With faster, cheaper, more precise technique, authors say it’s ‘off to the races’ toward new cell therapies

Date:
July 11, 2018

Source:
University of California – San Francisco

Summary:
In an achievement that has significant implications for research, medicine, and industry, scientists have genetically reprogrammed the human immune cells known as T cells without using viruses to insert DNA. The researchers said they expect their technique — a rapid, versatile, and economical approach employing CRISPR gene-editing technology — to be widely adopted in the burgeoning field of cell therapy, accelerating the development of new and safer treatments for cancer, autoimmunity, and other diseases, including rare inherited disorders.

 

The research team created CRISPR guides that would cause green fluorescent protein to be expressed in only certain cellular locations and structures.
Credit: Alex Marson’s Lab.

 

 

In an achievement that has significant implications for research, medicine, and industry, UC San Francisco scientists have genetically reprogrammed the human immune cells known as T cells without using viruses to insert DNA. The researchers said they expect their technique — a rapid, versatile, and economical approach employing CRISPR gene-editing technology — to be widely adopted in the burgeoning field of cell therapy, accelerating the development of new and safer treatments for cancer, autoimmunity, and other diseases, including rare inherited disorders.

The new method, described in the July 11, 2018 issue of Nature, offers a robust molecular “cut and paste” system to rewrite genome sequences in human T cells. It relies on electroporation, a process in which an electrical field is applied to cells to make their membranes temporarily more permeable. After experimenting with thousands of variables over the course of a year, the UCSF researchers found that when certain quantities of T cells, DNA, and the CRISPR “scissors” are mixed together and then exposed to an appropriate electrical field, the T cells will take in these elements and integrate specified genetic sequences precisely at the site of a CRISPR-programmed cut in the genome.

“This is a rapid, flexible method that can be used to alter, enhance, and reprogram T cells so we can give them the specificity we want to destroy cancer, recognize infections, or tamp down the excessive immune response seen in autoimmune disease,” said UCSF’s Alex Marson, MD, PhD, associate professor of microbiology and immunology, member of the UCSF Helen Diller Family Comprehensive Cancer Center, and senior author of the new study. “Now we’re off to the races on all these fronts.”

But just as important as the new technique’s speed and ease of use, said Marson, also scientific director of biomedicine at the Innovative Genomics Institute, is that the approach makes it possible to insert substantial stretches of DNA into T cells, which can endow the cells with powerful new properties. Members of Marson’s lab have had some success using electroporation and CRISPR to insert bits of genetic material into T cells, but until now, numerous attempts by many researchers to place long sequences of DNA into T cells had caused the cells to die, leading most to believe that large DNA sequences are excessively toxic to T cells.

To demonstrate the new method’s versatility and power, the researchers used it to repair a disease-causing genetic mutation in T cells from children with a rare genetic form of autoimmunity, and also created customized T cells to seek out and kill human melanoma cells.

Viruses cause infections by injecting their own genetic material through cell membranes, and since the 1970s scientists have exploited this capability, stripping viruses of infectious features and using the resulting “viral vectors” to transport DNA into cells for research, gene therapy, and in a well-publicized recent example, to create the CAR-T cells used in cancer immunotherapy.

T cells engineered with viruses are now approved by the U.S. Food and Drug Administration to combat certain types of leukemia and lymphoma. But creating viral vectors is a painstaking, expensive process, and a shortage of clinical-grade vectors has led to a manufacturing bottleneck for both gene therapies and cell-based therapies. Even when available, viral vectors are far from ideal, because they insert genes haphazardly into cellular genomes, which can damage existing healthy genes or leave newly introduced genes ungoverned by the regulatory mechanisms which ensure that cells function normally. These limitations, which could potentially lead to serious side effects, have been cause for concern in both gene therapy and cell therapies such as CAR-T-based immunotherapy.

“There has been thirty years of work trying to get new genes into T cells,” said first author Theo Roth, a student pursuing MD and PhD degrees in UCSF’s Medical Scientist Training Program who designed and led the new study in Marson’s lab. “Now there should no longer be a need to have six or seven people in a lab working with viruses just to engineer T cells, and if we begin to see hundreds of labs engineering these cells instead of just a few, and working with increasingly more complex DNA sequences, we’ll be trying so many more possibilities that it will significantly speed up the development of future generations of cell therapy.”

After nearly a year of trial-and-error, Roth determined the ratios of T cell populations, DNA quantity, and CRISPR abundance that, combined with an electrical field delivered with the proper parameters, would result in efficient and accurate editing of the T cells’ genomes.

To validate these findings, Roth directed CRISPR to label an array of different T cell proteins with green fluorescent protein (GFP), and the outcome was highly specific, with very low levels of “off-target” effects: each subcellular structure Roth’s CRISPR templates had been designed to tag with GFP — and no others — glowed green under the microscope.

Then, in complementary experiments devised to serve as proof-of-principle of the new technique’s therapeutic promise, Roth, Marson, and colleagues showed how it could potentially be used to marshal T cells against either autoimmune disease or cancer.

In the first example, Roth and colleagues used T cells provided to the Marson lab by Yale School of Medicine’s Kevan Herold, MD. The cells came from three siblings with a rare, severe autoimmune disease that has so far been resistant to treatment. Genomic sequencing had shown that the T cells in these children carry mutations in a gene called IL2RA. This gene contains instructions for a cell-surface receptor essential for the development of regulatory T cells, or Tregs, which keep other immune cells in check and prevent autoimmunity.

With the non-viral CRISPR technique, the UCSF team was able to quickly repair the IL2RA defect in the children’s T cells, and to restore cellular signals that had been impaired by the mutations. In CAR-T therapy, T cells that have been removed from the body are engineered to enhance their cancer-fighting ability, and then returned to the body to target tumors. The researchers hope that a similar approach could be effective for treating autoimmune diseases in which Tregs malfunction, such as that seen in the three children with the IL2RA mutations.

In a second set of experiments conducted in collaboration with Cristina Puig-Saus, PhD, and Antoni Ribas, MD, of the Parker Institute for Cancer Immunotherapy at UCLA, the scientists completely replaced native T cell receptors in a population of normal human T cells with new receptors that had been specifically engineered to seek out a particular subtype of human melanoma cells. T cell receptors are the sensors the cells use to detect disease or infection, and in lab dishes the engineered cells efficiently homed in on the targeted melanoma cells while ignoring other cells, exhibiting the sort of specificity that is a major goal of precision cancer medicine.

Without using viruses, the researchers were able to generate large numbers of CRISPR-engineered cells reprogrammed to display the new T cell receptor. When transferred into mice implanted with human melanoma tumors, the engineered human T cells went to the tumor site and showed anti-cancer activity.

“This strategy of replacing the T cell receptor can be generalized to any T cell receptor,” said Marson, also a member of the Parker Institute for Cancer Immunotherapy at UCSF and a Chan Zuckerberg Biohub Investigator. “With this new technique we can cut and paste into a specified place, rewriting a specific page in the genome sequence.”

Roth said that because the new technique makes it possible to create viable custom T cell lines in a little over a week, it has already transformed the research environment in Marson’s lab. Ideas for experiments that were previously deemed too difficult or expensive because of the obstacles presented by viral vectors are now ripe for investigation. “We’ll work on 20 ‘crazy’ ideas,” Roth said, “because we can create CRISPR templates very rapidly, and as soon as we have a template we can get it into T cells and grow them up quickly.”

Marson attributes the new method’s success to Roth’s “absolute perseverance” in the face of the widespread beliefs that viral vectors were necessary and that only small pieces of DNA could be tolerated by T cells. “Theo was convinced that if we could figure out the right conditions we could overcome these perceived limitations, and he put in a Herculean effort to test thousands of different conditions: the ratio of the CRISPR to the DNA; different ways of culturing the cells; different electrical currents. By optimizing each of these parameters and putting the best conditions together he was able to see this astounding result.”

Story Source:

Materials provided by University of California – San Francisco. Original written by Pete Farley. Note: Content may be edited for style and length.


Journal Reference:

  1. Theodore L. Roth, Cristina Puig-Saus, Ruby Yu, Eric Shifrut, Julia Carnevale, P. Jonathan Li, Joseph Hiatt, Justin Saco, Paige Krystofinski, Han Li, Victoria Tobin, David N. Nguyen, Michael R. Lee, Amy L. Putnam, Andrea L. Ferris, Jeff W. Chen, Jean-Nicolas Schickel, Laurence Pellerin, David Carmody, Gorka Alkorta-Aranburu, Daniela del Gaudio, Hiroyuki Matsumoto, Montse Morell, Ying Mao, Min Cho, Rolen M. Quadros, Channabasavaiah B. Gurumurthy, Baz Smith, Michael Haugwitz, Stephen H. Hughes, Jonathan S. Weissman, Kathrin Schumann, Jonathan H. Esensten, Andrew P. May, Alan Ashworth, Gary M. Kupfer, Siri Atma W. Greeley, Rosa Bacchetta, Eric Meffre, Maria Grazia Roncarolo, Neil Romberg, Kevan C. Herold, Antoni Ribas, Manuel D. Leonetti, Alexander Marson. Reprogramming human T cell function and specificity with non-viral genome targetingNature, 2018; DOI: 10.1038/s41586-018-0326-5

 

Source: University of California – San Francisco. “T cell engineering breakthrough sidesteps need for viruses in gene-editing: With faster, cheaper, more precise technique, authors say it’s ‘off to the races’ toward new cell therapies.” ScienceDaily. ScienceDaily, 11 July 2018. <www.sciencedaily.com/releases/2018/07/180711131204.htm>.

New solid-state silicon device may one day power space missions

Date:
July 9, 2018

Source:
DOE/Sandia National Laboratories

Summary:
Researchers have developed a tiny silicon-based device that can harness what was previously called waste heat and turn it into DC power.

 

This tiny silicon-based device developed at Sandia National Laboratories can catch and convert waste heat into electrical power. The rectenna, short for rectifying antenna, is made of common aluminum, silicon and silicon dioxide using standard processes from the integrated circuit industry.
Credit: Photo by Randy Montoya/Sandia National Laboratories

 

 

Directly converting electrical power to heat is easy. It regularly happens in your toaster, that is, if you make toast regularly. The opposite, converting heat into electrical power, isn’t so easy.

Researchers from Sandia National Laboratories have developed a tiny silicon-based device that can harness what was previously called waste heat and turn it into DC power. Their advance was recently published in Physical Review Applied.

“We have developed a new method for essentially recovering energy from waste heat. Car engines produce a lot of heat and that heat is just waste, right? So imagine if you could convert that engine heat into electrical power for a hybrid car. This is the first step in that direction, but much more work needs to be done,” said Paul Davids, a physicist and the principal investigator for the study.

“In the short term we’re looking to make a compact infrared power supply, perhaps to replace radioisotope thermoelectric generators.” Called RTGs, the generators are used for such tasks as powering sensors for space missions that don’t get enough direct sunlight to power solar panels.

Davids’ device is made of common and abundant materials, such as aluminum, silicon and silicon dioxide — or glass — combined in very uncommon ways.

Silicon device catches, channels and converts heat into power

Smaller than a pinkie nail, the device is about 1/8 inch by 1/8 inch, half as thick as a dime and metallically shiny. The top is aluminum that is etched with stripes roughly 20 times smaller than the width of a human hair. This pattern, though far too small to be seen by eye, serves as an antenna to catch the infrared radiation.

Between the aluminum top and the silicon bottom is a very thin layer of silicon dioxide. This layer is about 20 silicon atoms thick, or 16,000 times thinner than a human hair. The patterned and etched aluminum antenna channels the infrared radiation into this thin layer.

The infrared radiation trapped in the silicon dioxide creates very fast electrical oscillations, about 50 trillion times a second. This pushes electrons back and forth between the aluminum and the silicon in an asymmetric manner. This process, called rectification, generates net DC electrical current.

The team calls its device an infrared rectenna, a portmanteau of rectifying antenna. It is a solid-state device with no moving parts to jam, bend or break, and doesn’t have to directly touch the heat source, which can cause thermal stress.

Infrared rectenna production uses common, scalable processes

Because the team makes the infrared rectenna with the same processes used by the integrated circuit industry, it’s readily scalable, said Joshua Shank, electrical engineer and the paper’s first author, who tested the devices and modeled the underlying physics while he was a Sandia postdoctoral fellow.

He added, “We’ve deliberately focused on common materials and processes that are scalable. In theory, any commercial integrated circuit fabrication facility could make these rectennas.”

That isn’t to say creating the current device was easy. Rob Jarecki, the fabrication engineer who led process development, said, “There’s immense complexity under the hood and the devices require all kinds of processing tricks to build them.”

One of the biggest fabrication challenges was inserting small amounts of other elements into the silicon, or doping it, so that it would reflect infrared light like a metal, said Jarecki. “Typically you don’t dope silicon to death, you don’t try to turn it into a metal, because you have metals for that. In this case we needed it doped as much as possible without wrecking the material.”

The devices were made at Sandia’s Microsystems Engineering, Science and Applications Complex. The team has been issued a patent for the infrared rectenna and have filed several additional patents.

The version of the infrared rectenna the team reported in Physical Review Applied produces 8 nanowatts of power per square centimeter from a specialized heat lamp at 840 degrees. For context, a typical solar-powered calculator uses about 5 microwatts, so they would need a sheet of infrared rectennas slightly larger than a standard piece of paper to power a calculator. So, the team has many ideas for future improvements to make the infrared rectenna more efficient.

Future work to improve infrared rectenna efficiency

These ideas include making the rectenna’s top pattern 2D x’s instead of 1D stripes, in order to absorb infrared light over all polarizations; redesigning the rectifying layer to be a full-wave rectifier instead of the current half-wave rectifier; and making the infrared rectenna on a thinner silicon wafer to minimize power loss due to resistance.

Through improved design and greater conversion efficiency, the power output per unit area will increase. Davids thinks that within five years, the infrared rectenna may be a good alternative to RTGs for compact power supplies.

Shank said, “We need to continue to improve in order to be comparable to RTGs, but the rectennas will be useful for any application where you need something to work reliably for a long time and where you can’t go in and just change the battery. However, we’re not going to be an alternative for solar panels as a source of grid-scale power, at least not in the near term.”

Davids added, “We’ve been whittling away at the problem and now we’re beginning to get to the point where we’re seeing relatively large gains in power conversion, and I think that there’s a path forward as an alternative to thermoelectrics. It feels good to get to this point. It would be great if we could scale it up and change the world.”

The research was funded by Sandia’s Laboratory Directed Research and Development program.

Story Source:

Materials provided by DOE/Sandia National LaboratoriesNote: Content may be edited for style and length.


Journal Reference:

  1. Joshua Shank, Emil A. Kadlec, Robert L. Jarecki, Andrew Starbuck, Stephen Howell, David W. Peters, Paul S. Davids. Power Generation from a Radiative Thermal Source Using a Large-Area Infrared RectennaPhysical Review Applied, 2018; 9 (5) DOI: 10.1103/PhysRevApplied.9.054040

 

Source: DOE/Sandia National Laboratories. “Generating electrical power from waste heat: New solid-state silicon device may one day power space missions.” ScienceDaily. ScienceDaily, 9 July 2018. <www.sciencedaily.com/releases/2018/07/180709120135.htm>.

Confined mature cells lose their specialized characteristics by sixth day and completely transition into re-deployable stem cells by 10th day

Date:
July 10, 2018

Source:
National University of Singapore

Summary:
Recent research has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification — by confining them to a defined geometric space for an extended period of time.

 

A schematic showing the growth of a spherical cluster of stem cells from a mature cell on a confined substrate. Fibroblast cells that are confined to rectangular areas and allowed to grow over 10 days, form spherical clusters of cells. With the confinement, specific genomic markers normally associated with mature fibroblasts were lost by the sixth day and by the 10th day, the cells expressed genes normally associated with embryonic stem cells and iPSCs.
Credit: Mechanobiology Institute

 

 

Stem cells are the blank slate on which all specialised cells in our bodies are built and they are the foundation for every organ and tissue in the body.

Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the FIRC Institute of Molecular Oncology (IFOM) in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification — by confining them to a defined geometric space for an extended period of time.

“Our breakthrough findings will usher in a new generation of stem cell technologies for tissue engineering and regenerative medicine that may overcome the negative effects of geonomic manipulation,” said Prof Shivashankar.

Turning back the cellular clock

It has been over a decade since scientists first showed that mature cells can be reprogrammed in the lab to become pluripotent stem cells that are capable of being developed into any cell type in the body. In those early studies, researchers genetically modified mature cells by introducing external factors that reset the genomic programmes of the cells, essentially turning back the clock and returning them to an undifferentiated or unspecialised state. The resultant lab-made cells, known as induced pluripotent stem cells (iPSCs) can then be programmed into different cell types for use in tissue repair, drug discovery and even to grow new organs for transplant. Importantly, these cells did not need to be harvested from embryos.

However, a major obstacle is the tendency for any specialised cell that is developed from iPSCs, to form tumours after being introduced into the body. To understand why this occurred, researchers turned their focus to understanding how stem cell differentiation and growth is regulated in the body, and in particular, how cells naturally revert to an immature stem cell-like state, or convert to another cell type, during development, or in tissue maintenance.

Prof Shivashankar’s team of researchers has shown that mature cells can be reprogrammed, in vitro, into pluripotent stem cells without genetically modifying the mature cells, simply by confining the cells to a defined area for growth.

Resetting mature cells

When fibroblast cells (a type of mature cell found in connective tissue such as tendons and ligaments) were confined to rectangular areas, they quickly assumed the shape of the substrate (the surface or medium that the cells are attached to). Based on previous work from the Shivashankar lab, this indicated that the cells were measuring and responding to the physical properties of their environment, and conveying this information to the nucleus where DNA packaging and genome programmes would adapt accordingly.

The team grew the cells over 10 days until they formed spherical clusters of cells. Genetic analysis of the cells within these clusters revealed that specific characteristics of chromatin (the condensed form of packaged DNA) normally associated with mature fibroblasts were lost by the sixth day. By the 10th day, the cells expressed genes normally associated with embryonic stem cells and iPSCs. The researchers have now learnt that by confining the mature cells for an extended period of time, mature fibroblasts can be turned into pluripotent stem cells.

To confirm that the fibroblasts had indeed been reprogrammed into stem cells, the researchers then directed their growth, with high efficiency, into two different specialised cell types. Some cells were also directed back into fibroblasts.

Stem cell technologies redefined

The physical parameters used in the study are reflective of the transient geometric constraints that cells can be exposed to in the body. For example, during development, the establishment of geometric patterns and niches are essential in the formation of functional tissues and organs. Similarly, when tissue is damaged, either through injury or disease, cells will experience sudden alterations to their environment. In each case, mature cells may revert back to a pluripotent, stem cell-like state, before being redeployed as specialised cells for the repair or maintenance of the tissue.

“While it is well established that confining stem cells to defined geometric patterns and substrate properties can direct their differentiation into specialised cells, this study shows for the first time that mechanical cues can reset the genomic programmes of mature cells and return them to a pluripotent state,” Prof Shivashankar explained.

He added, “The use of geometric constraints to reprogramme mature cells may better reflect the process occurring naturally within the body. More importantly, our findings allow researchers to generate stem cells from mature cells with high efficiency and without genetically modifying them.”

Story Source:

Materials provided by National University of SingaporeNote: Content may be edited for style and length.


Journal Reference:

  1. Bibhas Roy, Saradha Venkatachalapathy, Prasuna Ratna, Yejun Wang, Doorgesh Sharma Jokhun, Mallika Nagarajan, G. V. Shivashankar. Laterally confined growth of cells induces nuclear reprogramming in the absence of exogenous biochemical factorsProceedings of the National Academy of Sciences, 2018; 115 (21): E4741 DOI: 10.1073/pnas.1714770115

 

Source: National University of Singapore. “Researchers confine mature cells to turn them into stem cells: Confined mature cells lose their specialized characteristics by sixth day and completely transition into re-deployable stem cells by 10th day.” ScienceDaily. ScienceDaily, 10 July 2018. <www.sciencedaily.com/releases/2018/07/180710113502.htm>.

Study in mice shows promise for treating genetic conditions during early stages of development

Date:
July 9, 2018

Source:
Carnegie Mellon University

Summary:
Researchers have for the first time used a gene editing technique to successfully cure a genetic condition in a mouse model. Their findings present a promising new avenue for research into treating genetic conditions during fetal development.

 

New research presents a promising new avenue for research into treating genetic conditions during fetal development.
Credit: © llhedgehogll / Fotolia

 

 

Researchers at Carnegie Mellon University and Yale University have for the first time used a gene editing technique to successfully cure a genetic condition in a mouse model. Their findings, published in Nature Communications, present a promising new avenue for research into treating genetic conditions during fetal development.

An estimated 8 million children are born each year with severe genetic disorders or birth defects. Genetic conditions can often be detected during pregnancy using amniocentesis, but there are no treatment options to correct these genetic conditions before birth.

“Early in embryonic development, there are a lot of stem cells dividing at a rapid pace. If we can go in and correct a genetic mutation early on, we could dramatically reduce the impact the mutation has on fetal development or even cure the condition,” said Danith Ly, professor of chemistry in Carnegie Mellon’s Mellon College of Science.

In this study, the researchers used a peptide nucleic acid-based gene editing technique that they had previously used to cure beta thalassemia, a genetic blood disorder that results in the reduced production of hemoglobin, in adult mice.

Peptide nucleic acids are synthetic molecules that combine a synthetic protein backbone with the nucleobases found in DNA and RNA. The PNAs used in this study were created by Ly at Carnegie Mellon’s Center for Nucleic Acids Science and Technology (CNAST), a leading center for PNA science.

Their technique uses an FDA-approved nanoparticle to deliver PNA molecules paired with donor DNA to the site of a genetic mutation. When the PNA-DNA complex identifies a designated mutation, the PNA molecule binds to the DNA and unzips its two strands. The donor DNA binds with the faulty DNA and spurs the cell’s DNA repair pathways into action, allowing it to correct the error.

In the current study, the researchers used a technique similar to amniocentesis to inject the PNA complex into the amniotic fluid of pregnant mice whose fetuses carried a mutation in the beta-globin gene that causes beta thalassemia.

With just one injection of the PNA during gestation, the researchers were able to correct 6 percent of the mutations. This 6 percent correction was enough to cause dramatic improvements in the mice’s symptoms of beta thalassemia ¬- and enough for the mice to be considered cured. Mice that were treated using PNA while in utero had levels of hemoglobin that were within the normal range, less spleen enlargement and increased survival rates.

The researchers also noted that there were no off-target effects from the treatment, a finding that might suggest this method would be preferable over other gene editing techniques like CRISPR/Cas9, which can erroneously damage off-target DNA.

“CRISPR is much easier to use, which makes it ideal for laboratory research. But the off-site errors make it less useful for therapeutics,” said Ly. “The PNA technique is more ideal for therapeutics. It doesn’t cut the DNA, it just binds to it and repairs things that seem unusual. We looked at 50 million samples and couldn’t find one offsite error when we used our PNA gene editing technique.”

The researchers believe that their technique might be able to achieve even higher success rates if they can administer it multiple times during gestation. They also hope to see if their technique can be applied to other conditions.

This work was made possible by the support of the DSF Charitable Foundation, who has donated $7 million to CNAST, enabling the center to engage in fundamental research aimed at developing synthetic chemistry solutions for the diagnosis and treatment of disease.

Additional study authors include Adele S. Ricciardi, Raman Bahal, James S. Farrelly, Elias Quijano, Anthony H. Bianci, Valerie L. Luks, Rachel Putman, Francesc Lopez-Giraldez, Suleyman Coskun, Eric Song, Yanfeng Liu, David H. Stitelman, Peter M. Glazer and W. Mark Saltzman from Yale, and Wei-Che Hsieh from Carnegie Mellon.

The research was funded by the Brain Research Foundation Scientific Innovations Award, the NIGMS Medical Scientist Training Program (GM07205), the National Heart, Lung and Blood Institute (HL134252), the Ohse Research Grant, Yale School of Medicine, the American Pediatric Surgical Association Foundation Grant and the DSF Charitable Foundation.

Story Source:

Materials provided by Carnegie Mellon University. Original written by Jocelyn Duffy. Note: Content may be edited for style and length.


Journal Reference:

  1. Adele S. Ricciardi, Raman Bahal, James S. Farrelly, Elias Quijano, Anthony H. Bianchi, Valerie L. Luks, Rachael Putman, Francesc López-Giráldez, Süleyman Coşkun, Eric Song, Yanfeng Liu, Wei-Che Hsieh, Danith H. Ly, David H. Stitelman, Peter M. Glazer, W. Mark Saltzman. In utero nanoparticle delivery for site-specific genome editingNature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-04894-2

 

Source: Carnegie Mellon University. “Gene-editing technique cures genetic disorder in utero: Study in mice shows promise for treating genetic conditions during early stages of development.” ScienceDaily. ScienceDaily, 9 July 2018. <www.sciencedaily.com/releases/2018/07/180709120133.htm>.

Judy Schloss Markowitz is Now a Retiree

 

From the desk of Dave Luke, PharmD, Sr. Director, Clinical and Scientific Affairs at Target Health Inc.

 

Target Health Inc. is announcing the retirement of a longtime colleague, Judith (Judy) Schloss Markowitz. Judy is a first generation American whose mother, Ruth, is a Holocaust survivor, and her father immigrated from Germany to the US when he was 2 years of age. A true New Yorker from Queens, with an accent and attitude to prove it, Judy graduated with a Master’s degree in Education from Queens College, CUNY.

 

Judy joined PhRMA as a clinical monitor at Ives Laboratories – which was then a division of American Home Products (AHP). She then watched the industry merge over her 32 year career from AHP to Ayerst Laboratories, to Wyeth-Ayerst, to Wyeth and finally to Pfizer. Judy joined Target Health as Senior Clinical Project Manager in 2010.

 

I had the privilege of meeting Judy 18 months ago when I joined Target Health. Judy helped me onboard and we worked very closely on many time-critical projects. I depended on Judy as a very experienced project manager and I will miss her more than I think she will miss her role. Over the last 5 weeks, I keep catching myself saying “What would Judy do?“ I don’t know the answer but Judy is just a phone call away. Judy will be missed but not easily forgotten.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext. 165). For additional information about software tools for paperless clinical trials, please also feel free to contact Dr. Jules T. Mitchel. The Target Health software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health Website.

 

To unsubscribe from the On Target mailing list, click on the following link: unsubscribeontarget@targethealth.com

 

Joyce Hays, Founder and Editor in Chief of On Target

Jules Mitchel, Editor

 

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The Apgar Score

Mind map showing summary for the Apgar score – Graphics credit: Madhero88 – Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=10396636

 

 

Apgar score is a method to quickly summarize the health of newborn 1) ___ against infant mortality. Dr. Virginia Apgar, an anesthesiologist at New York-Presbyterian Hospital, developed the score in 1952 to quantify the effects of obstetric anesthesia on babies. The Apgar 2) ___ is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing up the five values thus obtained. The resulting Apgar score ranges from zero to 10. The five criteria are summarized using words chosen to form a backronym (Appearance, Pulse, Grimace, Activity, Respiration).

 

The five criteria of the Apgar score:

Score of 0 Score of 1 Score of 2 Component of backronym
Skin color blue or pale all over blue at extremities
body pink
(acrocyanosis)
no cyanosis
body and extremities pink
Appearance
Pulse rate absent < 100 beats per minute > 100 beats per minute Pulse
Reflex irritability grimace no response to stimulation grimace on suction or aggressive stimulation cry on stimulation Grimace
Activity none some flexion flexed arms and legs that resist extension Activity
Respiratory effort absent weak, irregular, gasping strong, robust cry Respiration

 

 

The test is generally done at 1 and 5 minutes after 3) ___ and may be repeated later if the score is and remains low. Scores 7 and above are generally normal; 4 to 6, fairly low; and 3 and below are generally regarded as critically low and cause for immediate resuscitative efforts. A low score on the one-minute test may show that the neonate requires medical attention but does not necessarily indicate a long-term problem, particularly if the score improves at the five-minute test. An Apgar score that remains below 3 at later times, such as 10, 15, or 30 minutes, may indicate longer-term neurological damage, including a small but significant increase in the risk of cerebral palsy. However, the Apgar test’s purpose is to determine quickly whether or not a newborn needs immediate medical care. It is not designed to predict 4) ___-term health issues. A score of 10 is uncommon, due to the prevalence of transient cyanosis, and does not substantially differ from a score of 9. Transient cyanosis is common, particularly in babies born at high altitude. Cyanosis is defined as the 5) ___ or purplish discoloration of the skin or mucous membranes due to the tissues near the skin surface having low oxygen saturation.

A study that compared babies born in Peru near sea level with babies born at very high 6) ___ (4340 m or 14,138 ft) found a significant average difference in the first Apgar score but not the second. Oxygen saturation (see pulse oximetry) also was lower at high altitude.

 

Some ten years after initial publication, a backronym for APGAR was coined in the United States as a mnemonic learning aid: Appearance (skin color), Pulse (heart rate), Grimace (reflex irritability), Activity (muscle tone), and Respiration.

 

Spanish: Apariencia, Pulso, Gesticulacion, Actividad, Respiracion;

Portuguese: Aparencia, Pulso, Gesticulacao, Atividade, Respiracao;

French: Apparence, Pouls, Grimace, Activite, Respiration;

German: Atmung, Puls, Grundtonus, Aussehen, Reflexe, representing the same tests but in a different order (respiration, pulse, muscle tone, appearance, reflex).

 

Another eponymous backronym from Virginia Apgar’s name is American Pediatric Gross Assessment Record.

Another mnemonic for the test is “How Ready Is This Child?“, which summarizes the test criteria as Heart rate, Respiratory effort, Irritability, Tone, and Color.

 

Neonatal nursing is a subspecialty of nursing care for newborn infants up to 28 days after birth. The term neonatal comes from neo, “new“, and natal, “pertaining to birth or origin“. Neonatal 7) ___ requires a high degree of skill, dedication and emotional strength as the nurses care for newborn infants with a range of problems, varying between prematurity, birth defects, infection, cardiac malformations and surgical problems. Neonatal nurses are a vital part of the neonatal care team and are required to know basic newborn resuscitation, be able to control the newborn’s temperature and know how to initiate cardiopulmonary and pulse oximetry monitoring. Most neonatal nurses care for infants from the time of birth until they are discharged from the hospital. Approximately 40,000 low-birth-weight infants are born annually in the United States. In the United States, Healthcare institutions have varying entry-level requirements for neonatal nurses. Neonatal nurses are Registered Nurses (RNs), and therefore must have an Associate of Science in Nursing (ASN) or Bachelor of Science in Nursing (BSN) degree. Some countries or institutions may also require a midwifery qualification. Some institutions may accept newly graduated RNs who have passed the NCLEX exam; others may require additional experience working in adult-health or medical/surgical nursing. Some countries offer postgraduate degrees in neonatal nursing, such as the Master of Science in Nursing (MSN) and various doctorates. A nurse practitioner may be required to hold a postgraduate degree. The National Association of Neonatal Nurses recommends two years’ experience working in a NICU before taking graduate classes. 8) ___ nurses must complete the Neonatal Resuscitation Program. Some units prefer new graduates who do not have experience in other units, so they may be trained in the specialty exclusively, while others prefer nurses with more experience.

 

Intensive care nurses receive intensive didactic and clinical orientation, in addition to their general nursing knowledge, to provide highly specialized care for critical patients. Their competencies include the administration of high-risk medications, management of high-acuity patients requiring ventilator support, surgical care, resuscitation, advanced interventions such as extracorporeal membrane oxygenation or hypothermia therapy for neonatal encephalopathy procedures, as well as chronic-care management or lower acuity cares associated with premature infants such as feeding intolerance, phototherapy, or administering antibiotics. NICU RNs undergo annual skills tests and are subject to additional training to maintain contemporary practice.

 

The Apgar scoring system was intended as an evaluative measure of a newborn’s condition at and of the need for immediate attention. In the most recent past, individuals have unsuccessfully attempted to link Apgar scores with long-term developmental outcomes. This practice is not appropriate, as the Apgar score is currently defined. Expectant parents need to be aware of the limitations of the Apgar score and its appropriate uses. The Apgar score is performed at 1 and 5 minutes of 9) ___10) ___ scoring is best used in conjunction with additional evaluative techniques such as physical assessment and vital signs.

 

ANSWERS: 1) babies; 2) scale; 3) birth; 4) long; 5) bluish; 6) altitude; 7) nursing; 8) Neonatal; 9) life; 10) Apgar

 

Virginia Apgar

Dr. Virginia Apgar Photograph from Public Information Department, The National Foundation (the March of Dimes). Forms part of New York World-Telegram and the Sun Newspaper Photograph Collection (Library of Congress). Photo credit: March of Dimes – Library of Congress, Public Domain, https://commons.wikimedia.org/w/index.php?curid=43770603

 

Virginia Apgar (June 7, 1909 – August 7, 1974) was an American obstetrical anesthesiologist, best known as the inventor of the Apgar score, a way to quickly assess the health of a newborn child immediately after birth. She was a leader in the fields of anesthesiology and teratology, and introduced obstetrical considerations to the established field of neonatology. The youngest of three children, Apgar was born and raised in Westfield, New Jersey to a musical family, the daughter of Helen May (Clarke) and Charles Emory Apgar. Her father was an insurance executive, and also an amateur inventor and astronomer. She graduated from Westfield High School in 1925, knowing that she wanted to be a doctor.

 

Apgar graduated from Mount Holyoke College in 1929, where she studied zoology with minors in physiology and chemistry. In 1933, she graduated fourth in her class from Columbia University College of Physicians and Surgeons (P&S) and completed a residency in surgery at P&S in 1937. She was discouraged by Dr. Allen Whipple, the chairman of surgery at Columbia-Presbyterian Medical Center, from continuing her career as a surgeon because he had seen many women attempt to be successful surgeons and ultimately fail. He instead encouraged her to practice anesthesiology because he felt that advancements in anesthesia were needed to further advance surgery and felt that she had the “energy and ability“ to make a significant contribution. Deciding to continue her career in anesthesiology, she trained for six months under Dr. Ralph Waters at the University of Wisconsin-Madison, where he had established the first anesthesiology department in the United States. She then studied for a further six months under Dr. Ernest Rovenstine in New York at Bellevue Hospital. She received a certification as an anesthesiologist in 1937, and returned to P&S in 1938 as director of the newly formed division of anesthesia. She later received a Master’s Degree in Public Health at Johns Hopkins School of Hygiene and Public Health, graduating in 1959.

 

As the first woman to head a specialty division at Columbia-Presbyterian Medical Center (now New York-Presbyterian Hospital) and Columbia University College of Physicians and Surgeons, Apgar faced many obstacles. In conjunction with Dr. Allen Whipple, she started P&S’s anesthesia division. Apgar was placed in charge of the division’s administrative duties and was also tasked with coordinating the staffing of the division and its work throughout the hospital. Throughout much of the 1940s, she was an administrator, teacher, recruiter, coordinator and practicing physician. It was often difficult to find residents for the program, as anesthesiology had only recently been converted from a nursing specialty to a physician specialty. New anesthesiologists also faced scrutiny from other physicians, specifically surgeons, who were not used to having an anesthesia-specialized MD in the operating room. These difficulties led to issues in gaining funding and support for the division. With America’s entrance into World War II in 1941, many medical professionals enlisted in the military to help the war effort, which created a serious staffing problem for domestic hospitals, including Apgar’s division. When the war ended in 1945, interest in anesthesiology was renewed in returning physicians, and the staffing problem for Apgar’s division was quickly resolved. The specialty’s growing popularity and Apgar’s development of its residency program prompted P&S to establish it as an official department in 1949. Due to her lack of research, Apgar was not made the head of the department as was expected and the job was given to her colleague, Dr. Emmanuel Papper. Apgar was given a faculty position at P&S. In 1949, Apgar became the first woman to become a full professor at P&S, where she remained until 1959. During this time, she also did clinical and research work at the affiliated Sloane Hospital for Women, still a division of New York-Presbyterian Hospital. In 1953, she introduced the first test, called the Apgar score, to assess the health of newborn babies.

 

Between the 1930s and the 1950s, the United States infant mortality rate decreased, but the number of infant deaths within the first 24 hours after birth remained constant. Apgar noticed this trend and began to investigate methods for decreasing the infant mortality rate specifically within the first 24 hours of the infant’s life. As an obstetric anesthesiologist, Apgar was able to document trends that could distinguish healthy infants from infants in trouble. This investigation led to a standardized scoring system used to assess a newborn’s health after birth, with the result referred to as the newborn’s “Apgar score“. Each newborn is given a score of 0, 1, or 2 (a score of 2 meaning the newborn is in optimal condition, 0 being in distress) in each of the following categories: heart rate, respiration, color, muscle tone, and reflex irritability. Compiled scores for each newborn can range between 0 and 10, with 10 being the best possible condition for a newborn. The scores were to be given to a newborn one minute after birth, and additional scores could be given in five-minute increments to guide treatment if the newborn’s condition did not sufficiently improve. By the 1960s, many hospitals in the United States were using the Apgar score consistently. Entering into the 21st century the score continues to be used to provide an accepted and convenient method for reporting the status of the newborn infant immediately after birth.

 

In 1959, Apgar left Columbia and earned a Master of Public Health degree from the Johns Hopkins School of Hygiene and Public Health. From 1959 until her death in 1974, Apgar worked for the March of Dimes Foundation, serving as vice president for Medical Affairs and directing its research program to prevent and treat birth defects. As gestational age is directly related to an infant’s Apgar score, Apgar was one of the first at the March of Dimes to bring attention to the problem of premature birth, now one of the March of Dimes’ top priorities. During this time, she wrote and lectured extensively, authoring articles in popular magazines as well as research work. In 1967, Apgar became vice president and director of basic research at The National Foundation-March of Dimes.

 

During the rubella pandemic of 1964-65, Apgar became an advocate for universal vaccination to prevent mother-to-child transmission of rubella. Rubella can cause serious congenital disorders if a woman becomes infected while pregnant. Between 1964 and 1965, the United States had an estimated 12.5 million rubella cases, which led to 11,000 miscarriages or therapeutic abortions and 20,000 cases of congenital rubella syndrome. These led to 2,100 deaths in infancy, 12,000 cases of deafness, 3,580 cases of blindness due to cataracts and/or microphthalmia, and 1,800 cases of intellectual disability. In New York City alone, congenital rubella affected 1% of all babies born at that time. Apgar also promoted effective use of Rh testing, which can identify women who are at risk for transmission of maternal antibodies across the placenta where they may subsequently bind with and destroy fetal red blood cells, resulting in fetal hydrops or even miscarriage.

 

Apgar traveled thousands of miles each year to speak to widely varied audiences about the importance of early detection of birth defects and the need for more research in this area. She proved an excellent ambassador for the National Foundation, and the annual income of that organization more than doubled during her tenure there. She also served the National Foundation as Director of Basic Medical Research (1967-1968) and Vice-President for Medical Affairs (1971-1974). Her concerns for the welfare of children and families were combined with her talent for teaching in the 1972 book Is My Baby All Right?, written with Joan Beck. Apgar was also a lecturer (1965-1971) and then clinical professor (1971-1974) of pediatrics at Cornell University School of Medicine, where she taught teratology (the study of birth defects). She was the first to hold a faculty position in this new area of pediatrics. In 1973, she was appointed a lecturer in medical genetics at the Johns Hopkins School of Public Health.

 

Apgar published over sixty scientific articles and numerous shorter essays for newspapers and magazines during her career, along with her book, Is My Baby All Right? She received many awards, including honorary doctorates from the Woman’s Medical College of Pennsylvania (1964) and Mount Holyoke College (1965), the Elizabeth Blackwell Award from the American Medical Women’s Association (1966), the Distinguished Service Award from the American Society of Anesthesiologists (1966), the Alumni Gold Medal for Distinguished Achievement from Columbia University College of Physicians and Surgeons (1973), and the Ralph M. Waters Award from the American Society of Anesthesiologists (1973). In 1973 she was also elected Woman of the Year in Science by the Ladies Home Journal. Apgar was equally at home speaking to teens as she was to the movers and shakers of society. She spoke at March of Dimes Youth Conferences about teen pregnancy and congenital disorders at a time when these topics were considered taboo.

 

Throughout her career, Apgar maintained that “women are liberated from the time they leave the womb“ and that being female had not imposed significant limitations on her medical career. She avoided women’s organizations and causes, for the most part. Though she sometimes privately expressed her frustration with gender inequalities (especially in the matter of salaries), she worked around these by consistently pushing into new fields where there was room to exercise her considerable energy and abilities. Apgar never married nor had children, and died of cirrhosis on August 7, 1974, at Columbia-Presbyterian Medical Center. She is buried at Fairview Cemetery in Westfield.

 

Music was an integral part of family life, with frequent family music sessions. Apgar played the violin and her brother played piano and organ. She traveled with her violin, often playing in amateur chamber quartets wherever she happened to be. During the 1950s a friend introduced her to instrument-making, and together they made two violins, a viola, and a cello. She was an enthusiastic gardener, and enjoyed fly-fishing, golfing, and stamp collecting. In her fifties, Apgar started taking flying lessons, stating that her goal was to someday fly under New York’s George Washington Bridge.

 

Apgar has continued to earn posthumous recognition for her contributions and achievements. In 1994, she was honored by the United States Postal Service with a 20 cent Great Americans series postage stamp. In November 1995 she was inducted into the National Women’s Hall of Fame in Seneca Falls, New York. In 1999, she was designated a Women’s History Month Honoree by the National Women’s History Project. On June 7, 2018, Google celebrated Apgar’s 109th birthday with a Google Doodle.

 

Link Between Allergen in Red Meat and Heart Disease

 

The number of people with red meat allergies in the United States is unclear, but it has been estimated that it may be as high as 1% of the population in some areas. The number of people who develop blood antibodies to the red meat allergen without having full-blown symptoms is much higher — as much as 20% of the population in some areas.

 

Only in recent years has the main allergen in red meat, galactose-a-1,3-galactose, or alpha-Gal, a type of complex sugar, been identified.. Interestingly, the Lone Star tick sensitizes people to this allergen when it bites them. That is why red meat allergies tend to be more common where these ticks are more prevalent, such as the Southeastern United States, but also extending to other areas, including Long Island, New York. It has been suspected for some time that allergens can trigger certain immunological changes that might be associated with plaque buildup and artery blockages, but no one had identified a specific substance that is responsible for this effect. Now, according to an article published in Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB; 14 June 2018), results suggest a link of sensitivity to alpha-Gal to the buildup of plaque in the arteries of the heart. While high saturated fat levels in red meat have long been known to contribute to heart disease for people in general, this new finding suggests that a subgroup of the population may be at heightened risk for a different reason – a food allergen.

 

In the current study, it was shown for the first time that a specific blood marker for red meat allergy was associated with higher levels of arterial plaque, or fatty deposits on the inner lining of the arteries. The blood marker they identified is a type of antibody (immunoglobulin or IgE) that is specific to the alpha-Gal allergen. To identify this blood marker, the authors analyzed blood samples from 118 adults and detected antibodies to alpha-Gal in 26% of the samples, indicating sensitivity to red meat. Using an imaging procedure, it was found that the quantity of plaque was 30% higher in the alpha-Gal sensitized patients than in the non-sensitized patients. These plaques, a hallmark of atherosclerosis (hardening of the arteries), also tended to be more structurally unstable, which means that they have an increased likelihood of causing heart attack and stroke.

 

According to the authors, that since the evidence for a link between red meat allergens and coronary artery disease is still preliminary, they plan to conduct detailed animal and human studies to confirm their initial findings. Currently, the only treatment for red meat allergy once it is diagnosed is strict avoidance of red meat.

 

An “Old” Marketed Drug for T-Cell Lymphoma Restores Hearing in Mice

 

On October 6, 2006, the FDA granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies.

 

According to an article published online in Cell (28 June 2018), a novel drug therapy that partially restored hearing in mice, might shed light on molecular mechanisms of inherited form of progressive human deafness known as deafness, autosomal dominant 27 (DFNA27). The seed for this study was planted a decade ago, when the genomes of members of an extended family, dubbed LMG2, were analyzed. Deafness was genetically dominant in the LMG2 family, meaning that a child needs to inherit only one copy of the defective gene from a parent to have progressive hearing loss. The investigators then localized the deafness-causing mutation to a region on chromosome four called DFNA27, which includes a dozen or so genes. However, the precise location of the mutation eluded the research team.

 

A crucial clue to explain the DFNA27 form of progressive deafness arose from later studies of the mouse gene called Rest (RE1 Silencing Transcription Factor) when it was discovered that mouse Rest is regulated through an unusual mechanism in the sensory cells of the inner ear, and this regulation is critical for hearing in mice. Because the human counterpart of the mouse Rest gene is located in the DFNA27 region, the authors decided to rexamine the mystery of DFNA27 progressive deafness.

 

As a backgrounder, the coding sequence of a protein is generated from a gene by stitching together segments called exons while editing out the intervening segments. The resulting molecule serves as the template for a specific protein. Most previous studies had missed exon 4 in the Rest gene because this small exon is not edited into the Rest mRNA in most cells. The normal function of the REST protein is to shut off genes that need to be active only in a very few cell types. When the authors deleted exon 4 of Rest in mice, inner ear hair cells died, and mice became deaf. Many genes that should have been active were shut off in hair cells prior to their death. The team then pinpointed the deafness mutation in the LMG2 family and discovered that the mutation lies near exon 4, altering the boundaries of exon 4, and interferes with the inactivation of REST in hair cells. The authors then used Banfi’s exon 4-deficient mice as a model for DFNA27 deafness. Since REST suppresses gene expression through a process called histone deacetylation, they wanted to see if blocking this process could reduce hearing loss. Using small-molecule drug vorinostat, a HDAC inhibitor, it was possible to rescue the hearing of these mice.

 

According to the authors, these results demonstrate the value of studying the molecular mechanisms that underlie inherited forms of deafness, and that by following these genetic leads, it is possible to find novel and unexpected pathways that can, in cases such as this one, uncover unexpected potential treatment strategies in people.

 

Device Approved to Treat Breathing Difficulty in Severe Emphysema

 

The Centers for Disease Control and Prevention estimates that 3.5 million American adults have been diagnosed with emphysema. Emphysema, including severe emphysema, is a type of chronic obstructive pulmonary disease (COPD) due to damage to the air sacs (alveoli) in the lungs. Lung damage from emphysema is irreversible. The damaged alveoli can cause used air to become trapped in the lungs during exhalation. This can cause the diseased parts of the lung to get larger and put pressure on the healthy part of the lung, which makes it difficult to breathe. As a result, the body may not get the oxygen it needs. Treatment options are limited for people with emphysema who have severe symptoms that have not improved from taking medicines. These options include lung surgery, such as lung volume reduction or lung transplants, which may not be suitable or appropriate for all patients.

 

The FDA has approved a new device, the Zephyr Endobronchial Valve (Zephyr Valve), intended to treat breathing difficulty associated with severe emphysema. Using a flexible bronchoscope, the Zephyr Valves, similar in size to pencil erasers, are placed into the diseased areas of the lung airways during a hospital-based procedure. The design of the device is intended to prevent air from entering the damaged parts of the lung and allow trapped air and fluids to escape. During inhalation, the valves close, preventing air from entering the damaged part of the lung and during exhalation, the valves open, letting out trapped air, which is intended to relieve pressure. The FDA reviewed data from a multi-center study of 190 patients with severe emphysema. In this study, 128 patients were treated with Zephyr Valves and medical management according to current clinical guidelines, including medications (bronchodilators, corticosteroids, antibiotics or anti-inflammatory maintenance medications) and pulmonary rehabilitation, while 62 patients (the control group) received medical management only. Results of treatment were measured by how many patients in each arm of the study had at least a 15% improvement in pulmonary function scores (the volume of air that can forcibly be blown out in one second after full inhalation). At one year, 47.7% of patients treated with Zephyr Valves experienced at least a 15% improvement in their pulmonary function scores, compared with 16.8% of patients in the control group. Adverse events observed in the study include death, air leak (pneumothorax), pneumonia, worsening of emphysema, coughing up blood, shortness of breath and chest pain.

 

The Zephyr Valve device is contraindicated for patients with active lung infections; those who are allergic to nitinol, nickel, titanium or silicone; active smokers and those who are not able to tolerate the bronchoscopic procedure. Patients who have had major lung procedures, heart disease, large bubbles of air trapped in the lung or who have not responded to other treatments should talk with their providers to determine if the Zephyr Valve device is appropriate for them.

 

The Zephyr Valve was granted Breakthrough Device designation, meaning the FDA provided intensive interaction and guidance to the company on efficient device development, to expedite evidence generation and the agency’s review of the device. To qualify for such designation, a device must provide for more effective treatment or diagnosis of a life-threatening or irreversibly debilitating disease or condition, and meet one of the following criteria: the device must represent a breakthrough technology; there must be no approved or cleared alternatives; the device must offer significant advantages over existing approved or cleared alternatives; or the availability of the device is in the best interest of patients.

 

The FDA reviewed the Zephyr Valve device through the premarket approval review pathway, a regulatory pathway for the highest risk class of devices.

 

The FDA granted approval of the Zephyr Valve device to Pulmonx Inc.

 

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