Treating Asthma with Stem Cells | Technology Networks – Technology Networks

A study led by scientists at Monash University has shown that a new therapy developed through stem cell technology holds promise as a treatment for chronic asthma.

The Monash Biomedicine Discovery Institute (BDI) scientists provided the experimental expertise to test Cynata Therapeutics induced pluripotent stem cell-derived mesenchymal stem cells (MSCs) in a model of experimental asthma. Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from adult cells; they have the ability to be differentiated into a variety of tissue types and, in this case, MSCs that can regenerate damaged lung tissue.

Lead researchers Associate Professor Chrishan Samuel and Dr Simon Royce tested the efficacy of the MSCs on three key components of asthma in a preclinical model of chronic allergic airways disease: inflammation; airway remodeling (structural changes that occur in lungs as a result of prolonged inflammation); and airway hyperresponsiveness (the clinical symptom of asthma).

The study, published in the FASEB Journal, found that the MSCs could effectively reduce inflammation, reversed signs of airway remodelling and completely normalised airway/lung fibrosis and airway hyperresponsiveness, particularly when delivered intranasally.

It concluded that they may provide a novel stand-alone therapy or an adjunct therapy for groups of asthma sufferers who do not respond to current (corticosteroid) therapy.

Most importantly, what we found was you can treat fibrosis (hardening or scarring of the lung) very effectively, said Associate Professor Samuel, who heads the Monash BDIs Fibrosis Laboratory.

When weve tested other types of stem cells they havent been able to fully reverse scarring and lung dysfunction associated with asthma weve had to combine them with anti-scarring drugs to achieve that. These cells were remarkable on their own as they were able to effectively reverse the scarring that contributes to lung dysfunction and difficulty in breathing, he said.

One in nine - or around 2.5 million- Australians have asthma.

Further research will be conducted to test the MSCs in combination with, or compared to a clinically-used corticosteroid. Clinical trials using the cells as a novel target for asthma are then envisaged.

Cynata Therapeutics Limited is an Australian clinical-stage stem cell and regenerative medicine company developing therapies based on its proprietary Cymerus stem cell technology platform.

This article has been republished frommaterialsprovided by Monash University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Royce, S. G., Rele, S., Broughton, B. R., Kelly, K., & Samuel, C. S. (2017). Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease. The FASEB Journal. doi:10.1096/fj.201700178r

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Evotec in neurology iPSC drug discovery collaboration with stem-cell specialist Censo – FierceBiotech

Evotec has reached a collaboration with Censo Biotechnologies, using the latters patient-derived induced pluripotent stem cells (iPSC) to expand its platform for drug discovery.

Scientists get iPSCs by reprograming human adult somatic cells to make them resemble embryonic stem cells, which can become any cell type of the body. For this alliance, Censo will use its donors sourcing and cell reprograming technologies to create a bespoke library of hundreds of patient-derived iPS cell lines, and Evotec will use them for target validation, drug screening, drug metabolism and pharmacokinetics analyses.

These stem cell-like cells created from people suffering from a disease allow researchers to replicate or mimic the disease ex vivo under lab conditions. This approach is particularly helpful for understanding of the mechanism of diseases such as Parkinsons and Alzheimers. The current contract between Evotec and Censo, with an initial two-year term, will first focus on central nervous system diseases, an area that both companies excel in.

RELATED:Axiogenesis in stem cell collab with ion channel expert Metrion

The Hamburg, Germany-based Evotec has been involved in neurological research for over two decades, having taken part in the discovery process of about a dozen preclinical candidates. The CROs expertise spans some key target classes such as enzymes, GPCRs and ion channels, and in therapeutic areas of neurodegenerative diseases, neuroinflammation, among others.

Censo is the product of a 2016 merger between Roslin Cellab and Roslin Cell Sciencestwo spinouts from the Roslin Institute both focused on using stem cells for drug discovery. Operating from its Edinburgh and Cambridge facilities in the U.K., Censo can generate iPSCs from large cohorts of samples for drug researches, and usually partner with other companies for assay development.

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Evotec in neurology iPSC drug discovery collaboration with stem-cell specialist Censo - FierceBiotech

The Stem Cell Revolution – Seeking Alpha

By Manisha Samy, ARK analyst

Discovered nearly thirty years ago in 1988[1], stem cell technology has failed to transform the field of regenerative medicine until now. After delivering only one treatment during three decades of development, stem cell technology could finally become the all-purpose tool for repairing the body, thanks to rapid and precise genome editing techniques such as CRISPR and TALENs. Several obstacles in stem cell technology- high costs, safety concerns, and bioethical considerations are beginning to fall away. In particular, the introduction of induced pluripotent stem cells (iPSCs) eliminated many of the initial bioethical concerns stirred by the the source of stem cells. Now, advances in genome-editing is accelerating the pace of progress.

Stem cells exist in a state of possibility. Two key markers of stem cells are 1) the ability to self-renew and 2). The ability to become any specialized cell. Broadly speaking, a stem cell can evolve into any of the ~200 specialized human cell types, as illustrated in Figure 1. Directing stem cells to become any one of the 200 cell types has proven challenging.

Moreover, before the introduction of iPSCs, which are derived from adult cells, most human stem cells were sourced from human embryos or cord blood. The political and ethical controversies surrounding embryonic research curtailed stem cell funding. As a result, after a quarter century of research, bone marrow transplantation is the only FDA-approved stem cell application in the United States.

Figure 1

Breakthroughs in cheap, rapid genome-editing have re-invogored momentum in stem cell research. As shown in Figure 2, the number of publications on PubMed mentioning both stem cells and gene-editing hit a tipping point upon the discovery of CRISPR in 2012, three years after the first instance of precise TALENs-based genome-editing in human cells. Based on the current trajectory, ARK estimates that the number of scientific publications including both genome-editing and stem cells will approach 300 this year, accounting for nearly 20% of the total number of publications.

Figure 2

As illustrated in Figure 3, while the discovery of iPSC cells in 2006 boosted stem cell research noticeably beginning in 2008, the introduction of CRISPR in 2012 has further catapulted the stem cell field, with combined gene-editing and stem cell publications taking share.

Figure 3

Why Is The Addition of Gene-Editing So Important to Stem Cell Research and Therapy?

Figure 4

Ultimately, CRISPR edited iPSCs should unlock the code to human disease at a cellular level. Three public CRISPR companies are in a good position for the impending stem cell revolution. Editas Medicine (EDIT) signed a stem cell pact with GlaxoSmithKline (GSK) and Biogen (BIIB) for next-gen stem-cell therapies; CRISPR Therapeutics (CRSP) CRSP),+Casebia+Therapeutics+Sign+Commercial+License+Agreement+to+MaxCyte/12664463.html" rel="nofollow">licensed a CRISPR delivery mechanism for blood stem cells and has formed a CRISPR joint venture with Bayer (BAYZF); and Intellia Therapeutics (NTLA) has partnered with biotech giant Novartis NVS to focus on stem-cell based therapies. These companies, among others, finally might unleash the limitless possibilities that stem cells once promised in regenerative medicine, extending human life spans considerably.

Notes

[1] The Weissman Lab at Stanford University first isolated hematopoietic (blood) stem cells from mice bone marrow in 1988; it would be another decade before human stem cells were isolated.

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Disclaimer: 2017, ARK Investment Management LLC ("ARK"). All content is original and has been researched and produced by ARK unless otherwise stated. No part of ARK's original content may be reproduced in any form, or referred to in any other publication, without the express written permission of ARK. The content is available for informational purposes only and is subject to change without notice. All statements made regarding companies or securities or other financial information on this site or any sites relating to ARK are strictly beliefs and points of view held by ARK or the third party making such statement and are not endorsements by ARK of any company or security or recommendations by ARK to buy, sell or hold any security. For a list of all purchases and sales made by ARK for client accounts during the past year that could be considered by the SEC as recommendations, click here. It should not be assumed that recommendations made in the future will be profitable or will equal the performance of the securities in this list. For full disclosures, please see the Terms of Use for this site.

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The Stem Cell Revolution - Seeking Alpha

When C9ORF72 Silences U2, Spliceosomes Can’t Find What They … – Alzforum

30 Jun 2017

Expanded C9ORF72 hexanucleotide repeats cause many cases of amyotrophic lateral sclerosis and frontotemporal dementia, but exactly how these expansions work their mischief remains a mystery. Researchers have proposed several different pathogenic mechanisms, including that aberrant dipeptide repeat (DPR) proteins made from the expansion interfere with mRNA splicing. In the June 13 Cell Reports, researchers led by Robin Reed at Harvard Medical School describe how this could happen. Using in vitro assays, they found that DPRs prevented spliceosome assembly through interactions with one portion of this splicing complex, the U2 small nuclear ribonucleoprotein (snRNP) particle. In cells, C9ORF72 DPRs caused the U2 complex to mislocalize to the cytoplasm, away from splicing sites in the nucleus. Subsequent bioinformatics analyses suggested that disruption of U2 function accounts for about 40 percent of the mis-splicing seen in C9ORF72 patient cells, Reednoted.

The data for the mechanism are compelling, but it remains unclear how much it contributes to neurotoxicity, noted Johnathan Cooper-Knock at the University of Sheffield, England, in an email to Alzforum. He was not involved in the research. One way to address this might be to examine its correlation with clinical phenotype, he suggested (see full commentbelow).

In control motor neurons (left), the U2 splicing complex (red) occupies the nucleus, but in C9ORF72 motor neurons (right), much of it lurks in cytoplasm. [Courtesy of Cell Reports, Yin etal.]

Previous research had found that C9ORF72 expansions caused mis-splicing in cultured cells (see Aug 2014 news; Conlon et al., 2016). In one study, the degree of this mis-splicing correlated with faster ALS progression (Cooper-Knock et al., 2015).The papers proposed different explanations for how mis-splicing occurred, however, from dipeptide repeat proteins physically gumming up the splicing machinery in the nucleolus to C9ORF72-expanded RNAs sequestering crucial splicing factors such asHNRNPH.

To try to nail down the mechanism, first author Shanye Yin used a cell-free system developed in the Reed lab that combined nuclear extract from HeLa cells with a DNA template for the fly Ftz gene. In this assay, the Ftz gene is transcribed by RNA polymerase and the resulting RNA is then spliced to yield mature transcript. However, when the authors added a 20-repeat length of the toxic DPRs glycine-arginine (GR) or proline-arginine (PR), splicing ground to a halt. The effectiveness of the block depended on the dose of DPR. Further analysis showed that in the presence of DPRs, the spliceosome failed to assemble properly. C9ORF72 RNA, by contrast, had no effect on splicing in thissystem.

The authors next searched for proteins that associated with GR and PR using pull-down assays, and identified these interactors by mass spectrometry. The most common were components of the U2 snRNP, although other proteins were present as well. The list of interacting proteins largely matches that seen in previous proteomic screens of DPRs, noted Paul Taylor at St. Jude Childrens Research Hospital in Memphis, Tennessee. That gives us confidence in the data, he toldAlzforum.

The findings suggested a direct interaction of DPRs with the splicing machinery in vitro. Would the same thing happen in patients? The authors examined motor neurons made from induced pluripotent stem cells of people who carried the C9ORF72 expansion. They were surprised to find U2 snRNP lingering outside the nucleus in about half these cells (see image above). It was unclear if the complex leaked out of the nucleus, or simply never made it inside in the first place, Reed noted. U2 snRNP is assembled in the cytoplasm, and faulty transport across the nuclear membrane has quickly become a hallmark of C9ORF72 disease, with many nuclear proteins, such as TDP43 and FUS, getting stuck en route (Jan 2010 news;Aug 2015 news).DPRs are known to build up in the cytoplasm, suggesting they could be sequestering the U2 snRNP there. Overexpressing PR in HeLa cells also caused U2 snRNP to loiter in cytoplasm, supporting a direct causal role for these peptides in U2 mislocalization. This was specific to U2, as other components of the splicing apparatus stayed confined to thenucleus.

The authors next wondered how big a role U2 mis-splicing might play in disease. U2 snRNP normally helps splice about one-quarter of all transcripts (see Kfir et al., 2015). Analyzing published RNA expression data from C9ORF72 cerebella and frontal cortices (Prudencio et al., 2015), the authors found that the mis-spliced mRNA was enriched for U2-dependent transcripts. Altogether, U2 snRNP may account for nearly half of the mis-splicing in these cells, they calculated. They saw a much smaller role for HNRNPH-dependent splicing. Notably, in brain samples from sporadic ALS cases, U2-dependent transcripts were no more likely to be mis-spliced than any others, indicating this mechanism is specific for C9ORF72expansions.

In theory, mis-splicing could lead to toxicity by knocking out essential proteins. In support of this, the authors found numerous transcripts involved in mitochondrial function and gene expression among the disrupted set. Both of these processes are known to be perturbed inALS.

However, DPRs sequester other proteins as well, which may play an equally important role in damaging cell function, Taylor noted. Many of the proteins bound by DPRs contain low-complexity domains. Such proteins are now believed to be crucial in assembling many cellular organelles (Oct 2015 webinar; May 2017 conference news).Madolyn BowmanRogers

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When C9ORF72 Silences U2, Spliceosomes Can't Find What They ... - Alzforum