasting the market over the coming ten years, the report also provides our independent view on various technological and non-commercial trends emerging in the industry. This opinion is solely based on our knowledge, research and understanding of the relevant market gathered from various secondary and primary sources of information.

Chapter Outlines

Chapter 2 is an executive summary of the insights captured in our report. The summary offers a high level view on the current state of the cell therapy manufacturing market and its likely evolution over the coming decade.

Chapter 3 provides a general introduction to the cell-based therapies and ATMPs, their classification and definitions. It includes a detailed discussion on manufacturing of cell-based therapies, associated challenges, and application of the currently available for cell therapies. The chapter also provides a detailed description on the regulatory landscape for cell therapies.

Chapter 4 identifies the contract service providers / in-house manufacturers that are actively involved in the manufacturing of ATMPs. It provides details on the ATMP manufacturing capabilities of these organizations, specifically focusing on the type of organization, geographic location of their facilities, scale of operation, type of cells manufactured and the purpose of manufacturing (in-house requirement / third party manufacturing). It contains world maps highlighting the geographical locations of cell therapy manufacturing facilities. Further, it discusses the development trends within the overall cell therapy manufacturing landscape.

Chapter 5 provides details on the roadmaps published by different organizations in various geographies, specifically in the US. These roadmaps describe the strategies that are helpful in accelerating the translation from laboratory to clinics.

Chapter 6 contains detailed profiles of in-house manufacturers. Each profile provides a brief overview of the company, its financial performance, details on manufacturing capabilities and facilities, and the relevant collaborations that have been inked over the last few years.

Chapter 7 contains detailed profiles of key industrial contract manufacturers that have clinical and / or commercial scale manufacturing capacities. Each profile provides a brief overview of the company, details on manufacturing capabilities and facilities, and the relevant collaborations that have been inked over the last few years.

Chapter 8 contains detailed profiles of key academic players that offer contract manufacturing services for cell therapies. Each profile provides a brief overview of the organization, and details on manufacturing capabilities and facilities.

Chapter 9 discusses the role of non-profit organizations in advancing cellular therapies. It provides a list of prominent organizations and profiles of key organizations in different regions. Additionally, the chapter provides information of international / national societies that help in disseminating knowledge about the advancement of these therapies in the community.

Chapter 10 features a comprehensive analysis of the collaborations and partnerships that have been forged between the players in this market. It includes a brief description on the various types of partnership models that are employed by stakeholders in this domain. We have categorized the deals / agreements, which have been captured during our research, into different models and have provided analysis on trend of partnerships over time.

Chapter 11 presents a ten year forecast to highlight the likely growth of the cell therapy manufacturing market. We have segregated the financial opportunity by type of cell therapy (T-cell immunotherapy, cell-based cancer vaccines, stem cell therapies and other ATMPs) and the source of cells (autologous and allogeneic). All our predictions are backed by robust analysis of data procured from both secondary and primary sources. Due to the uncertain nature of the market, we have presented three different growth tracks outlined as the conservative, base and optimistic scenarios.

Chapter 12 provides a SWOT analysis capturing the key elements and factors that are likely to influence the market's future.

Chapter 13 summarizes the entire report. It presents a list of key takeaways and offers our independent opinion on the current market scenario and evolutionary trends that are likely to determine the future of this segment of the industry.

Chapter 14 presents insights from the survey conducted for this study. We invited over 100 stakeholders involved in the development of different types of cell therapies. The participants, who were primarily Director / CXO level representatives of their respective companies, helped us develop a deeper understanding on the nature of their services and the associated commercial potential.

Chapter 15 is a collection of interview transcripts of the discussions held with key stakeholders in the industry.

Chapter 16 is an appendix, which provides tabulated data and numbers for all the figures in the report.

Chapter 17 is an appendix, which contains the list of companies and organizations that have been mentioned in the report.

SummaryThe use of live cells for therapeutic purposes can be traced back to 1968, when patients were first successfully treated with allogeneic human hematopoietic stem cell transplants. This practice has now become an integral part of clinical procedures in the space of bone marrow regeneration and organ transplantation. Cell-based therapies are an emerging segment of the overall biopharmaceutical industry.

Post the approval of first cell-based therapy, Carticel, in 1997 in the US, the field has rapidly advanced and a number of such therapies are currently under development. Given the personalized nature of these treatment options, they are highly specific and hold the potential to address unmet medical needs associated with the treatment of several disorders. The promising therapeutic potential has led many pharmaceutical companies and investors to put in a significant amount of capital towards the development and commercialization of these therapies.

Popular examples of approved cell-based therapies include (in order of their year of approval) Carticel, CreaVax-RCC, JACE, ReliNethra, PROVENGE and Prochymal. In addition, over 500 cell-based therapy candidates are currently in different stages of clinical development; these are being evaluated in over 1,000 active clinical studies in various regions across the globe. The growing number of cell therapy candidates, coupled with their rapid progression through the various phases of clinical development, continues to create an increasing demand for facilities that offer manufacturing services for these therapies.

The market already has a wide array of well-established players, mid-sized companies and start-ups. Several industry players as well as academic institutes are significantly contributing to the production of GMP grade cell types. In addition, the market has witnessed the entry of several players that offer novel technology solutions, aimed at improving and upgrading existing cell-based therapies and their manufacturing processes. We have observed that such players have signed multiple partnerships / collaborations with an aim to optimize, scale-up and expand the capabilities for production of cell-based therapies.

Looking at the evolutionary trends, we believe that the cell therapy manufacturing market will continue to be steadily driven in the mid to long term by expansion of existing manufacturing facilities and establishment of new dedicated facilities. Technological advancements to mitigate challenges posed by conventional methods of production will act as a key enabler to this growth.

Read the full report: http://www.reportlinker.com/p04796888-summary/view-report.html

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Cell Therapy Manufacturing Market, 2017-2027 - PR Newswire (press release)

Nohla Therapeutics Announces Collaboration with University of … – GlobeNewswire (press release)

March 28, 2017 05:30 ET | Source: Nohla Therapeutics

SEATTLE, March 28, 2017 (GLOBE NEWSWIRE) -- Nohla Therapeutics Inc. (Nohla), a leading innovator in the development of off-the-shelf universal donor cellular therapies, announced today the initiation of a collaboration with the University of California, Davis (UC Davis). Manufacturing and sublease agreements will enable Nohla to utilize UC Davis expertise in cell therapy Good Manufacturing Practices (GMP) and state-of-the-art infrastructure to facilitate the further development and commercialization of NLA101, the Companys expanded off-the-shelf universal donor stem and progenitor cell therapy for treatment of patients with blood cancers.

This collaboration allows Nohla to capitalize on the expertise at UC Davis to scale manufacturing for NLA101 and increase our ability to supply product for multiple clinical trials, commented Katie Fanning, President and Chief Executive Officer of Nohla.

Under a manufacturing agreement, UC Davis will perform clinical manufacturing and quality control testing of NLA101 on behalf of Nohla in the cGMP Cell Therapy Manufacturing Facility at the UC Davis Institute of Regenerative Cures (IRC) in Sacramento, California. Nohla will contribute additional infrastructure to support increased manufacturing capacity at the IRC. This collaboration will allow the Company to manufacture sufficient quantities of NLA101 to supply its clinical trials for Hematopoietic Cell Transplant (HCT) and Chemotherapy Induced Neutropenia (CIN). Further collaborative efforts will refine and optimize the NLA101 manufacturing processes, a key step in achieving commercial viability.

In addition, Nohla has signed a sublease agreement with UC Davis for approximately 2800 sq. ft. of office and laboratory space in the Oak Park Research Center, located adjacent to the IRC. The new facility, staffed by Nohla, will serve as a warehouse and distribution center to supply raw materials to the IRC to be used in GMP manufacturing, and will function as a depot to store and deliver NLA101 to clinical trial sites.

We are particularly excited to partner with Nohla for the development of this groundbreaking technology as it demonstrates our commitment to work with innovative companies developing lifesaving therapies, commented Lars Berglund, Associate Vice Chancellor for Biomedical Research and Vice Dean for Research at UC Davis School of Medicine.

NLA101, Nohlas lead off-the-shelf universal donor product (which does not require any HLA matching), has been used safely across multiple clinical studies in over 100 patients at risk of severe infection and other complications after intensive chemotherapy or cord blood transplantation. This product is currently being evaluated in a multicenter, randomized Phase 2b study in the setting of myeloablative cord blood transplant for leukemia and other blood cancers. The Company also plans to initiate a Phase 2 randomized study in the setting of high dose chemotherapy for acute myelogenous leukemia (AML).

About Nohla Therapeutics

Nohla Therapeutics Inc. (Nohla) is a clinical stage biopharmaceutical company dedicated to the development of universal donor cellular therapies for the treatment of patients with blood cancers and other life threatening conditions. The Company is leveraging a platform developed over the past two decades at Fred Hutchinson Cancer Research Center which enables the ex vivo expansion and directed differentiation of stem/progenitor cells resulting in off-the-shelf universal donor cellular therapies (which can be used on demand without the need for HLA matching). Nohla is evaluating the ability of the first of these off-the-shelf products to reduce infection and other complications of neutropenia in two lead programs involving multi-center, randomized clinical trials: a Phase 2b study in the setting of cord blood transplant and a global Phase 2 study in the setting of high dose chemotherapy for acute myelogenous leukemia (AML). Nohla is supported by top-tier healthcare dedicated institutional investors including ARCH Venture Partners, 5AM Ventures, and Jagen Group.

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Study shows potential of stem cell therapy to repair lung damage – Drug Target Review

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A new study has found that stem cell therapy can reduce lung inflammation in an animal model of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Although, still at a pre-clinical stage, these findings have important potential implications for the future treatment of patients.

Lung damage caused by chronic inflammation in conditions such as COPD and cystic fibrosis, leads to reduced lung function and eventually respiratory failure. Mesenchymal stem cell (MSC) therapy is currently being investigated as a promising therapeutic approach for a number of incurable, degenerative lung diseases. However, there is still limited data on the short and long-term effects of administering stem cell therapy in chronic respiratory disease.

The new research investigated the effectiveness of MSC therapy in a mouse model of chronic inflammatory lung disease, which reflects some of the essential features of diseases such as COPD and cystic fibrosis.

Researchers delivered stem cells intravenously to b-ENaC overexpressing mice at 4 and 6 weeks of age, before collecting samples tissue and cells from the lungs at 8 weeks. They compared these findings to a control group that did not receive the MSC therapy.

The results showed that inflammation was significantly reduced in the group receiving MSC therapy. Cells counts for both monocytic cells and neutrophils, both signs of inflammation, were significantly reduced after MSC therapy. Analysis of lung tissue revealed a reduction in the mean linear intercept and other measures of lung destruction in MSC treated mice. As well as reducing inflammation in the lung, MSC therapy also resulted in significant improvements in lung structure, suggesting that this form of treatment has the potential to repair the damaged lung.

Dr Declan Doherty, from Queens University Belfast, UK, commented, These preliminary findings demonstrate the potential effectiveness of MSC treatment as a means of repairing the damage caused by chronic lung diseases such as COPD. The ability to counteract inflammation in the lungs by utilising the combined anti-inflammatory and reparative properties of MSCs could potentially reduce the inflammatory response in individuals with chronic lung disease whilst also restoring lung function in these patients. Although further research is needed to improve our understanding of how MSCs repair this damage, these findings suggest a promising role for MSC therapy in treating patients with chronic lung disease.

Professor Rachel Chambers, ERS Conferences and Research Seminars Director, commented, This paper offers novel results in a pre-clinical model which demonstrates the potential of MSC stem cell therapy for the treatment of long-term lung conditions with exciting potential implications for the future treatment of patients with COPD and cystic fibrosis. Although, still at an early stage in terms of translation to the human disease situation, this paper aims to provide an international platform to highlight novel experimental lung research with therapeutic potential. We rely on high quality basic and translational respiratory science, such as these latest findings, to develop novel therapeutic approaches for the millions of patients suffering from devastating and often fatal respiratory conditions.

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Study shows potential of stem cell therapy to repair lung damage - Drug Target Review

Cell therapy approach could lead to novel treatments for asthma – Medical Xpress

March 27, 2017 Obstruction of the lumen of a bronchiole by mucoid exudate, goblet cell metaplasia, and epithelial basement membrane thickening in a person with asthma. Credit: Yale Rosen/Wikipedia/CC BY-SA 2.0

The incidence of asthma is increasing steadily, especially in developed countries. One of the reasons given for this rise is excessive levels of hygiene. Epidemiological studies have, indeed, shown that exposure to a so-called "non-hygienic" environment, rich in microbes, plays a protective role against the development of allergies, including asthma. Conversely, an excessively hygienic environment predisposes children to asthma, although the reasons are not known. In allergic reactions such as asthma, the immune system does not function properly and overreacts to harmful allergens present in the environment (pollens, mites, etc.).

In an article published in Immunity, researchers at the University of Lige show that exposure to bacterial DNA (one of the microbial compounds) drastically amplifies a population of pulmonary macrophages and makes them strongly immunosuppressive, which prevents and treats asthma in mice. This discovery offers promising prospects for the development of a cell therapy based on the administration of these regulatory macrophages to asthmatic patients.

Led by Professor Fabrice Bureau (Ordinary Professorand Welbio Investigator - Walloon Excellence in Life Sciences and Biotechnology) and Dr. Thomas Marichal (Research Associate of the F.R.S.-FNRS), both researchers at the GIGA-University of Lige, the scientific team has discovered how a non-hygienic environment, rich in bacterial DNA, helps to protect against asthma. Notably, synthetic compounds mimicking bacterial DNA have been tested in other studies in humans for their therapeutic effect in the treatment of asthma, but until now, none of these compounds have been approved on the market. This may be due to their toxicity or the lack of basic knowledge about their mechanisms of action. Now, the mechanisms of action have been identified, and this study could allow a cell therapy approach that would avoid the use of potentially toxic compounds.

In this study in mice, researchers first looked at how exposure to microbial compounds (such as bacterial wall components, or their own DNA), or whole microbes modifies the immune environment of the lung. They found that bacterial DNA, unlike the other compounds, was able to strongly amplify a population of so-called interstitial macrophages, and that this expansion persisted for several months in the individual.

Surprisingly, if these same macrophages were isolated from a mouse and re-injected into the lungs of a naive recipient mouse, the individual was not capable of developing asthma against house dust mite extracts. Similarly, if these macrophages were transferred to an asthmatic mouse, the asthmatic mouse was cured and no more symptoms of asthma were present. Based on these results, the researchers now envision developing macrophages with similar properties in vitro from monocytes, a white blood cell type found in human blood.

"If it is possible to create a suppressive macrophage from blood monocytes of asthmatic patients, it is quite conceivable to reinject these macrophages into the lungs of these same patients during routine bronchoscopy procedures performed by pneumologists here at the CHU Lige, and to evaluate the therapeutic potential of these cells," concludes Prof. Fabrice Bureau.

Explore further: Scientists discover peptide that could reduce the incidence of RSV-related asthma

More information: "Bacterial CpG-DNA protects against asthma by expanding lung interstitial regulatory macrophages from local and splenic reservoir monocytes." Immunity, 2017.

Journal reference: Immunity

Provided by: University de Liege

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The University of Virginia School of Medicine has again shown that a part of the body thought to be disconnected from the immune system actually interacts with it, and that discovery helps explain cases of male infertility, ...

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Cell therapy approach could lead to novel treatments for asthma - Medical Xpress

Replicel’s cell therapy candidate RCT-01 shows treatment effect in patients with degenerated Achilles tendon – Seeking Alpha

Results from an eight-subject Phase 1/2 clinical trial, ReaCT, assessing a single injection of Replicel Life Sciences' (OTCQB:REPCF) RCT-01 into the Achilles tendon of patients with Achilles tendinosis showed clinically important improvements including pain sensation, physical function, blood supply and tendon composition.

Achilles tendinosis is a degenerative process of the tendon that does to present with signs like inflammation either clinically or by examining tissue samples under a microscope, but is associated with pain and loss of function. There are no effective therapies for the condition.

Participants showed clinically relevant signs of healing six months after injection as measured by an overall 15.3% improvement in a scale called VISA-A. Two patients achieved almost total recovery. Four of five patients who completed questionnaires showed relevant signs of improvement in pain on loading (running/jumping) based on a scale called VAS. The average improvement in VAS score from baseline was 62.9%. Three of the five patients experienced improvements in pain on palpation (feeling the tendon with the hands during a physical exam). The average improvement in VAS score from baseline was 55.2%.

All study participants except one experienced at least one adverse event, either injection site soreness or observation of a partial thickness tear in the tendon after the injection.

RCT-01 is an autologous cell therapy that uses non-bulbar dermal sheath cells isolated from the hair follicle sheath. Developmentis ongoing.

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Replicel's cell therapy candidate RCT-01 shows treatment effect in patients with degenerated Achilles tendon - Seeking Alpha