Stem cell patents a landscape analysis



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The potential therapeutic applications of stem cells are unlimited. However, the ongoing political and social debate surrounding the intellectual property and patenting considerations of stem cell research has led to the implementation of strict legislative regulations. In Australia the patent landscape surrounding stem cells has evolved considerably over the past 20 years. The Australian Patents Act includes a specific exclusion to the patentability of human beings and of biological processes for their generation. However, this exclusion has received no judicial consideration to date, and so its scope and potential impact on stem cell patents is unclear. The stem cell era began with the first bone marrow transplants performed in human patients in

Content:
  • Pascal and Francis Bibliographic Databases
  • Patent Landscape Reports by Other Organizations
  • Biotechnology Patents and Genetically Modified Organisms
  • LULL(ed) into complacency: a perspective on licenses and stem cell translational science
  • An Analysis of the First Three Issued Patents Related to Induced Pluripotent Stem Cells
  • Stem Cell Intellectual Property
  • Industry Sector Lead:
  • Intellectual Property
WATCH RELATED VIDEO: CRISPR Patent Landscape - COMPLETE Breakdown! (CRSP, BEAM, NTLA, CRBU, GRPH, VERV, EDIT)

Pascal and Francis Bibliographic Databases

Eight schizophrenia and 8 control cerebral organoids were studied. Oxygen consumption rate results shown for basal rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption rate as well as values for extracellular acidification rate.

Data collected from 3 technical replicates in each condition and values are shown as median IQR. Normality was tested via Kolmogorov-Smirnov, but because all data were not normally distributed, Mann-Whitney U test was performed. A, Basal: 2-tailed, sum of ranks in control column, ; schizophrenia column, ; Mann-Whitney U ,C, Proton leak: 2-tailed, sum of ranks in control column, ; schizophrenia column, ; Mann-Whitney U ,D, Nonmitochondrial oxygen consumption rate: sum of ranks in control column, ; schizophrenia column, ; Mann-Whitney U,Oxygen consumption rate.

Extracellular acidification rate. Data shown for schizophrenia and control cerebral organoids in the setting of different perturbations. A, Overlap of upregulated differentially expressed genes DEGs with genes expressed in excitatory and inhibitory neurons. B, Overlap of downregulated DEGs with genes expressed in excitatory and inhibitory neurons. C, Quantification of raster plot data collected before and after stimulus. D, Quantification of raster plot data collected with and without 30mM potassium chloride KCl.

Data collected from 4 control and 4 schizophrenia cerebral organoids, with 2 technical replicates in each condition. Values are shown as mean SD. The data have a normal distribution confirmed via Kolmogorov-Smirnov. Unpaired t test with Welch correction: control stimulus vs schizophrenia stimulus, R 2 , 0.

Gene ontology GO analysis of differentially expressed genes DEGs in schizophrenia cerebral organoids. Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response. Not all submitted comments are published. Please see our commenting policy for details. JAMA Psychiatry. Question What cellular processes are dysregulated in cerebral organoids generated from stem cells with patient-specific genetic backgrounds in schizophrenia? Cerebral organoids showed specific deficits in mitochondrial physiology and a diminished response to stimulation and depolarization.

Meaning Patient-specific 3-dimensional brain organoids may reveal differences in specific biological pathways in schizophrenia. Importance Three-dimensional cerebral organoids generated from patient-derived induced pluripotent stem cells iPSCs may be used to interrogate cellular-molecular underpinnings of schizophrenia.

Objective To determine transcriptomic profiles and functional characteristics of cerebral organoids from patients with schizophrenia using gene expression studies, complemented with investigations of mitochondrial function through measurement of real-time oxygen consumption rate, and functional studies of neuronal firing with microelectrode arrays.

Design, Setting, and Participants This case-control study was conducted at Massachusetts General Hospital between andTranscriptomic profiling of iPSC-derived cerebral organoids from 8 patients with schizophrenia and 8 healthy control individuals was undertaken to identify cellular pathways that are aberrant in schizophrenia. Induced pluripotent stem cells and cerebral organoids were generated from patients who had been diagnosed as having schizophrenia and from heathy control individuals.

Main Outcomes and Measures Transcriptomic analysis of iPSC-derived cerebral organoids from patients with schizophrenia show differences in expression of genes involved in synaptic biology and neurodevelopment and are enriched for genes implicated in schizophrenia genome-wide association studies GWAS.

Results The study included iPSC lines generated from 11 male and 5 female white participants, with a mean age ofRNA sequencing data from iPSC-derived cerebral organoids in schizophrenia showed differential expression of genes involved in synapses, in nervous system development, and in antigen processing. Analysis of the gene expression profiles suggested dysregulation of genes involved in mitochondrial function and those involved in modulation of excitatory and inhibitory pathways.

Studies of mitochondrial respiration showed lower basal consumption rate, adenosine triphosphate production, proton leak, and nonmitochondrial oxygen consumption in schizophrenia cerebral organoids, without any differences in the extracellular acidification rate. Microelectrode array studies of cerebral organoids showed no differences in baseline electrical activity in schizophrenia but revealed a diminished response to stimulation and depolarization.

Conclusions and Relevance Investigations of patient-derived cerebral organoids in schizophrenia revealed gene expression patterns suggesting dysregulation of a number of pathways in schizophrenia, delineated differences in mitochondrial function, and showed deficits in response to stimulation and depolarization in schizophrenia. Cellular reprogramming methods enable generation of induced pluripotent stem cells iPSCs from human somatic cells.

Most studies to date of iPSC-derived neurons in schizophrenia have used 2-dimensional neuronal cultures. In this study, iPSCs of 8 patients with schizophrenia and 8 healthy control individuals were used to grow cerebral organoids.

Transcriptomic studies were carried out to identify disease-specific differences in the cerebral organoids. RNA sequencing RNA-seq results showed aberrant gene expression in pathways involved in synaptic biology, nervous system development, immune response, and mitochondrial function and indicated an imbalance in excitatory and inhibitory pathways.

Mitochondrial function was further studied through measurement of oxygen consumption. Functional studies of the cerebral organoids were undertaken using microelectrode arrays, which showed that schizophrenia organoids had basal electrical firing patterns similar to control organoids, but they had a diminished response to electrical stimulation and to depolarization.

These results show the power and utility of interrogating schizophrenia disease biology using 3-dimensional cellular models generated from patient iPSCs. Fibroblasts were collected with approval from McLean Hospital and Massachusetts General Hospital institutional review boards.

Written informed consent was obtained from study participants. Demographic and clinical descriptions are shown in eTable 1 in Supplement 1. Induced pluripotent stem cells were reprogrammed through induction with modified mRNA or with transient transfection with retroviruses eFigure 2A in Supplement 1.

On day 10, the media were switched to expansion media, which was changed every 3 to 4 days. On day 30, brain-derived neurotrophic factor was added to the media, with media changed every 3 to 4 days.

Secondary antibodies diluted in phosphate-buffered saline were applied for 1 hour at room temperature and put on a coverslip using Vectashield Hardset Mounting Medium. Antibodies are listed in eTable 5 in Supplement 1. Total RNA-seq was performed for organoids from 8 patients with schizophrenia and 8 control individuals.

From each sample, we obtained a mean of 60 million reads. For gene expression analyses, trimmed reads with Cutadapt were aligned to the reference genome hg38 UCSC assembly using TopHat, version 2. Differential expression testing was performed using Cuffdiff, version 2. Quantitative polymerase chain reaction validation performed on selected genes are presented in eFigure 5 in Supplement 1.

Default parameters were used to perform gene set enrichment analysis GSEA using the GSEA software for all expressed genes with fragments per kilobase of exon model per million reads mapped values calculated by Cufflinks against following data sets, version 6. Mitochondrial genes were downloaded from the Human MitoCarta2.

The Agilent Seahorse XF Cell Mito Stress Test assay was used to assess mitochondrial respiration in 9-month-old cerebral organoids, measuring the effect of the following perturbations recorded sequentially: 2mM oligomycin, 2mM carbonyl cyanide 4- trifluoromethoxy phenylhydrazone, 2mM rotenone, and 2mM antimycin and rotenone.

Organoids cultured for 9 months were cut into 3 sections and plated on the microplates for the experiments. Data were analyzed with Seahorse Wave desktop software, version 2. Six-month-old organoids were attached to microelectrode array MEA well plates that contained 16 electrodes in each well Med64; Presto and had been coated with poly-L-ornithine and laminin.

Organoids were cultured for 3 more months in MEA plates, media changed twice weekly, and electrical activity recorded when organoids were aged 9 months. After recording spontaneous activity, 10 electrical pulses at 0. While 6-month-old organoids showed no electrical activity, 9-month-old organoids showed regular and consistent activity.

One millimolar tetrodotoxin was added to validate neuronal electrical activity eFigure 2C in Supplement 1. Total RNA-seq was performed on organoids aged 6 months. Principal component analysis revealed a distinct separation between schizophrenia and control organoids eFigure 4C in Supplement 1.

Differentially expressed genes showed a distinct difference in the pattern of gene expression for both coding and noncoding genes between schizophrenia and control organoids eFigure 3A and B in Supplement 1. Differentially expressed genes were categorized into upregulated and downregulated genes, and the top 25 hits were rank ordered according to significance P value eFigure 3C-E in Supplement 1. The most significant GO processes that were downregulated in schizophrenia were nervous system development, neurogenesis, and generation of neurons, while the most upregulated GO processes were antigen processing and presentation of exogenous peptide antigen via major histocompatibility complex class I, extracellular matrix organization, and cellular response to chemical stimulus eFigure 3C in Supplement 1.

Gene ontology localization analysis showed significant downregulation in the neuron, synapse, and neuronal projections categories in schizophrenia while showing upregulation in categories of the endoplasmic reticulum ER , ER to Golgi transport, and extracellular regions eFigure 3D in Supplement 1.

Gene ontology molecular process analysis revealed downregulation of cytoskeletal protein binding and upregulation of peptide antigen binding eFigure 3E in Supplement 1.

The upregulation of genes involved in peptide antigen processing and presentation via MHC class I are interesting because the MHC locus has the strongest genetic association for schizophrenia and is suggestive of aberrant synaptic pruning in schizophrenia. Gene Set Enrichment Analysis enables one to determine whether a set of genes can separate 2 biological categories in a statistically significant manner.

These results indicate pivotal roles for synapse biology in schizophrenia. The enriched pathway for GO localization analysis was the synapse eTable 2 in Supplement 1 , consistent with enrichment for synaptic proteins in schizophrenia risk genes. Twenty-three percent of genes that have genome-wide significance in schizophrenia 38 were differentially regulated in schizophrenia and control organoids: 10 GWAS genes were upregulated in schizophrenia organoids while 15 GWAS genes were downregulated Table.

There is shared genetic susceptibility between neuropsychiatric disorders, reflected in polygenic overlap and shared neuropathology. Gene ontology localization analyses of DEGs shared with autism genes revealed genes localized to the lumenal side of ER membrane. This suggests that shared biology in schizophrenia and autism may be associated with immune signaling and ER stress, consistent with transcriptomic profiling of cortical tissue in schizophrenia and autism that showed shared dysregulation of immune response genes.

Previous postmortem results had reported differences in presynaptic proteins in schizophrenia and bipolar disorder. Gene ontology analyses of DEGs revealed downregulation of the phosphatidylserine and hexadecanoylcarnitine pathways eFigure 7A in Supplement 1. Phosphatidylserine is imported into mitochondria for decarboxylation to form phosphatidylethanolamine via a domain of the ER mitochondria-associated membranes that transiently forms associations between the ER and mitochondria and regulates mitochondrial network morphology.

To examine the role of oxidative stress and mitochondrial dysfunction in schizophrenia, 49 live-cell metabolic experiments were undertaken with a Seahorse Cell Mito Stress Test using 9-month-old organoids. There was significant difference in the oxygen consumption rate between schizophrenia and control organoids in the setting of the different perturbations but not in the extracellular acidification rate Figure 3.

Interestingly, a study in lymphoblastoid cell lines from patients with schizophrenia had previously demonstrated decreased oxygen consumption rates. To investigate DEGs involved in synaptic transmission, a PPI network was built using a network from the neural subtype transcriptome 52 and schizophrenia-associated genes eFigure 4B in Supplement 1. Among upregulated DEGs, genes were expressed in excitatory synapses and 68 in inhibitory synapses, while were expressed in both Figure 4 A.

Among downregulated DEGs, 97 were expressed in excitatory synapses and 72 were expressed in inhibitory synapses, while were expressed in both Figure 4 B. An MEA system was used to evaluate functional properties in organoids. When neuronal firing was measured with electrical stimulation at 0. When spike frequency was measured in setting of neuronal depolarization with 30mM potassium chloride, spike frequencies were again significantly increased in control organoids but not in schizophrenia organoids Figure 4 D; eFigure 8A and 8B in Supplement 1.

These experiments indicate that schizophrenia cerebral organoids have similar baseline electrical activity as control organoids, but they exhibit a diminished response to electrical stimulation and potassium chloride depolarization.


Patent Landscape Reports by Other Organizations

UK, remember your settings and improve government services. We also use cookies set by other sites to help us deliver content from their services. You can change your cookie settings at any time. If you have any queries about our research programme please contact our research team research ipo. If you would like the opportunity to tender for the IPO research please register your interest with our procurement department procurement ipo. Older patent research publications are available from The National Archives. The following reports have been added to the document collection: A worldwide overview of patents in a range of technology areas, including relating to offshore wind power, low-carbon hydrogen, advanced nuclear power, greener vehicles, greener buildings and heat pumps, carbon capture usage and storage patents, and flood and coastal defences.

PCR7, stem cell lines8, genetic diagnostics9, performed a patent landscape analysis to The patent landscape is now in the calm.

Biotechnology Patents and Genetically Modified Organisms

Who owns my DNA? Cumberland Law Review. The authors discuss the problems surrounding federal regulation of cloning and use of embryonic stem cells. Considering the multifaceted and nuanced moral arguments on either side, it is obvious that the subject is far from reaching national, let alone international, legal agreement. Caulfield TA. From human genes to stem cells: new challenges for patent law? Trends in Biotechnology.

LULL(ed) into complacency: a perspective on licenses and stem cell translational science

Human blood is a specialized bodily fluid that amounts to seven to eight percent of human body weight. This essential fluid performs the critical function of transporting oxygen and nutrients to the body cells and transporting back carbon dioxide, ammonia, and other waste products away from cells. Oxygen carrying capacity of human blood to lungs is attributed to the presence of red blood cells RBCs which are of utmost importance. Artificial blood substitutes are being researched and developed as alternatives for replacing RBCs for oxygen carrying capacity. Regular human blood has a shelf life of only 42 days which limits their utilization over more extended periods.

United Kingdom. By Dr.

An Analysis of the First Three Issued Patents Related to Induced Pluripotent Stem Cells

Facebook Twitter Linkedin print rss. How do biotechnology patents affect the generation, use and distribution of genetically modified organisms, such as knockout mice or transgenic animal models? What is a licensing agreement and what are the implications of licensing or not licensing methods and technologies used in biomedical research? Can you use the new model you recently obtained from a collaborator for your research program? What Do Biotechnology Patents Cover? In a nutshell, patents protect intellectual property by granting inventors the right to exclude others from making, using or selling their invention.

Stem Cell Intellectual Property

Louie's deep technical background is the foundation of his patent strategies for biotechnology and pharmaceutical clients. Louie has extensive experience in preparing and prosecuting U. Drafted and prosecuted a ground-breaking small molecule cancer drug developed by a biotechnology start-up company, leading to the acquisition of the patent portfolio by a multi-national pharmaceutical company, and continued representation of the multi-national pharmaceutical company in follow-up patent prosecution to cover intellectual property arising from clinical trials of the small molecule drug. Managed world-wide prosecution of a patent portfolio for a large pharmaceutical company and secured patents covering a small molecule drug that recently received FDA approval. Led strategic planning and execution of company formation, followed by patent portfolio development and management, for a China-based pharmaceutical company with US presence, and continued to advise the client for clinical trial. Developed global patent prosecution strategy for a biotechnology start-up company that has developed a novel class of related small molecule cancer drugs, and assisted IP licensing negotiation with a large pharmaceutical company to out-license a portion of the patent portfolio. Routinely advises international clients from Europe and Asia about US-specific issues such as on sale bar, patent term adjustment, double patenting, and patent term extension under the Hatch-Waxman Act. We do not provide legal advice on this website.

“Induced Pluripotent Stem Cells: A U.S. Patent Landscape Analysis.” Genetic Engineering & Biotechnology News (May

Industry Sector Lead:

Our team of registered patent attorneys partner with you to navigate the complex patent landscape in Australia, New Zealand and across international markets. Obtaining a patent for your invention is complex. And as patents become harder both to get and defend, there are now many factors to consider during the process. Which part of the invention to patent?

Intellectual Property

A comprehensive intellectual property IP protection plan is multi-faceted and specific to your business. When developing biotechnological innovations, patenting is typically the keystone of a solid IP protection plan; however, depending upon your business model, other considerations may be just as important, including: licensing of acquired patents or current applications; analysis of the competitive IP landscape, or due diligence in advance of asset acquisition. Regardless of your specific needs and desires, the attorneys at HRFM provide highly skilled and experienced legal counsel and stand ready to help you achieve your objectives. At HRFM, our Biotechnology practice group has significant experience drafting and prosecuting patent applications for both domestic and international filing, strategically developing and protecting large patent portfolios, and managing U. We also have extensive experience in freedom to operate analysis and opinion writing, agreement drafting, competitive analyses, and due diligence.

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The global intellectual property landscape for induced pluripotent stem cell patents was analyzed. Patent filing trends were reviewed for geographic filing preferences, ownership differences, inventorship distribution, and citation strengths. Although significant growth in this field has been made since , Shinya Yamanaka is still the leading inventor for iPSC patents, and his patent has the most forward citations. Academic and non-profit institutions hold more iPSC patents than for-profit organizations by a ratio ofInduced pluripotent stem cells iPSCs have become essential to regenerative medicine since they were first developed in

Metrics details. The US has had a very successful model for facilitating the translation of a basic discovery to a commercial application. The success of the model has hinged on providing clarity on ownership of a discovery, facilitating the licensing process, providing adequate incentive to the inventors, and developing a self-sustaining model for reinvestment. In recent years, technological, political, and regulatory changes have put strains on this model and in some cases have hindered progress rather than facilitated it.


Watch the video: What are embryonic stem cells? Narrated by Dr. Janet Rossant


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