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The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

Posted in Artificial Intelligence in CANCER, Artificial Intelligence in Medicine - Applications in Therapeutics, Autophagy, Autophagy-Modulating Proteins, BioIT: BioInformatics, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Investment in Technological Breakthrough, Machine Learning, Proteolysis, Proteosome, Signaling, Signaling & Cell Circuits, Technology Transfer: Biotech and Pharmaceutical, Ubiquitin, Ubiquitinylation, Unfolded Protein Response (UPR), tagged Artificial intelligence, biotech startup, early ventures, Machine Learning, philadelphia, PROTAC, Proteovant, Therapeutic innovations, ubiquitin-proteosome, University of Michigan, Venture capital on October 26, 2021| Leave a Comment »

The Vibrant Philly Biotech Scene: Proteovant Therapeutics Using Artificial Intelligence and Machine Learning to Develop PROTACs

Reporter: Stephen J. Williams, Ph.D.

It has been a while since I have added to this series but there have been a plethora of exciting biotech startups in the Philadelphia area, and many new startups combining technology, biotech, and machine learning. One such exciting biotech is Proteovant Therapeutics, which is combining the new PROTAC (Proteolysis-Targeting Chimera) technology with their in house ability to utilize machine learning and artificial intelligence to design these types of compounds to multiple intracellular targets.

PROTACs (which actually is under a trademark name of Arvinus Operations, but is also refered to as Protein Degraders. These PROTACs take advantage of the cell protein homeostatic mechanism of ubiquitin-mediated protein degradation, which is a very specific targeted process which regulates protein levels of various transcription factors, protooncogenes, and receptors. In essence this regulated proteolyic process is needed for normal cellular function, and alterations in this process may lead to oncogenesis, or a proteotoxic crisis leading to mitophagy, autophagy and cellular death. The key to this technology is using chemical linkers to associate an E3 ligase with a protein target of interest. E3 ligases are the rate limiting step in marking the proteins bound for degradation by the proteosome with ubiquitin chains.

Structure-Based PROTAC Design: Project Overview

A review of this process as well as PROTACs can be found elsewhere in articles (and future articles) on this Open Access Journal.

Protevant have made two important collaborations:

Oncopia Therapeutics: came out of University of Michigan Innovation Hub and lab of Shaomeng Wang, who developed a library of BET and MDM2 based protein degraders. In 2020 was aquired by Riovant Sciences.
Riovant Sciences: uses computer aided design of protein degraders

Proteovant Company Description:

Proteovant is a newly launched development-stage biotech company focusing on discovery and development of disease-modifying therapies by harnessing natural protein homeostasis processes. We have recently acquired numerous assets at discovery and development stages from Oncopia, a protein degradation company. Our lead program is on track to enter IND in 2021. Proteovant is building a strong drug discovery engine by combining deep drugging expertise with innovative platforms including Roivant’s AI capabilities to accelerate discovery and development of protein degraders to address unmet needs across all therapeutic areas. The company has recently secured $200M funding from SK Holdings in addition to investment from Roivant Sciences. Our current therapeutic focus includes but is not limited to oncology, immunology and neurology. We remain agnostic to therapeutic area and will expand therapeutic focus based on opportunity. Proteovant is expanding its discovery and development teams and has multiple positions in biology, chemistry, biochemistry, DMPK, bioinformatics and CMC at many levels. Our R&D organization is located close to major pharmaceutical companies in Eastern Pennsylvania with a second site close to biotech companies in Boston area.

Protein degradation
Source: Protevant

The ubiquitin proteasome system (UPS) is responsible for maintaining protein homeostasis. Targeted protein degradation by the UPS is a cellular process that involves marking proteins and guiding them to the proteasome for destruction. We leverage this physiological cellular machinery to target and destroy disease-causing proteins.

Unlike traditional small molecule inhibitors, our approach is not limited by the classic “active site” requirements. For example, we can target transcription factors and scaffold proteins that lack a catalytic pocket. These classes of proteins, historically, have been very difficult to drug. Further, we selectively degrade target proteins, rather than isozymes or paralogous proteins with high homology. Because of the catalytic nature of the interactions, it is possible to achieve efficacy at lower doses with prolonged duration while decreasing dose-limiting toxicities.

Biological targets once deemed “undruggable” are now within reach.

About Riovant Sciences: from PRNewsWire https://www.prnewswire.com/news-releases/roivant-unveils-targeted-protein-degradation-platform-301186928.html

Roivant develops transformative medicines faster by building technologies and developing talent in creative ways, leveraging the Roivant platform to launch “Vants” – nimble and focused biopharmaceutical and health technology companies. These Vants include Proteovant but also Dermovant, ImmunoVant,as well as others.

Roivant’s drug discovery capabilities include the leading computational physics-based platform for in silico drug design and optimization as well as machine learning-based models for protein degradation.

The integration of our computational and experimental engines enables the rapid design of molecules with high precision and fidelity to address challenging targets for diseases with high unmet need.

Our current modalities include small molecules, heterobifunctionals and molecular glues.

Roivant Unveils Targeted Protein Degradation Platform

– First therapeutic candidate on track to enter clinical studies in 2021

– Computationally-designed degraders for six targets currently in preclinical development

– Acquisition of Oncopia Therapeutics and research collaboration with lab of Dr. Shaomeng Wang at the University of Michigan to add diverse pipeline of current and future compounds

– Clinical-stage degraders will provide foundation for multiple new Vants in distinct disease areas

– Platform supported by $200 million strategic investment from SK Holdings

USPTO Guidance On Patentable Subject Matter

Posted in Academic Publishing, Advanced Drug Manufacturing Technology, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Cancer Screening, Cardiac & Vascular Repair Tools Subsegment, Clinical Diagnostics, Computational Biology/Systems and Bioinformatics, Curation, Diagnostic Immunology, Drug Delivery Platform Technology, Ecosystems & Industrial Concentration in the Medical Device Sector, Experimental validation, FDA Regulatory Affairs, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Health Law & Patient Safety, HealthCare IT, Imaging-based Cancer Patient Management, Immunodiagnostics, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Innovations in Neurophysiology & Neuropsychology, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, International Global Work in Pharmaceutical, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Mass automation of plasma proteins, Mechanical Assist Devices: LVAD, RVAD, BiVAD, Artificial Heart, Medical Devices R&D and Inventions, Medical Devices R&D Investment, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Mitral Valve: Repair and Replacement, Monoclonal Immunotherapy, Nanotechnology for Drug Delivery, Open Access Journals, Patents, PCI, Pharmaceutical Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Prescription Drugs Costs, Rapid automation of plasma protein pools, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Stents & Tools, Technology Advance Assessment of, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Valves & Tools, tagged Clinical trial, FDA, FDA innovation route, gene, gene expression, gene patents, genomics, Innovation, Innovation Act, innovative applications, mutation, nanotechnology, research, science, tachnology protection, Therapeutic innovations, US Supreme Court, USPTO on July 3, 2014| Leave a Comment »

USPTO Guidance On Patentable Subject Matter

Curator and Reporter: Larry H Bernstein, MD, FCAP

LH Bernstein

Revised 4 July, 2014

http://pharmaceuticalintelligence.com/2014/07/03/uspto-guidance-on-patentable-subject-matter

I came across a few recent articles on the subject of US Patent Office guidance on patentability as well as on Supreme Court ruling on claims. I filed several patents on clinical laboratory methods early in my career upon the recommendation of my brother-in-law, now deceased. Years later, after both brother-in-law and patent attorney are no longer alive, I look back and ask what I have learned over $100,000 later, with many trips to the USPTO, opportunities not taken, and a one year provisional patent behind me.

My conclusion is

(1) that patents are for the protection of the innovator, who might realize legal protection, but the cost and the time investment can well exceed the cost of startup and building a small startup enterprize, that would be the next step.

(2) The other thing to consider is the capability of the lawyer or firm that represents you. A patent that is well done can be expected to take 5-7 years to go through with due diligence. I would not expect it to be done well by a university with many other competing demands. I might be wrong in this respect, as the climate has changed, and research universities have sprouted engines for change. Experienced and productive faculty are encouraged or allowed to form their own such entities.

(3) The emergence of Big Data, computational biology, and very large data warehouses for data use and integration has changed the landscape. The resources required for an individual to pursue research along these lines is quite beyond an individuals sole capacity to successfully pursue without outside funding. In addition, the changed designated requirement of first to publish has muddied the water.

Of course, one can propose without anything published in the public domain. That makes it possible for corporate entities to file thousands of patents, whether there is actual validation or not at the time of filing. It would be a quite trying experience for anyone to pursue in the USPTO without some litigation over ownership of patent rights. At this stage of of technology development, I have come to realize that the organization of research, peer review, and archiving of data is still at a stage where some of the best systems avalailable for storing and accessing data still comes considerably short of what is needed for the most complex tasks, even though improvements have come at an exponential pace.

I shall not comment on the contested views held by physicists, chemists, biologists, and economists over the completeness of guiding theories strongly held. Only history will tell. Beliefs can hold a strong sway, and have many times held us back.

I am not an expert on legal matters, but it is incomprehensible to me that issues concerning technology innovation can be adjudicated in the Supreme Court, as has occurred in recent years. I have postgraduate degrees in Medicine, Developmental Anatomy, and post-medical training in pathology and laboratory medicine, as well as experience in analytical and research biochemistry. It is beyond the competencies expected for these type of cases to come before the Supreme Court, or even to the Federal District Courts, as we see with increasing frequency, as this has occurred with respect to the development and application of the human genome.

I’m not sure that the developments can be resolved for the public good without a more full development of an open-access system of publishing. Now I present some recent publication about, or published by the USPTO.

DR ANTHONY MELVIN CRASTO

Dr. Melvin Castro – Organic Chemistry and New Drug Development

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USPTO Guidance On Patentable Subject Matter: Impediment to Biotech Innovation

Joanna T. Brougher, David A. Fazzolare J Commercial Biotechnology 2014 20(3):Brougher

jcbiotech-patents

Abstract In June 2013, the U.S. Supreme Court issued a unanimous decision upending more than three decades worth of established patent practice when it ruled that isolated gene sequences are no longer patentable subject matter under 35 U.S.C. Section 101.While many practitioners in the field believed that the USPTO would interpret the decision narrowly, the USPTO actually expanded the scope of the decision when it issued its guidelines for determining whether an invention satisfies Section 101.

The guidelines were met with intense backlash with many arguing that they unnecessarily expanded the scope of the Supreme Court cases in a way that could unduly restrict the scope of patentable subject matter, weaken the U.S. patent system, and create a disincentive to innovation. By undermining patentable subject matter in this way, the guidelines may end up harming not only the companies that patent medical innovations, but also the patients who need medical care. This article examines the guidelines and their impact on various technologies.

Keywords: patent, patentable subject matter, Myriad, Mayo, USPTO guidelines

Full Text: PDF

References

35 U.S.C. Section 101 states “Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.

” Prometheus Laboratories, Inc. v. Mayo Collaborative Services, 566 U.S. ___ (2012)

Association for Molecular Pathology et al., v. Myriad Genetics, Inc., 569 U.S. ___ (2013).

Parke-Davis & Co. v. H.K. Mulford Co., 189 F. 95, 103 (C.C.S.D.N.Y. 1911)

USPTO. Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products.

http://www.uspto.gov/patents/law/exam/myriad-mayo_guidance.pdf

Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948)

USPTO. Guidance For Determining Subject Matter Eligibility Of Claims Reciting Or Involving Laws of Nature, Natural Phenomena, & Natural Products.

http://www.uspto.gov/patents/law/exam/myriad-mayo_guidance.pdf

Courtney C. Brinckerhoff, “The New USPTO Patent Eligibility Rejections Under Section 101.” PharmaPatentsBlog, published May 6, 2014, accessed http://www.pharmapatentsblog.com/2014/05/06/the-new-patent-eligibility-rejections-section-101/

DOI: http://dx.doi.org/10.5912/jcb664

Science 4 July 2014; 345 (6192): pp. 14-15 DOI: http://dx.doi.org/10.1126/science.345.6192.14

IN DEPTH

INTELLECTUAL PROPERTY

Biotech feels a chill from changing U.S. patent rules

Kelly Servick*

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A 2013 Supreme Court decision that barred human gene patents is scrambling patenting policies.

PHOTO: MLADEN ANTONOV/AFP/GETTY IMAGES

A year after the U.S. Supreme Court issued a landmark ruling that human genes cannot be patented, the biotech industry is struggling to adapt to a landscape in which inventions derived from nature are increasingly hard to patent. It is also pushing back against follow-on policies proposed by the U.S. Patent and Trademark Office (USPTO) to guide examiners deciding whether an invention is too close to a natural product to deserve patent protection. Those policies reach far beyond what the high court intended, biotech representatives say.

“Everything we took for granted a few years ago is now changing, and it’s generating a bit of a scramble,” says patent attorney Damian Kotsis of Harness Dickey in Troy, Michigan, one of more than 15,000 people who gathered here last week for the Biotechnology Industry Organization’s (BIO’s) International Convention.

At the meeting, attorneys and executives fretted over the fate of patent applications for inventions involving naturally occurring products—including chemical compounds, antibodies, seeds, and vaccines—and traded stories of recent, unexpected rejections by USPTO. Industry leaders warned that the uncertainty could chill efforts to commercialize scientific discoveries made at universities and companies. Some plan to appeal the rejections in federal court.

USPTO officials, meanwhile, implored attendees to send them suggestions on how to clarify and improve its new policies on patenting natural products, and even announced that they were extending the deadline for public comment by a month. “Each and every one of you in this room has a moral duty … to provide written comments to the PTO,” patent lawyer and former USPTO Deputy Director Teresa Stanek Rea told one audience.

At the heart of the shake-up are two Supreme Court decisions: the ruling last year in Association for Molecular Pathology v. Myriad Genetics Inc. that human genes cannot be patented because they occur naturally (Science, 21 June 2013, p. 1387); and the 2012 Mayo v. Prometheus decision, which invalidated a patent on a method of measuring blood metabolites to determine drug doses because it relied on a “law of nature” (Science, 12 July 2013, p. 137).

Myriad and Mayo are already having a noticeable impact on patent decisions, according to a study released here. It examined about 1000 patent applications that included claims linked to natural products or laws of nature that USPTO reviewed between April 2011 and March 2014. Overall, examiners rejected about 40%; Myriad was the basis for rejecting about 23% of the applications, and Mayo about 35%, with some overlap, the authors concluded. That rejection rate would have been in the single digits just 5 years ago, asserted Hans Sauer, BIO’s intellectual property counsel, at a press conference. (There are no historical numbers for comparison.) The study was conducted by the news service Bloomberg BNA and the law firm Robins, Kaplan, Miller & Ciseri in Minneapolis, Minnesota.

USPTO is extending the decisions far beyond diagnostics and DNA?

The numbers suggest USPTO is extending the decisions far beyond diagnostics and DNA, attorneys say. Harness Dickey’s Kotsis, for example, says a client recently tried to patent a plant extract with therapeutic properties; it was different from anything in nature, Kotsis argued, because the inventor had altered the relative concentrations of key compounds to enhance its effect. Nope, decided USPTO, too close to nature.

In March, USPTO released draft guidance designed to help its examiners decide such questions, setting out 12 factors for them to weigh. For example, if an examiner deems a product “markedly different in structure” from anything in nature, that counts in its favor. But if it has a “high level of generality,” it gets dinged.

The draft has drawn extensive criticism. “I don’t think I’ve ever seen anything as complicated as this,” says Kevin Bastian, a patent attorney at Kilpatrick Townsend & Stockton in San Francisco, California. “I just can’t believe that this will be the standard.”

USPTO officials appear eager to fine-tune the draft guidance, but patent experts fear the Supreme Court decisions have made it hard to draw clear lines. “The Myriad decision is hopelessly contradictory and completely incoherent,” says Dan Burk, a law professor at the University of California, Irvine. “We know you can’t patent genetic sequences,” he adds, but “we don’t really know why.”

Get creative in using Draft Guidelines!

For now, Kostis says, applicants will have to get creative to reduce the chance of rejection. Rather than claim protection for a plant extract itself, for instance, an inventor could instead patent the steps for using it to treat patients. Other biotech attorneys may try to narrow their patent claims. But there’s a downside to that strategy, they note: Narrower patents can be harder to protect from infringement, making them less attractive to investors. Others plan to wait out the storm, predicting USPTO will ultimately rethink its guidance and ease the way for new patents.

Public comment period extended

USPTO has extended the deadline for public comment to 31 July, with no schedule for issuing final language. Regardless of the outcome, however, Stanek Rea warned a crowd of riled-up attorneys that, in the world of biopatents, “the easy days are gone.”

United States Patent and Trademark Office

Today we published and made electronically available a new edition of the Manual of Patent Examining Procedure (MPEP). Manual of Patent Examining Procedure uspto.gov http://www.uspto.gov/web/offices/pac/mpep/index.html Summary of Changes

PDF Title Page
PDF Foreword
PDF Introduction
PDF Table of Contents
PDF Chapter 600 –
PDF Parts, Form, and Content of Application Chapter 700 –
PDF   Examination of Applications Chapter 800 –
PDF Restriction in Applications Filed Under 35 U.S.C. 111; Double Patenting Chapter 900 –
PDF Prior Art, Classification, and Search Chapter 1000 –
PDF  Matters Decided by Various U.S. Patent and Trademark Office Officials Chapter 1100 –
PDF Statutory Invention Registration (SIR); Pre-Grant Publication (PGPub) and Preissuance Submissions Chapter 1200 –
PDF   Appeal Chapter 1300 –
PDF Allowance and Issue Appendix L –
PDF Patent Laws Appendix R –
PDF Patent Rules Appendix P –
PDF Paris Convention Subject Matter Index
PDF Zipped version of the MPEP current revision in the PDF format.

Manual of Patent Examining Procedure (MPEP)Ninth Edition, March 2014

The USPTO continues to offer an online discussion tool for commenting on selected chapters of the Manual. To participate in the discussion and to contribute your ideas go to:
http://uspto-mpep.ideascale.com.

Manual of Patent Examining Procedure (MPEP) Ninth Edition, March 2014
The USPTO continues to offer an online discussion tool for commenting on selected chapters of the Manual. To participate in the discussion and to contribute your ideas go to: http://uspto-mpep.ideascale.com.

Note: For current fees, refer to the Current USPTO Fee Schedule.
Consolidated Laws – The patent laws in effect as of May 15, 2014. Consolidated Rules – The patent rules in effect as of May 15, 2014. MPEP Archives (1948 – 2012)
Current MPEP: Searchable MPEP

See the user manual or quick reference guide for help with search features (e.g., default operators, proximity searches, and wild cards) and navigation.

The documents updated in the Ninth Edition of the MPEP, dated March 2014, include changes that became effective in November 2013 or earlier.
All of the documents have been updated for the Ninth Edition except Chapters 800, 900, 1000, 1300, 1700, 1800, 1900, 2000, 2300, 2400, 2500, and Appendix P.
More information about the changes and updates is available from the “Blue Page – Introduction” of the Searchable MPEP or from the “Summary of Changes” link to the HTML and PDF versions provided below. Discuss the Manual of Patent Examining Procedure (MPEP) Welcome to the MPEP discussion tool!

We have received many thoughtful ideas on Chapters 100-600 and 1800 of the MPEP as well as on how to improve the discussion site. Each and every idea submitted by you, the participants in this conversation, has been carefully reviewed by the Office, and many of these ideas have been implemented in the August 2012 revision of the MPEP and many will be implemented in future revisions of the MPEP. The August 2012 revision is the first version provided to the public in a web based searchable format. The new search tool is available at http://mpep.uspto.gov. We would like to thank everyone for participating in the discussion of the MPEP.

We have some great news! Chapters 1300, 1500, 1600 and 2400 of the MPEP are now available for discussion. Please submit any ideas and comments you may have on these chapters. Also, don’t forget to vote on ideas and comments submitted by other users. As before, our editorial staff will periodically be posting proposed new material for you to respond to, and in some cases will post responses to some of the submitted ideas and comments.Recently, we have received several comments concerning the Leahy-Smith America Invents Act (AIA). Please note that comments regarding the implementation of the AIA should be submitted to the USPTO via email t aia_implementation@uspto.gov or via postal mail, as indicated at the America Invents Act Web site. Additional information regarding the AIA is available at www.uspto.gov/americainventsact We have also received several comments suggesting policy changes which have been routed to the appropriate offices for consideration. We really appreciate your thinking and recommendations!

FDA Guidance for Industry:Electronic Source Data in Clinical Investigations

Electronic Source Data

The FDA published its new Guidance for Industry (GfI) – “Electronic Source Data in Clinical Investigations” in September 2013.
The Guidance defines the expectations of the FDA concerning electronic source data generated in the context of clinical trials. Find out more about this Guidance.
http://www.gmp-compliance.org/enews_4288_FDA%20Guidance%20for%20Industry%3A%20Electronic%20Source%20Data%20in%20Clinical%20Investigations
_8534,8457,8366,8308,Z-COVM_n.html

After more than 5 years and two draft versions, the final version of the Guidance for
Industry (GfI) – “Electronic Source Data in Clinical Investigations” was published in
September 2013. This new FDA Guidance defines the FDA’s expectations for sponsors,
CROs, investigators and other persons involved in the capture, review and retention of
electronic source data generated in the context of FDA-regulated clinical trials.In an
effort to encourage the modernization and increased efficiency of processes in clinical
trials, the FDA clearly supports the capture of electronic source data and emphasizes
the agency’s intention to support activities aimed at ensuring the reliability, quality,
integrity and traceability of this source data, from its electronic source to the electronic
submission of the data in the context of an authorization procedure. The Guidance
addresses aspects as data capture, data review and record retention. When the
computerized systems used in clinical trials are described, the FDA recommends
that the description not only focus on the intended use of the system, but also on
data protection measures and the flow of data across system components and
interfaces. In practice, the pharmaceutical industry needs to meet significant
requirements regarding organisation, planning, specification and verification of
computerized systems in the field of clinical trials. The FDA also mentions in the
Guidance that it does not intend to apply 21 CFR Part 11 to electronic health records
(EHR). Author: Oliver Herrmann Q-Infiity Source: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM328691.pdf Webinar: https://collaboration.fda.gov/p89r92dh8wc

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Targeted delivery of therapeutics to bone and connective tissues: current status and challenges- Part I

Posted in Biomarkers & Medical Diagnostics, Bone Disease and Musculoskeletal Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged 3D, advanced, bone, bone architecture, bone mineral density, bone physiology, bone repair, bone therapeutics, bone turnover, Cell therapy, delivery, nanoparticles, nanotechnology, nanotubes, novel, pharmaceutical drugs, theme, Therapeutic innovations, therapies, Therapy, treatment on September 23, 2012| 22 Comments »

Reporter Aviral Vatsa, PhD MBBS

Annual treatment costs for musculoskeletal diseases in the US are roughly 7.7% (~ $849 billion) of total gross domestic product. Such disorders are the main cause of physical disability in US. Almost half of all chronic conditions in people can be attributed to bone and joint disorders. In addition there is increasing ageing population and associated increases in osteoporosis and other diseases, rising incidences of degenerative intervertebral disk diseases and numbers of revision orthopedic arthroplasty surgeries, and increases in spinal fusions. All these factors contribute towards the increasing requirement of bone regeneration and reconstruction methods and products. Delivery of therapeutic grade products to bone has various challenges. Parenteral administration limits the efficient delivery of drugs to the required site of injury and local delivery methods are often expensive and invasive. The theme issue of Advance Drug Delivery reviews focuses on the current status of drug delivery to bone and the issues facing this field. Here is the first part of these reviews and research articles.

1. Demineralized bone matrix in bone repair: History and use

Abstract

Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive commercial biomaterial and approved medical device used in bone defects with a long track record of clinical use in diverse forms. True to its name and as an acid-extracted organic matrix from human bone sources, DBM retains much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates and some trace cell debris. Many of DBM’s proteinaceous components (e.g., growth factors) are known to be potent osteogenic agents. Commercially sourced as putty, paste, sheets and flexible pieces, DBM provides a degradable matrix facilitating endogenous release of these compounds to the bone wound sites where it is surgically placed to fill bone defects, inducing new bone formation and accelerating healing. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopedic repair and regenerative medicine contexts are attractive.

2. Biomimetic hydrogels for controlled biomolecule delivery to augment bone regeneration

Abstract

The regeneration of large bone defects caused by trauma or disease remains a significant clinical problem. Although osteoinductive growth factors such as bone morphogenetic proteins have entered clinics, transplantation of autologous bone remains the gold standard to treat bone defects. The effective treatment of bone defects by protein therapeutics in humans requires quantities that exceed the physiological doses by several orders of magnitude. This not only results in very high treatment costs but also bears considerable risks for adverse side effects. These issues have motivated the development of biomaterials technologies allowing to better control biomolecule delivery from the solid phase. Here we review recent approaches to immobilize biomolecules by affinity binding or by covalent grafting to biomaterial matrices. We focus on biomaterials concepts that are inspired by extracellular matrix (ECM) biology and in particular the dynamic interaction of growth factors with the ECM. We highlight the value of synthetic, ECM-mimicking matrices for future technologies to study bone biology and develop the next generation of ‘smart’ implants.

3. Calcium phosphate cements as drug delivery materials

Abstract

Calcium phosphate cements are used as synthetic bone grafts, with several advantages, such as their osteoconductivity and injectability. Moreover, their low-temperature setting reaction and intrinsic porosity allow for the incorporation of drugs and active principles in the material. It is the aim of the present work to: a) provide an overview of the different approaches taken in the application of calcium phosphate cements for drug delivery in the skeletal system, and b) identify the most significant achievements. The drugs or active principles associated to calcium phosphate cements are classified in three groups, i) low molecular weight drugs; ii) high molecular weight biomolecules; and iii) ions.

4. Silk constructs for delivery of musculoskeletal therapeutics

Abstract

Silk fibroin (SF) is a biopolymer with distinguishing features from many other bio- as well as synthetic polymers. From a biomechanical and drug delivery perspective, SF combines remarkable versatility for scaffolding (solid implants, hydrogels, threads, solutions), with advanced mechanical properties and good stabilization and controlled delivery of entrapped protein and small molecule drugs, respectively. It is this combination of mechanical and pharmaceutical features which renders SF so exciting for biomedical applications. This pattern along with the versatility of this biopolymer has been translated into progress for musculoskeletal applications. We review the use and potential of silk fibroin for systemic and localized delivery of therapeutics in diseases affecting the musculoskeletal system. We also present future directions for this biopolymer as well as the necessary research and development steps for their achievement.

5. Demineralized bone matrix as a vehicle for delivering endogenous and exogenous therapeutics in bone repair

Abstract

As a unique human bone extract approved for implant use, demineralized bone matrix (DBM) retains substantial amounts of endogenous osteoconductive and osteoinductive proteins. Commercial preparations of DBM represent a clinically accessible, familiar, widely used and degradable bone-filling device, available in composite solid, strip/piece, and semi-solid paste forms. Surgically placed and/or injected, DBM releases its constituent compounds to bone sites with some evidence for inducing new bone formation and accelerating healing. Significantly, DBM also has preclinical history as a drug carrier by direct loading and delivery of several important classes of therapeutics. Exogenous bioactive agents, including small molecule drugs, protein and peptide drugs, nucleic acid drugs and transgenes and therapeutic cells have been formulated within DBM and released to bone sites to enhance DBM’s intrinsic biological activity. Local release of these agents from DBM directly to surgical sites in bone provides improved control of dosing and targeting of both endogenous and exogenous bioactivity in the context of bone healing using a clinically familiar product. Given DBM’s long clinical track record and commercial accessibility in standard forms and sources, opportunities to formulate DBM as a versatile matrix to deliver therapeutic agents locally to bone sites in orthopedic repair and regenerative medicine contexts are attractive.

6. Nanofiber-based delivery of bioactive agents and stem cells to bone sites

Abstract

Biodegradable nanofibers are important scaffolding materials for bone regeneration. In this paper, the basic concepts and recent advances of self-assembly, electrospinning and thermally induced phase separation techniques that are widely used to generate nanofibrous scaffolds are reviewed. In addition, surface functionalization and bioactive factor delivery within these nanofibrous scaffolds to enhance bone regeneration are also discussed. Moreover, recent progresses in applying these nanofiber-based scaffolds to deliver stem cells for bone regeneration are presented. Along with the significant advances, challenges and obstacles in the field as well as the future perspective are discussed.

7. Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone

Abstract

Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health and economic consequences. To overcome such healing deficits, various concepts for a local drug delivery to bone have been developed during the last decades. However, in many cases these concepts do not meet the specific requirements of either surgeons who must use these strategies or individual patients who might benefit from them. We describe currently available methods for local drug delivery and their limitations in therapy. Various solutions for drug delivery to bone focusing on clinical applications and intra-operative constraints are discussed and drug delivery by implant coating is highlighted. Finally, a new set of design and performance requirements for intra-operatively customized implant coatings for controlled drug delivery is proposed. In the future, these requirements may improve approaches for local and intra-operative treatment of patients.

8. Local delivery of small and large biomolecules in craniomaxillofacial bone

Abstract

Current state of the art reconstruction of bony defects in the craniomaxillofacial (CMF) area involves transplantation of autogenous or allogenous bone grafts. However, the inherent drawbacks of this approach strongly urge clinicians and researchers to explore alternative treatment options. Currently, a wide interest exists in local delivery of biomolecules from synthetic biomaterials for CMF bone regeneration, in which small biomolecules are rapidly emerging in recent years as an interesting adjunct for upgrading the clinical treatment of CMF bone regeneration under compromised healing conditions. This review highlights recent advances in the local delivery small and large biomolecules for the clinical treatment of CMF bone defects. Further, it provides a perspective on the efficacy of biomolecule delivery in CMF bone regeneration by reviewing presently available reports of pre-clinical studies using various animal models.

9. Immobilized antibiotics to prevent orthopaedic implant infections

Abstract

Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal–antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection.

10. Local delivery of nitric oxide: Targeted delivery of therapeutics to bone and connective tissues

Abstract

Non-invasive treatment of injuries and disorders affecting bone and connective tissue remains a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several important roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair.

Bibliography

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History of medicine, science, and society: 200 Years of the New England Journal of Medicine

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Infectious Disease & New Antibiotic Targets, Medical and Population Genetics, Population Health Management, Genetics & Pharmaceutical, tagged Allan M. Brandt, Ether Dome, John Collins Warren, Massachusetts General Hospital, Massachusetts Medical Society, Medical Knowledge, New England, New England Journal of Medicine, Science and Medicine, Therapeutic innovations on July 2, 2012| 1 Comment »

New England Journal of Medicine an Interview with Allan M. Brandt, Ph.D.

N Engl J Med 2012; 366:1-7 January 5, 2012

http://www.nejm.org/doi/full/10.1056/NEJMp1112812

Reporter: Aviva Lev-Ari PhD, RN

With this issue, the New England Journal of Medicine marks its 200th anniversary. In January 1812, as the first issue came off the handset letterpress, few of its founders could have predicted such continuity and success. (See Figure 1FIGURE 1Illustration from “Cases of Organic Diseases of the Heart and Lungs,” by John C. Warren, April 1, 1812, Issue of the Journal., from an 1812 issue.) John Collins Warren, the renowned Boston surgeon, his colleague James Jackson, a founder of Massachusetts General Hospital, and the small group of distinguished colleagues who joined them in starting the New England Journal of Medicine and Surgery, and the Collateral Branches of Science expressed modest and largely local aspirations for the enterprise. Boston, a growing urban center, and the wider New England environs had no medical journal of their own, although much medical knowledge and practice was considered region-specific. Although the name and format of the Journal would vary until 1928, 7 years after its ownership passed to the Massachusetts Medical Society, it remains the longest continuously published medical periodical in the world. The prospectus for the Journal, a call for papers issued in late 1811, explained the goals of Warren and his collaborators: “The editors have been encouraged to attempt this publication by the opinion, that a taste for medical literature has greatly increased in New England within a few years past. New methods of practice, good old ones which are not sufficiently known, and occasional investigations of the modes in common use, when thus distributed among our medical brethren in the country, will promote a disposition for inquiry and reflection, which cannot fail to produce the most happy results.”1

At a time of intense debate and controversy regarding the causes of disease, the nature of therapeutics, and the basis of professional authority, the young Journal worked to steer a middle course. This was certainly advisable from a commercial point of view, since it could easily alienate diverse medical readers by endorsing a particular therapeutic system or theory. But this approach also established the ecumenical temper of theJournal, which based its early publications on a commitment to empirical observation and an outlook skeptical of conventional medical wisdoms. As the editors explained in 1837, “It has been a point of ambition with us . . . to make these pages the vehicle of useful intelligence, rather than the field of warfare. . . . The Journal is to all intents and purposes, designed to be a record of medical and surgical facts. It is the medium through which the profession may interchange sentiments and publish the results of their experience” (see Historical Journal Articles Cited).

THE ENDURING PROBLEM OF DISEASE

The observation and investigation of disease is perhaps the most salient consistent feature of theJournal. From the meticulous description of angina pectoris in the first issue to the early descriptions of AIDS in the early 1980s, there has been an ongoing recognition that therapeutic approaches must await the sharp articulation of symptoms. The first decades of the Journal‘s history reflected the intensive concern with the epidemics affecting New England and the new nation, and it was not unusual during the early years for authors to direct attention to the environment as a critical variable in the production of disease. John Gorham, an editor writing in 1828, offered a “Medical Report of the Weather and Prevalent diseases for the last Three months.” Such articles may appear both quaint and humorous from our contemporary scientific perch, but they reveal a serious commitment to understanding more fully the vagaries of epidemic disease that could devastate town and country in short order. Furthermore, they offer a complex notion of causality that characterized much 19th-century medicine, in which disease was seen as the result of interactions of the patient’s individual “constitution” with an ever-changing and often dangerous environment.2 By the late 20th century, many observers would renew concerns voiced more than a century earlier about the environment’s relationship to disease.

DOCUMENTING THERAPEUTIC INNOVATION

The Journal provides a powerful record of the course taken by medical science and its applications over a 200-year period. It quickly became a conduit for reporting new investigations and findings and for summarizing and disseminating evolving medical knowledge across the widest range of practice. After issuing favorable reports on bloodletting, herbal treatments, and other “heroic” practices of the early 19th century, the Journal began to reflect a growing skepticism toward such approaches. Authors increasingly pointed to the benefits of the healing powers of nature — vis medicatrix naturae — as physicians came to recognize some of the iatrogenic effects of their interventions that had previously been difficult to differentiate from the course of serious disease.3Therapeutics based on ancient notions of humoral excess and depletion gave way to a renewed emphasis on empirical observation and experiment. The first demonstration of surgical anesthesia, conducted at Massachusetts General Hospital in 1846 in an amphitheater soon to be renamed the “Ether Dome,” was first reported in the Journal (Figure 2FIGURE 2“First Operation under Ether,” 1846, with Related Journal Report.). Others quickly began using ether in their practices. One surgeon wrote in the Journal, “I performed the amputation of an arm, the second under the use of ether, while the patient was dreaming of her harvest labors in Ireland, and felt grating but not painful sensations, `as if a reaping-hook was in her arm’” (1850).

EDUCATION AND THE DISSEMINATION OF MEDICAL KNOWLEDGE

From the beginning, the Journal has critically covered essential debates about the character and quality of medical education. The editors considered one of their primary goals to be educating the profession, so assessment of medical school programs was in harmony with their mission; after all, these schools produced their readers. In the late 19th century, the Journal frequently noted the great inconsistencies in educational standards and quality. A decade before the publication of the Flexner reforms, prominent Boston physician Henry Bowditch anticipated many key aspects of the report when he called for linking medical education to universities, lengthening the course of study, and demanding deeper preparation in the sciences and wider domains of knowledge (1900). He argued for active learning to replace didactics, a theme that would echo through the debates about medical education. As late as 1900, when Bowditch proposed his reforms in the Journal, less than half the students at Harvard Medical School had completed a college education. After the publication of the Flexner Report in 1910 and the massive changes that followed, the Journalapplauded the consolidation of medical education on a new scientific foundation.

TOO MUCH TO KNOW

With the radical expansion and shifting of the scientific basis of medicine at the turn of the 20th century, the Journal recorded growing interest in and concern about specialization. From a largely undifferentiated notion of medical training and expertise, many new and specific divisions of the medical profession developed.6 Whereas the Journal came to view specialization as the inevitable result of exploding medical knowledge, the creation of medical “specializm” was viewed with considerable skepticism and lamentation, if not outright hostility. Much ink was spilled in attempts to determine the relationship of general knowledge and practice to increasingly specific (and limited) areas of expertise. How would the “whole patient” be treated when specialties had divided the body into organ systems and medicine into categories of disease and authority over various technologies and techniques?

THE PERMEABLE BOUNDARIES OF SCIENCE AND MEDICINE

Despite the Journal‘s deep commitment to empirical reasoning and scientific rationality, cultural and political beliefs and values are ever apparent in its pages. In some instances, professional prerogatives and social assumptions are exposed. For example, when the introduction of women students at Harvard Medical School was debated in 1878, the Journal expressed concern: “It would . . . be impossible to avoid an indiscriminate mingling of the sexes in the dissecting or autopsy rooms, and in the amphitheatres, to witness exercises which justly have hitherto been thought of a character to be witnessed by one sex alone.” Harvard would ultimately admit women in 1945, when the war caused a shortage of male candidates. In the 1950s, the Journal expressed regret that some women physicians with children “have found it impossible to carry on their practices” (1954).

REFLECTIONS ON THE JOURNAL AT 200

While the Journal embraced new science and the critical apparatus of peer review, it rejected a narrow notion of specialism, continuing to cover the widest range of contributions to medical knowledge. In an increasingly atomized medical world, the commitment to publish on cross-cutting educational, professional, ethical, and policy issues pulled together diverse readers, including physicians and other health care providers, public health experts, and policymakers, around issues that were often beyond their immediate expertise. The radical growth of teaching hospitals, federal funding for basic science and clinical research, and academic medical centers (all developments reflected in the Journal) have been crucially linked to the Journal‘s growth, stability, and success.

During the Journal’s first 200 years of publication, medicine and health care moved from the social periphery to become dominant aspects of our science, culture, and economy. The Journalunquestionably owes its success and stability to this monumental shift in the status, authority, and impact of biomedicine. But the Journal has also played a critical role in these developments. By combining a commitment to publishing papers of scrupulous scientific merit across wide-ranging domains, with a recognition of the central questions and values uniting the profession, the Journalhas remained true to its founders’ vision. It has recognized that advances in medical science can finally be assessed only in the context of delivery, care, and outcome. The Journal reflects today, as at its inception, a view that medical science and its applications are fundamentally tied to patient care and public health. It therefore continues to draw a range of readers wider than Warren could have imagined. Today, the ability to disseminate publications so widely through digital technologies promises to bring innovations in medical knowledge to a new set of global constituents. The first hundred issues of Warren’s journal were, of course, distributed on horseback.