Arch Biopartners, a biotechnology company that develops new products and technologies for pharmaceutical and industrial companies, has entered into a one year option agreement to license the commercial rights of a University of Cincinnati-developed technology for treating bacterial respiratory infections associated with diseases such as cystic fibrosis and COPD. The novel treatment utilizes acidified nitrite, a non-antibiotic method developed by Dr. Daniel Hasset, a UC Professor in the Department of Molecular Genetics, Biochemistry and Microbiology.
During the one year option, the company will be working with Dr. Hassett and his team to assess the potential and logistics of conducting a Phase II clinical trial. The goal is to test how effective the UC technology can be when bacteria is resistant to antibiotics.
Gram-negative bacterium Pseudomonas aeruginosa (PA) represents a major concern in this area. Highly resistant to antibiotics and phagocyte-mediated killing, it is the primary cause of pulmonary exacerbations that leads cystic fibrosis and COPD patients to frequent hospitalizations. These two diseases, characterized by airway bacterial infections, are both deadly and chronic, and affect approximately 40,000 and 14.2 million individuals, respectively, in the United States.
When patients come in contact with the mucoid form of PA, their overall lung function declines, which is why it is so urgent to develop novel treatments in this field. In the first phase II human trial, Arch and Dr. Hassett’s team are will test the technology on cystic fibrosis patients presenting with mucoid PA. If the technology proves to be successful, testing will be expanded to include COPD patients.
Phase I Clinical Trial Results
The Phase I results revealed that the new drug is safe at or below the maximal tolerated dose. The previous trial involved over 80 healthy volunteers with single dose and multiple ascending dose studies for up to one week.
Although some adverse events were observed, such as dizziness, methemoglobinemia (methemoglobin was less than 5% of hemoglobin), and a drop in systemic blood pressure, the drug had no adverse effect on human epithelial cells at concentrations up to 300 millimolar, 20 times higher than the dose needed to kill mucoid PA. The 14 patients with pulmonary arterial hypertension (PAH) had no significant adverse events.
Células madre adultas son encontradas en diferentes lugares del cuerpo incluyendo cerebro, hígado, medula ósea, vasos sanguíneos etc… Los científicos creen que están “dormidas” en los tejidos hasta que ocurre la lesión o daño, entonces ellas se diferencian en las células que necesitan reemplazar.
Si, parece que tiene células madre que se encargarían de reparar cuando ocurre alguna lesión o enfermedad, pero todavía no se ha podido identificar cuales serian las células “multipotenciales” que podrían cumplir esa función.
Existen en el epitelio que cubre la vía respiratoria unas células que se llaman basales y parece que esas podrían ser las células madres locales del pulmón. Pero el otro problema parecería ser que esas células madres locales no alcanzan a reparar el daño si este es muy importante-
La medula ósea que está en los huesos tiene células madre hematopoyéticas y mesenquimales que se sabe pueden adoptar la forma y función de células de otros tejidos. Krause y col en el 2001 demostraron injertos en varios órganos y tejidos a través de la infusión de una única célula madre.
Un ratón hembra fue irradiado letalmente para destruir su medula ósea. Luego se le hizo una infusión de una única célula madre hematopoyética de un ratón macho. Esta única célula transfundida fue capaz de repoblar la medula ósea con todas sus líneas celulares y también se injerto en varios órganos. Hasta el 20 % del tejido pulmonar de la rata hembra contenía Cromosoma Y (masculino). Cell 2001; 105:369-77
por el pulmón dañado para ayudar en su reparación. Aunque este injerto pulmonar no ha sido confirmado en todos los estudios, parece que si ocurre pero en muy pequeño porcentaje. La reparación pulmonar parece ser un fenómeno tanto local como por células madre circulantes.
En un estudio se usaron células madres y se mezclaron en cultivo con células de epitelio respiratorio de pacientes FQ. Las células madres fueron capaces de diferenciarse en células epiteliales y parcialmente corregir el defecto del CFTR.
Las células madres tienen muchas aplicaciones a nivel pulmonar. Enfermedades Agudas: SDRA Enfermedades Crónicas: Enfisema, fibrosis pulmonar, fibrosis quística.
Controversias y dudas ¿Qué células se deben injertar? ¿El injerto realmente ocurre? ¿Se pueden desarrollar tumores con estas células madres injertadas? ¿No serán estas células rechazadas? ¿Pueden las células injertadas producir más daño que reparación?
Estas y otras mas son las dudas sobre el uso de las células madres para reparar el daño pulmonar o curar enfermedades como la Fibrosis Quística
Sabemos que la reparación celular no es una realidad por ahora pero quizás en los próximos años tengamos importantes avances con estas líneas de investigación. Bibliografia: Stem cells for lung disease-, Loebinger M ,Janes S.- Chest 2007,132:279-285
Children with cystic fibrosis and their families are to be offered new support to assist with daily physiotherapy sessions.
Young people with cystic fibrosis have to adhere to a daily regimen of treatment for their condition which some children and parents find lengthy and difficult.
However, academics at the University of Stirling are embarking on a £200,000 project to develop a treatment support kit – for DVD, phone apps and web – that will make adherence to treatment more appealing.
The project – which is being funded by the Chief Scientist Office (CSO) of the Scottish Government and the Cystic Fibrosis Trust – will draw on the collaborative expertise of academics and clinicians from across the UK.
Project leader Dr Emma France, who works in the CSO-funded Nursing Midwifery and Allied Health Professions Research Unit based in Stirling’s School of Nursing, Midwifery and Health and Glasgow Caledonian University’s Institute for Applied Health Research, said: “Our earlier research funded by the CSO showed that when daily chest physiotherapy was perceived as difficult by children and their families, physiotherapy sessions were often skipped.
“In developing this new audio-visual package, filled with a range of engaging activities, our work will lead to a cost-effective and accessible intervention tool. It will change the way children and their carers experience their condition and treatment, particularly in the crucial early years when commitment to that treatment is so vital.
“Some of the approaches will be just for the adults, with a focus on boosting parents’ morale and determination.”
Cystic fibrosis – a life-shortening, genetic condition which causes breathing difficulties, chest infections, digestive problems and malnutrition – affects approximately one in every 2500 babies born in the UK. Damage to the lungs is exacerbated by poor adherence to treatment – especially in relation to chest physiotherapy.
The support tool will encourage children with cystic fibrosis and their parents to view chest physiotherapy as a positive experience by providing them with a bank of novel and enjoyable strategies – such as activities, games and songs.
Many of these approaches – which are being collated in consultation with parents, children, physiotherapists, psychologists, clinicians and the Cystic Fibrosis Trust – allow members of the wider family to get involved.
Ideas already proposed include clearing the lungs by blowing through a straw to move a Ping-Pong ball around a table; creating an atmosphere of joviality during treatment by singing songs together; and keeping spirits high by telling stories or watching television programmes together while treatment is in progress.
The researchers hope the tool will be adopted by multiple organisations and disseminated widely – contributing to an increase in physiotherapy treatment adherence in young children with cystic fibrosis. They anticipate this would reduce the health burden on children and the costs for families and the NHS, and lead to an improvement in families’ quality of life.
Minister for Public Health, Michael Matheson said: “The Scottish Government wants to see more patients benefit from the range of care that research like this makes available.
“That is why our Chief Scientist Office has provided £188,000 funding for this research into a debilitating condition, which was identified as a national priority for children and young people‘s services in Scotland. I hope this research will inform further improvement in the care and treatment of those affected by cystic fibrosis.”
Dr Janet Allen, Director of Research at the Cystic Fibrosis Trust said: “It is important parents know how vital physiotherapy is to prevent lung damage and fundamental they encourage treatment adherence in their children at as early an age as possible.
“The support kit created from this research project will provide inspiration and encouragement. We hope it will change families’ perceptions of cystic fibrosis and chest physiotherapy treatment by reassuring them that support is available and showing them how the treatment can be turned into an enjoyable experience.”
Bacteria that infect the lungs of cystic fibrosis sufferers lose their ability to work together, becoming more selfish and less cooperative the longer the infection, say scientists.
Researchers hope that by better understanding how the potentially-fatal infection changes over time it will make it easier to treat.
The team wanted to confirm whether Pseudomona aeruginosa bacteria become more inactive during chronic lung infections in cystic fibrosis patients.
‘This infection is fairly special because it’s very long-lived. You can normally cure a bacterial infection in a week but for people with cystic fibrosis, a lung infection can persist for years,’ explains Dr Ashleigh Griffin of the University of Oxford, lead researcher on the study published in Plos One.
‘During chronic infections, bacteria will change their behaviour towards each other. It’s interesting, because we can watch the change over time in patients.’
Griffin and her colleagues looked at four different so-called cooperative traits to see how the bacteria evolved during infections.
These included production of signal molecules bacteria use to communicate with other – called quorum sensing molecules, the concentration of protein-digesting molecules called proteases, the production of bright green pyoverdine, which is used to bind iron, and how good the bacteria were at forming biofilms. Biofilms are formed by groups of microorganisms in which cells stick to each other on a surface, in this case, a Cystic Fibrosis patients’ lungs.
They found that the longer the bacteria had been infecting the lung, the fewer signals they sent out to other cells, the less biofilm they formed and the less pyoverdin they produced.
Pyoverdin is a bright green secretion which the bacteria use to bind iron, which is essential for their respiration.
‘When cystic fibrosis sufferers first contract Pseudomona aeruginosa, it’s what you might call healthy. It’s making lots of this bright green pyoverdin, but over time it becomes very pale and quiet, as it’s not making this molecule and it doesn’t send out many signals. It seems odd because not communicating is not usually in the bacteria’s best interest,’ Griffin says.
Griffin explains that people have been very sceptical of the idea that the bacteria are getting themselves into a hole, where they can’t make these molecules and the team have encountered resistance to this idea.
The team are now interested to understand whether the bacteria are adapting to the lung environment or forced to behave in a way that may harm them by competition with neighbouring bacterial cells of their own species. They think there may be alternative explanations for what they’ve seen.
‘If bacteria don’t need iron because the lung is an iron-rich environment, then they won’t need to make this pyoverdin, or something else may be happening that means they don’t need to signal to one another as much,’ Griffin explains.
By understanding how these bacteria evolve, and why they choose certain behaviours over others, will make it easier for treatments to eventually be found.
He has toured 47 states and 23 countries to increase awareness of cystic fibrosis (CF)—a genetic disorder that causes mucus to build up and clog some organs of the body, primarily the lungs—and he gets hugs everywhere he goes. This furry advocate is Burke P. Bear, a cuddly teddy bear named in honor of Burke P. Derr, who died two days before his 19th birthday in 1997 from complications of CF.
Today Burke’s memory lives on through the work of his father, Bob Derr, for Pennsylvania Cystic Fibrosis, Inc. (PACFI), and the CF researchers it supports, including Antoinette Moran, M.D., a renowned pediatric endocrinologist in the University of Minnesota Medical School’s Department of Pediatrics.
Burke was a pretty typical kid in most regards, but his CF landed him in the hospital about three times a year for weeks at a time. Some of his friends, on top of their CF, also had cystic fibrosis-related diabetes (CFRD), which affects about 20 percent of adolescents and 40 to 50 percent of adults who have CF.
In the past, people with CF who developed diabetes faced a much higher mortality rate than those without diabetes. Gradually, as doctors have become more aggressive about screening for diabetes, the number of deaths stemming from CFRD has decreased.
Much of that progress is thanks to Moran’s work. She pioneered CFRD research during her residency at the University of Minnesota in the 1980s when she noticed that a surprisingly high number of CF patients were developing diabetes. And much of Moran’s progress was made possible by PACFI, which has supported her CFRD studies for the last decade.
Moran has used the PACFI funding to get fledgling research ideas off the ground. Currently, she’s putting the organization’s money toward a study focused on updating mortality rate trends in CFRD patients.
The progress holds special meaning for Bob Derr and for everyone who knew Burke. “To lose someone you love and to have something like this come out of it is remarkable,” Derr says.
- Grace Birnstengel
Cutting edge aircraft engineering and pulmonary medicine might seem to have as much in common as chalk and cheese, but they both involve air flow dynamics, and scientists at the University of Cincinnati are researching the use of computer simulations developed for aircraft design to improve treatment of human airways in a variety of diseases such as cystic fibrosis, asthma, sleep apnea and snoring. A UC release reports that a more accurate and successful, yet complex approach used in designing an airplane is now taking off in the health care industry. The end result is helping patients with pulmonary disorders breathe easier, and their surgeons in considering novel treatment approaches.
Goutham Mylavarapu a senior research associate in the University of Cincinnati Department of Aerospace Engineering, and Ephraim Gutmark, PhD,, Ohio Eminent Scholar and UC distinguished professor of aerospace engineering and engineering mechanics, presented their research involving Computational Fluid Dynamics at the 39th American Institute of Aeronautics and Astronautics (AIAA) Dayton-Cincinnati Aerospace Sciences Symposium held on March 5 in Dayton, Ohio.
[Photo caption: Goutham Mylavarapu, left, and Ephraim Gutmark - Image credit: Jay Yocis]
Computational Fluid Dynamics, or CFD, uses computer algorithms to solve the flow of air or fluids for various applications. These algorithms are typically applied in aircraft design where CFD is often considered both an accurate and less expensive means of testing theories prior to investing in building physical models and testing in air tunnels.
However, over the past decade or so, CFD has also been applied to biological flows in the study of certain medically-related problems, including respiratory disorders like cystic fibrosis, and has gained a great deal of interest. Computer simulations originally developed in the field of aircraft design are finding new use in treating health conditions such as cystic fibrosis, asthma, sleep apnea and snoring.
The human respiratory tract is a pathway of hard and soft structures that take in and push out airflow. Dr. Mylavarapu explains that several pulmonary upper airway disorders are associated with vibration and/or deformation of the soft structures around the airway, leading to partial or complete collapse of the airway, as in the case of sleep apnea. In more severe cases, these airway obstructions or deformations can significantly impact quality of life and can even lead to death.
The researchers are using CFD simulations crossed over from the aerospace industry on actual medical data from patients with breathing disorders. Applying the equations to analyze the information being sought in an MRI can provide surgeons with a better idea on how to treat the problem, increasing the potential success of any surgical approach as well as reducing the number of surgeries (therefore a better recovery and less of a medical expense) for the patient.
“Historically, the evaluation of a patient’s airway is limited to clinical diagnosis with medical imaging,” explains Dr. Mylavarapu. “But the variability and complexity in the airway anatomy can limit the success rate of surgery. CFD provides a better understanding of respiratory flow and enables individualized treatment when applied to what we’re seeing with medical imaging.”
“Surgery is sometimes based on experience-based intuition, and it’s not always guaranteed that the end result will be effective,” says Dr. Gutmark. “CFD is another tool to provide surgeons with more quantitative information about the possible outcome during the planning of a surgical procedure.”
Last year, Dr. Gutmark was recognized for his outstanding contributions to physics with the award of an American Physical Society (APS) Fellowship — a designation limited to no more than one half of one percent of the APS membership and therefore a distinct honor signifying recognition by one’s professional peers.
According to APS, Dr. Gutmark’s “pioneering contributions to the fundamental flow physics of noise, combustion, and propulsion, and the development of flow control methodologies to achieve quiet aircraft engines, clean, stable and efficient combustion, and innovative propulsion systems” earned him the honor of fellowship in the society.
Spanning 30 years, Dr. Gutmark’s research and development of innovative fluid engineering applications have impacted diverse technical areas including turbomachinery for power generation and automotive turbochargers, aerodynamic flight control, and biomedical applications, among others. Since joining UC, Dr. Gutmark has been instrumental in generating over 30 new research projects in a range of interdisciplinary topics with a budget of over $27 million.
Dr. Gutmark credits UC for steadily backing his research efforts. “I get a lot of good support from UC,” he commented in a release. “From the beginning, I was given a nice space to develop my lab and the basic infrastructure to start activities was here so that really helped a lot to develop my ideas.”
During the last five years, Dr. Gutmark has also been working in collaboration with the UC Medical School and Cincinnati Children’s Hospital on researching new and innovative uses for fluid dynamics in biomedical applications. “We use fluid dynamics to understand the formation in voice and how to treat disorders of voice,” he observes.
Dr. Gutmark’s project with Cincinnati Children’s Hospital studies children with Down syndrome who suffer from sleep apnea. “We are looking to understand what leads to sleep apnea, how to prevent it or better treat it and how to help physicians to make good decisions on the treatment,” he says, noting that the common denominator of all of these activities is the application of fluid dynamics. “I see a lot of potential for growth and for more activities in the future,” he observes. Dr. Gutmark is optimistic that the physics disciplines of fluid dynamics will result in a stream of new techniques, procedures and aids to improve these medical treatments, noting that “Surgery is sometimes based on experience-based intuition, and it’s not always guaranteed that the end result will be effective. CFD is another tool to provide surgeons with more quantitative information about the possible outcome during the planning of a surgical procedure.”
The researchers are using CFD to examine both the flow and structure equations of the respiratory challenges of individual patients. They also applied the method to a virtual surgery involving a medical case in Sweden, leading to a successful outcome for the patient.
The research, conducted in UC’s Gas Dynamics and Propulsion Lab, is a partnership with Cincinnati Children’s Hospital Medical Center and the UC Medical Center, and is supported by funding from the National Institutes of Health (NIH #1R01HL105206-01).
Dr. Gutmark’s name and APS fellowship citation were published in the March 2013 issue of APS News for his pioneering contributions to the fundamental flow physics of noise, combustion, and propulsion, and the development of flow control methodologies to achieve quiet aircraft engines, clean, stable and efficient combustion, and innovative propulsion systems, nominated by the Division of Fluid Dynamics
The AIAA Dayton-Cincinnati Aerospace Sciences Symposium showcases cutting-edge aerospace research in the region and covers all general areas of aerospace science and technology. The event is organized and sponsored by the executive council of the AIAA Dayton-Cincinnati section and is sponsored by several organizations including the University of Cincinnati.
UC’s aerospace program is recognized by the Ohio Board of Regents as an Ohio Center of Excellence in Aerospace for its contributions to research and to the state’s economy. UC’s College of Engineering and Applied Science is a leader in engineering education, research and innovation, and is the world founder of cooperative education.
Sources: University of Cincinnati
Photo credits: University of Cincinnati – Jay Yocis
PHIL Lewis knows the life saving work of The Alfred and Australia’s organ donation program inside and out.
Soon after starting work as a medical scientist at The Alfred almost 20 years ago Mr Lewis received a double lung transplant at his own hospital, saving him from cystic fibrosis.
Still working at The Alfred, Mr Lewis has become proof of just how successful organ donation can be: this week he celebrated a 40th birthday nobody dreamt he would get anywhere near.
In the lead-up to his transplant, Mr Lewis was buoyed by statistics showing the operation would give him a good chance of being alive two years later.
He was also cautioned against dreaming of having children, because he might not be able to see many of their birthdays.
Now there is the promise of many more milestones to celebrate with his wife Amy and five-year-old son Kieran.
“I guess my life post-transplant is a pretty good example of what can be done,” Mr Lewis said.
“Before transplant I had a very short-term set of goals. I was just happy to see what came my way and I guess I have been doing that for 18 years now.
“I don’t think anybody could have said anything to me back then that could have prepared me mentally for the possibility that I would still be around and physically capable nearly 20 years later.”
But Mr Lewis has also experienced the tragic side of organ transplants: his brother Jeff died just a year after a double lung transplant because of cystic fibrosis.
“I have been in and out of hospital since I was six or seven years old,” Mr Lewis said.
“I get a lot of value out of the thought that I might actually be contributing something to a system that has benefited me so much
“Even when things look bad on paper, even when you have upsets, mishaps and misfortune, as long as you can push out the other side, the future really is unknown,” he said.
“So you might as well look positively at it, because you may be surprised.”
Vertex Pharmaceuticals has a number of ongoing clinical trials investigating the use of Ivacaftor in cystic fibrosis patients with mutations in the gene coding for cystic fibrosis transmembrane conductance regulator (CFTR). Two of its Phase III trials, which are studying patients homozygous for the F508del-CFTR mutation, recently switched the primary and secondary endpoints. TRAFFIC and TRANSPORT are still evaluating the efficacy and safety of Lumacaftor in combination with Ivacaftor (tradename Kalydeco), but the primary outcome measure is now “an absolute change in percent predicted forced expiratory volume in one second (FEV1).” The original primary endpoint was a relative change in lung function but is now a secondary endpoint.
The switch was made as “part of ongoing discussions with the FDA and was not based on anything going on in the study or anything observed in the study,” said Zach Barber, spokesman for Vertex.
Get more information about Cystic Fibrosis.
Both studies have three treatment arms. The first treatment arm is receiving 600 mg of lumacaftor daily and 250 mg of ivacaftor every 12 hours, the second is receiving 400 mg of lumacaftor and 250 mg of ivacaftor every 12 hours, and the third is receiving placebo throughout the 24-week period. The study began in March 2013, and completion is expected in April 2014. Results of these studies have the potential to generate $6 billion in new sales for Vertex.
Cystic fibrosis affects the lungs and digestive system, and the Cystic Fibrosis Foundation reports that 30,000 children and adults in the United States have the inherited chronic disease. Mutations in the CFTR gene lead to a defective protein that causes a buildup of thick, sticky mucus in the lungs and intestines, causing life-threatening lung infections and poor pancreatic enzyme activity to break down food. The drug Ivacaftor has been approved by the Food and Drug Administration since January 2012 for some subsets of cystic fibrosis patients. It improves the transport of chloride ions through CFTR by increasing the number of open channels.
US-based Proteostasis Therapeutics has extended its collaboration with Cystic Fibrosis Foundation Therapeutics (CFFT), to research, develop and commercialize therapeutic candidates to treat people with cystic fibrosis (CF) who have the most common CF mutation, ΔF508del.
CFFT is the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation.
The extension will focus on moving the company’s lead compounds toward a development candidate in 2014.
It will also focus on the company’s ain of filing an investigational new drug (IND) application with the US Food and Drug Administration in 2015.
The deal will continue to focus on the development of small molecule proteostasis regulators that modulate protein homeostasis pathways within the cell to correct the folding, trafficking and functional activity of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
The preclinical results have showed that ability of compounds to increase functional activity in ?F508 human bronchial epithelial cells.
In addition, the company’s lead candidates have shown significant synergistic properties with existing clinical-stage corrector candidates, more than doubling maximal activity and providing a strong foundation for the potential of combination therapies.
Proteostasis Therapeutics chief scientific officer Markus Haeberlein said the company is happy to continue its collaboration with CFFT, which has supported some of the most innovative and successful research in the field.
“This extension represents an endorsement of our novel approach to correcting CFTR activity and of the preclinical results that we have generated during the past 18 months,” Haeberlein said.