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Friday, January 4, 2019

Select Medical Holdings Corporation: Announces Business Outlook for 2019


Select Medical Holdings Corporation (“Select Medical”) (NYSE: SEM), today announced its business outlook for calendar year 2019.
Select Medical expects consolidated net operating revenues for the full year 2019 to be in the range of $5.2 billion to $5.4 billion.  Select Medical expects net income before interest, income taxes, depreciation and amortization, stock compensation expense, other income/(expense), and equity in earnings/(losses), or Adjusted EBITDA for the full year 2019 to be in the range of $660 million to $700 million.  Select Medical expects fully diluted income per common share for the full year 2019 to be in the range of $0.97 to $1.13.
Select Medical assumed a 25.5% effective tax rate when preparing the above business outlook for 2019. Select Medical assumed total shares outstanding of 135 million when preparing the above business outlook for 2019. This share count includes unvested restricted shares, which have participation rights and are allocated an equitable portion of earnings under the two-class method for calculating income per common share.
The following is a reconciliation of full year 2019 Adjusted EBITDA expectations as computed to the low and high points of the range to the closet comparable GAAP financial measure.  Refer to Select Medical’s most recent Form 10-Q filing for a discussion of Select Medical’s use of Adjusted EBITDA in evaluating financial performance and determining resource allocation.  Each item presented in the table below is an estimation of full year 2019 expectations (dollars in millions).
Range
Non-GAAP Measure Reconciliation
Low
High
Net Income attributable to Select Medical
$             132
$             153
Net Income attributable to non-controlling interests
56
65
Net Income
188
218
Income tax expense
64
74
Interest expense
200
200
Equity in earnings of unconsolidated subsidiaries
(25)
(25)
Income from operations
427
467
Stock compensation expense
27
27
Depreciation and amortization
206
206
Adjusted EBITDA
$             660
$             700
Select Medical is one of the largest operators of critical illness recovery hospitals (previously referred to as long term acute care hospitals), rehabilitation hospitals (previously referred to as inpatient rehabilitation facilities), outpatient rehabilitation clinics, and occupational health centers in the United States based on the number of facilities. Our reportable segments include the critical illness recovery hospital segment, rehabilitation hospital segment, outpatient rehabilitation segment, and Concentra segment. As of September 30, 2018, Select Medical operated 97 critical illness recovery hospitals in 27 states, 26 rehabilitation hospitals in 11 states, and 1,649 outpatient rehabilitation clinics in 37 states and the District of Columbia. Select Medical’s joint venture subsidiary Concentra operated 525 occupational health centers in 41 states. Concentra also provides contract services at employer worksites and Department of Veterans Affairs community-based outpatient clinics. At September 30, 2018, Select Medical had operations in 47 states and the District of Columbia. Information about Select Medical is available at www.selectmedical.com.

Low-Dose Amitriptyline Effective for Chronic Low Back Pain


Efficacy of Low-Dose Amitriptyline for Chronic Low Back Pain: A Randomized Clinical Trial

Urquhart DM, Wluka AE, van Tulder M, et al
JAMA Intern Med. 2018;178:1474-1481

Study Summary

The largest contributor to global disability is low back pain, for which various treatments are available but are of limited efficacy. International clinical guidelines recommend low-dose antidepressants for management of chronic low back pain, and these are often prescribed for this widespread condition. To date, however, there has been no evidence that they are effective for this indication.
The goal of this double-blind, randomized clinical trial was to compare the efficacy of 6 months of treatment with a low-dose antidepressant (amitriptyline, 25 mg/day) versus an active comparator (benztropine mesylate, 1 mg/day) in reducing pain, disability, and work absence and interference in adults with chronic, nonspecific low back pain.
Participants (n = 146; mean age, 54.8 ± 13.7 years; 61.6% male) were recruited from hospital/medical clinics and through advertising. Pain intensity at 3 and 6 months was measured with the visual analogue scale, and the Descriptor Differential Scale was the primary outcome. The Roland Morris Disability Questionnaire and the Short Form-Health and Labour Questionnaire were used to determine secondary outcomes of disability and work absence and interference.
Among 118 participants (81%) who completed 6-month follow-up, pain reduction with low-dose amitriptyline or the comparator did not differ significantly at 6 months (adjusted difference, -7.81; 95% confidence interval [CI], -15.7 to 0.10) or at 3 months (-1.05; 95% CI, -7.87 to 5.78), independent of baseline pain. The low-dose amitriptyline group versus the comparator group had a statistically significantly better improvement in disability at 3 months (adjusted difference, -1.62; 95% CI, -2.88 to -0.36), but not at 6 months (-0.98; 95% CI, -2.42 to 0.46). Work outcomes of absence or hindrance at 6 months or 3 months and the number of participants who withdrew because of adverse events (12%) did not differ significantly between the groups.

Viewpoint

This trial is limited by the heterogeneity of patients with chronic, nonspecific low back pain and its possibly insufficient power to detect differences in work or additional outcomes. Nonetheless, this first double-blind, randomized controlled trial of a low-dose tricyclic antidepressant for this condition suggests that it may be effective. Compared with an active agent, low-dose amitriptyline was associated with a reduction in disability at 3 months and a nonsignificant improvement in pain intensity at 6 months. The two treatments appeared to be equally well tolerated and effective for pain relief.
The findings merit further testing in large-scale randomized trials that include dose escalation. Given the global opioid overuse epidemic, clinicians may find it useful to consider low-dose amitriptyline while awaiting these results, particularly if the only alternative is opioids.
Low-dose amitriptyline has been shown to be effective in other pain conditions, and its off-label prescription for low back pain is rapidly increasing. Because low back pain management focuses on progressively increasing activity levels, low-dose amitriptyline may be relevant to overall therapy by reducing pain, disability, and fear, which are important barriers to activity.

Cognitive Risks Tied to High Blood Pressure Brain Changes


Changes in periventricular white matter hyperintensities (WMH) accompanied development of mild cognitive impairment in adults with hypertension, a longitudinal population-based study in Spain found.
Hypertensive older adults who showed a marked progression of periventricular WMH had a sixfold risk of incident mild cognitive impairment compared with patients without this progression (OR 6.184, 95% CI 1.506-25.370, P=0.011), according to Pilar Delgado Martinez, MD, PhD, of the Institut de Recerca Hospital Vall d’Hebron in Barcelona, and colleagues.
These patients also demonstrated a significant decrease in global cognition (adjusted mean -0.519 ± 0.176 vs 0.057 ± 0.044, P=0.004), the team reported in Hypertension.
Finding new ways to detect cognitive impairment may help identify who is at risk for dementia, the authors noted. “As patients with hypertension are at high risk for cerebral small vessel disease progression, the identification of specific lesions that have higher odds of impairing cognition may have useful implications in clinical practice.”
The study builds upon prior research about cerebral small vessel disease and cognitive function, noted Ilya Nasrallah, MD, PhD, of the University of Pennsylvania in Philadelphia, who was not involved with the study.
“Understanding the link between small vessel disease and cognition is important because we are currently able to alter the course of small vessel disease,” Nasrallah told MedPage Today. “In the SPRINT study, for example, we showed that intensive treatment of hypertension to <120 mm Hg systolic resulted in lower incident mild cognitive impairment and lower progression of cerebral white matter lesions.”
In the Barcelona study, the researchers followed 345 hypertensive men and women in the ISSYS (Investigating Silent Strokes in Hypertensives: A Magnetic Resonance Imaging Study) cohort, an ongoing epidemiological, observational study. At baseline (from 2010 to 2012), participants were a median age of 65 and had no previous dementia or stroke. Most — 94.2% — were being treated for hypertension and 55.4% were male.
Mean follow-up was 3.95 years and average blood pressure at follow-up was 144.5/76.5 mm Hg.
At baseline and follow-up, patients underwent evaluations that included brain MRI and cognitive testing. The researchers used the Dementia Rating Scale 2nd version (DRS-2) to assess a general measure of cognitive function, and asked participants whose DRS-2 scores suggested cognitive impairment to undergo a second evaluation to establish a cognitive diagnosis. They qualitatively defined MRI changes in periventricular white matter hyperintensities and deep white matter hyperintensities as “none,” “minor,” or “marked.”
During the study, 9.1% of participants developed mild cognitive impairment. Incident lacunar infarcts occurred in 6.1% of participants and cerebral microbleeds in 5.5%. Minor or marked periventricular WMH progression appeared in 22% of patients and deep WMH progression occurred in 48%.
Only marked progression of periventricular WMH was associated with incident mild cognitive decline; changes in deep WMH, incident infarcts, and cerebral microbleeds were not tied to incident cognitive impairment. Incident cerebral microbleeds, however, were tied to a decline in attention.
“This study confirms previous observations on the effects of hypertension on brain vasculature and cognitive function in elderly individuals,” observed Oscar Lopez, MD, of the University of Pittsburgh, who was not involved with the research. “It emphasizes the importance of a strict adherence to antihypertensive treatments,” he told MedPage Today.
The researchers noted several limitations to their study. Due to budget constraints, patients were selected for follow-up based on the severity of baseline cerebral small vessel disease, so results may not apply to all patients with hypertension. Volumetric approaches to measuring MRI changes in hyperintensities would have been more precise than qualitative assessments. The team also did not include neurodegeneration markers like tau or amyloid-beta which may be related to hypertension and cerebral small vessel disease lesions.
This research was funded by the Instituto de Salud Carlos III and AGAUR, with the support of the Secretary of Universities and Research of the Department of Economy and Knowledge, and the European Regional Development Fund.
The researchers reported no disclosures.

Cosmetic, Plastic Surgeons Squabble Over ‘Board Certified’ Label


Scope of practice fights are never pretty.
But one pitting cosmetic surgeons against plastic surgeons has turned particularly ugly, with charges of medical negligence, anti-competitiveness, and bias flying in both directions during a recent California licensing board meeting, viewable on webcast.
The rift is over whether California members of the American Board of Cosmetic Surgery (ABCS) can advertise themselves as “board certified,” which the Medical Board of California does not currently allow. Physicians can say they specialize in cosmetic procedures such as breast augmentations, hair transplants, and tummy tucks — typically elective and paid for in cash — but they cannot use the magic words “board certified” in the specialty.
That privilege is reserved for those physicians certified by boards that have proven to state regulators that their diplomates are sufficiently “trained and tested” in a way that is — and this is a mouthful — “equivalent” to an American Board of Medical Specialties board or is certified by an association with a postgraduate training program approved by the Accreditation Council for Graduate Medical Education.
But California law allows the board to grant exceptions, and it has done so for fourspecialty boards not meeting the above criteria yet able to prove their certification protocols were equivalent. (These boards govern facial and plastic reconstructive surgery, sleep medicine, pain medicine, and spine surgery.) The medical board had twice before rejected the cosmetic surgeons’ petition, but now the ABCS says it has revised its programs and deserves its own exception.
Saying they’re board certified is critically important, they say, and without that their ability to communicate their proficiencies directly to prospective patients is crippled. Cosmetic providers are not included in insurance plan networks, so they publicize themselves through internet and marketing materials.
But thus far, the cosmetic surgeons’ effort has fallen short, with the board issuing a final denial of their petition in a Dec. 18 vote.
Right to free speech
“Why is there such opposition to the ABCS?”, its president, Alex Sobel, DO, rhetorically asked members of the state board. “These are elective surgical procedures and patients see providers directly rather than by a referral network.”
“What California is doing with its restricted position is not allowing this specialty and board organization to grow,” he continued, calling it a wrongful restriction of commercial free speech, and a longstanding “turf battle” between plastic and cosmetic surgeons.
He and his colleagues submitted hundreds of pages to document the specialty’s strict fellowships and training protocols, and are the only specialty that provides that. Besides, Texas and Oklahoma licensing agencies accept their training as “equivalent,” they said.
But the American Board of Plastic Surgeons, an ABMS-member board, vehemently objected. Testifying in October against the ABCS petition for “board equivalency,” Debra Johnson, MD, former American Society of Plastic Surgeons president and a Sacramento plastic surgeon, hurled a raft of accusations at the ABCS’s training.
“Secret shopper”
For starters, she said, her organization engaged in “secret shopping” of a fellowship program to inquire whether the fellow in training or the doctor would do a breast augmentation procedure on a patient. An emailed reply said “the fellow only watches the surgery, and the doctor does all the work.”
“Pardon me, but this is laughable,” Johnson told the board.
She also questioned cosmetic surgeons’ ability to provide safe care, saying that after reviewing all of ABCS’s members in California, 24% “had disciplinary actions compared to less than 4%” of those certified in plastic surgery.
On top of that, her review of the websites of dozens of California cosmetic surgeons showed 26 were flouting the law by advertising themselves as “board certified cosmetic surgeons.” She said her group was filing 26 complaints with the board to make them stop.
In an interview, Johnson called the ABCS “a bogus board and a marketing tool.”
“We hope they will remain in their scope of practice, which is dermatology or ENT or ob/gyn. It is not plastic surgery.”
Sobel and his colleagues vehemently denied so many of their members have had disciplinary actions, or that their training lacks equivalent value and integrity.
Rather, those practicing other specialties who venture into cosmetic surgery without appropriate training are the ones endangering public safety.
“The clear anti-competitive intent and bias [from plastic surgery groups] truly prohibits… patient safety and care,” Sobel told the board. He said doctors from other specialties wish “to capitalize on consumer demand and profit from offering cosmetic procedures, despite minimal or no training in cosmetic medicine.”
Plastic surgeons had more comebacks. Their training takes place in academic settings rather than small office practices. “There’s clearly a high degree of variability in the breadth of patient experiences and patient care,” added Michael Wong, MD, president of the California Society of Plastic Surgeons.
Who gets more reprimands?
Cosmetic surgeons come to that specialty after training in other fields, such as ophthalmology, otolaryngology, dermatology, or obstetrics and gynecology, and have “their own subset” of knowledge, Wong continued. “In contrast, plastic surgery training covers the whole body of surgical anatomy… from head to toe.”
Cosmetic breast procedures, a large portion of cosmetic care, are a case in point. “You can see these physician specialties have notable deficiencies in knowledge of anatomy and pathology of the breast” that can’t be obtained in a one-year fellowship, he said.
Jacob Haiavy, MD of Rancho Cucamonga, past ABCS president, shot back. “Our colleagues, with all due respect, think that they are the only ones that should be practicing this specialty.”
He denied a higher number of licensing reprimands among cosmetic surgeons and noted plastic surgeons with disciplinary actions, singling one out.
“Look up Kenneth Benjamin Hughes who still has his license, has killed three people, one fat embolism, 10 bowel perforations, one thromboembolism and other patients are really, really sick.”
So many confusing claims prompted the medical board to hire Neal Fleming, MD, vice-chair of education and director of cardiovascular and thoracic anesthesiology at the University of California, Davis, to verify the ABCS’s training regimen. After reviewing “three volumes” of documents, Fleming couldn’t vouch for the ABCS.
“The educational resources provided by the sponsoring institutions, when listed, appear to be largely limited to a computer and maybe an office. The emphasis is on clinical case volume,” he wrote in a lengthy October review.
The Supreme Court “tooth-whitening” case
But Sobel and his ABCS colleagues protested again. They suggested the licensing agency’s members were putting themselves in legal peril, given the U.S. Supreme Court’s 2015 ruling in North Carolina Board of Dental Examiners v. Federal Trade Commission. At issue was whether the state’s dentist-controlled board could block non-dentists from performing tooth-whitening procedures.
In a nutshell, the court said licensing boards composed of market participants (that is, practicing providers) only have immunity from antitrust law when they are actively supervised by the state, which physicians on California’s medical board are not. Thus, the ABCS suggested, California medical board members are not only exceeding their authority in preventing cosmetic surgeons from claiming board certification, but are illegally suppressing competition.
The medical board debated at length, then asked Fleming to take another look.
So he did, asking the ABCS to elaborate on some 15 concerns that prompted his October recommendation.
But again, Fleming found that ABCS training programs as well as its responses to his questions fell short. For example, training program directors didn’t always have academic appointments or were engaged in verifiable scholarly activities, Fleming said.
“No documentation is provided to assure that even these most minimal of requirements are consistently provided by the training programs,” Fleming wrote in a Dec. 14 report to the board.
Of particular concern was that even though the ABCS had improved its training, cosmetic surgeons who had undergone their training before then would be grandfathered. “They were certified under guidelines previously not felt to be acceptable,” Fleming wrote.
Sobel and his ABCS colleagues reacted viscerally. They fired off an 11-page rebuttal, accusing Fleming, and perhaps the board, of “egregious dereliction of responsibility” and “predetermined bias” with “an unwillingness to get to the truth of the matter.”
Fleming was overly influenced by plastic surgeons, specifically CSPS president Wong, who works at UC Davis, said ABCS executive director attorney Peter Canalia. He likened it to “demanding that Chevrolet seek Ford’s approval to sell their cars in California.”
Fleming told the board he was dismayed by the rebuttal’s “gratuitous personal insults” since he’d done his best to find documentation to support the ABCS’s petition. The ABCS’s tone didn’t help.
The board unanimously voted to deny the petition. And that may be the end of the story — a state sunset rule prohibits the board from revisiting the issue.
But, asked if the ABCS might go to court based on the North Carolina Board ruling, Sobel replied that the ABCS is “considering all possible pathways forward.”

Fungi cause brain infection and impair memory


Fungal infections are emerging as a major medical challenge, and a team led by researchers at Baylor College of Medicine has developed a mouse model to study the short-term consequences of fungal infection in the brain.
The researchers report in the journal Nature Communications the unexpected finding that the common yeast Candida albicans, a type of fungus, can cross the blood-brain barrier and trigger an inflammatory response that results in the formation of granuloma-type structures and temporary mild memory impairments in mice. Interestingly, the granulomas share features with plaques found in Alzheimer’s disease, supporting future studies on the long-term neurological consequences of sustained C. albicans infection.
“An increasing number of clinical observations by us and other groups indicates that fungi are becoming a more common cause of upper airway allergic diseases such as asthma, as well as other conditions such as sepsis, a potentially life-threatening disease caused by the body’s response to an infection,” said corresponding author Dr. David B. Corry, professor of medicine-immunology, allergy and rheumatology and Fulbright Endowed Chair in Pathology at Baylor College of Medicine.
Importantly, explains Corry, fungal infections causing airway allergic diseases and sepsis have been associated with increased risk for dementia later.
“These observations led us to investigate the possibility that fungus might produce a brain infection and, if so, the consequences of having that kind of infection,” said Corry, who also is a member of the Dan L Duncan Comprehensive Cancer Center.
The researchers began their investigation by developing a mouse model of a low-grade fungus infection with the common yeast C. albicans that would not cause severe disease, but might carry implications for brain function. They tested several doses and finally settled on one dose of 25,000 yeasts.
They injected C. albicans into the blood stream of mice and were surprised to discover that the yeast can cross the blood-brain barrier, a robust protective mechanism the brain employs to exclude all kinds of large and small molecules, as well as a number of microorganisms that can potentially damage the brain.
“We thought that yeast would not enter the brain, but it does,” Corry said. “In the brain, the yeast triggered the activity of microglia, a resident type of immune cell. The cells became very active ‘eating and digesting’ the yeast. They also produced a number of molecules that mediated an inflammatory response leading to the capture of the yeasts inside a granule-type structure inside the brain. We called it fungus-induced glial granuloma, or FIGG.”
Corry and his colleagues also tested the animals’ memory in both yeast-infected and non-infected mice. They found that infected mice had impaired spatial memory, which reversed when the infection cleared.
The mice cleared the yeast infection in about 10 days; however, the microglia remained active and the FIGGs persisted well past this point, out to at least day 21. Intriguingly, as the FIGGs formed, amyloid precursor proteins accumulated within the periphery and amyloid beta molecules built up around yeast cells captured at the center of FIGGs. These amyloid molecules are typically found in plaques that are the trademark of Alzheimer’s disease.
“These findings suggest that the role fungi play in human illness potentially goes well beyond allergic airway disease or sepsis,” Corry said. “The results prompted us to consider the possibility that in some cases, fungi also could be involved in the development of chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s and multiple sclerosis. We are currently exploring this possibility.”
“For these reasons, if we better understand how our immune system deals with this kind of constant threat and what are the weaknesses in our immunological armor that occur with aging that allow fungal disease to take root, then we would likely increases the possibility of finding ways to fight back, ” Corry said.
Story Source:
Materials provided by Baylor College of MedicineNote: Content may be edited for style and length.

Journal Reference:
  1. Yifan Wu, Shuqi Du, Jennifer L. Johnson, Hui-Ying Tung, Cameron T. Landers, Yuwei Liu, Brittany G. Seman, Robert T. Wheeler, Mauro Costa-Mattioli, Farrah Kheradmand, Hui Zheng, David B. Corry. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficitsNature Communications, 2019; 10 (1) DOI: 10.1038/s41467-018-07991-4

Our bodies may cure themselves of diabetes in the future


Diabetes is caused by damaged or non-existing insulin cells inability to produce insulin, a hormone that is necessary in regulating blood sugar levels. Many diabetes patients take insulin supplements to regulate these levels.
In collaboration with other international researchers, researchers at the University of Bergen have, discovered that glucagon.producing cells in the pancreas, can change identity and adapt so that they do the job for their neighbouring damaged or missing insulin cells.
“We are possibly facing the start of a totally new form of treatment for diabetes, where the body can produce its own insulin, with some start-up help,” says Researcher Luiza Ghila at the Raeder Research Lab, Department of Clinical Science, University of Bergen (UiB).
Cells can change identity
The researchers discovered that only about 2 per cent the neighbouring cells in the pancreas could change identity. However, event that amount makes the researchers are optimistic about potential new treatment approaches.
For the first time in history, researchers were able to describe the mechanisms behind the process of cell identity. It turns out that this is not at passive process, but is a result of signals from the surrounding cells. In the study, researchers were able to increase the number of insulin producing cells to 5 per cent, by using a drug that influenced the inter-cell signalling process. Thus far, the results have only been shown in animal models.
“If we gain more knowledge about the mechanisms behind this cell flexibility, then we could possibly be able to control the process and change more cells’ identities so that more insulin can be produced, ” Ghila explains.
Possible new treatment against cell death
According to the researchers, the new discoveries is not only good news for diabetes treatment.
“The cells´ ability to change identity and function, may be a decisive discovery in treating other diseases caused by cell death, such as Alzheimer´s disease and cellular damage due to heart attacks,” says Luiza Ghila.
Facts: Pancreas
  • There are three different types of cells in the pancreas: alpha-cells, beta-cells and delta-cells. These produce different kinds of hormones for blood sugar regulation.
  • The cells make clusters. Alpha-cells produce glucagon, which increases the blood sugar levels. Beta-cells produce insulin, which decreases glucagon levels. Delta-cells produce somatostatin, which controls the regulation of the Alpha and Beta Cells.
  • Persons with diabetes have a damaged beta-cell function, and therefore have constant high blood sugar levels.
Story Source:
Materials provided by The University of BergenNote: Content may be edited for style and length.

Journal Reference:
  1. Valentina Cigliola, Luiza Ghila, Fabrizio Thorel, Léon van Gurp, Delphine Baronnier, Daniel Oropeza, Simone Gupta, Takeshi Miyatsuka, Hideaki Kaneto, Mark A. Magnuson, Anna B. Osipovich, Maike Sander, Christopher E. V. Wright, Melissa K. Thomas, Kenichiro Furuyama, Simona Chera, Pedro L. Herrera. Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon α-cellsNature Cell Biology, 2018; 20 (11): 1267 DOI: 10.1038/s41556-018-0216-y

Lung disease patients may find relief by breathing in messenger RNA molecules


Messenger RNA, which can induce cells to produce therapeutic proteins, holds great promise for treating a variety of diseases. The biggest obstacle to this approach so far has been finding safe and efficient ways to deliver mRNA molecules to the target cells.
In an advance that could lead to new treatments for lung disease, MIT researchers have now designed an inhalable form of mRNA. This aerosol could be administered directly to the lungs to help treat diseases such as cystic fibrosis, the researchers say.
“We think the ability to deliver mRNA via inhalation could allow us to treat a range of different disease of the lung,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study.
The researchers showed that they could induce lung cells in mice to produce a target protein — in this case, a bioluminescent protein. If the same success rate can be achieved with therapeutic proteins, that could be high enough to treat many lung diseases, the researchers say.
Asha Patel, a former MIT postdoc who is now an assistant professor at Imperial College London, is the lead author of the paper, which appears in the Jan. 4 issue of the journal Advanced Materials. Other authors of the paper include James Kaczmarek and Kevin Kauffman, both recent MIT PhD recipients; Suman Bose, a research scientist at the Koch Institute; Faryal Mir, a former MIT technical assistant; Michael Heartlein, the chief technical officer at Translate Bio; Frank DeRosa, senior vice president of research and development at Translate Bio; and Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute.
Treatment by inhalation
Messenger RNA encodes genetic instructions that stimulate cells to produce specific proteins. Many researchers have been working on developing mRNA to treat genetic disorders or cancer, by essentially turning the patients’ own cells into drug factories.
Because mRNA can be easily broken down in the body, it needs to transported within some kind of protective carrier. Anderson’s lab has previously designed materials that can deliver mRNA and another type of RNA therapy called RNA interference (RNAi) to the liver and other organs, and some of these are being further developed for possible testing in patients.
In this study, the researchers wanted to create an inhalable form of mRNA, which would allow the molecules to be delivered directly to the lungs. Many existing drugs for asthma and other lung diseases are specially formulated so they can be inhaled via either an inhaler, which sprays powdered particles of medication, or a nebulizer, which releases an aerosol containing the medication.
The MIT team set out to develop a material that could stabilize RNA during the process of aerosol delivery. Some previous studies have explored a material called polyethylenimine (PEI) for delivering inhalable DNA to the lungs. However, PEI doesn’t break down easily, so with the repeated dosing that would likely be required for mRNA therapies, the polymer could accumulate and cause side effects.
To avoid those potential side effects, the researchers turned to a type of positively charged polymers called hyperbranched poly (beta amino esters), which, unlike PEI, are biodegradable.
The particles the team created consist of spheres, approximately 150 nanometers in diameter, with a tangled mixture of the polymer and mRNA molecules that encode luciferase, a bioluminescent protein. The researchers suspended these particles in droplets and delivered them to mice as an inhalable mist, using a nebulizer.
“Breathing is used as a simple but effective delivery route to the lungs. Once the aerosol droplets are inhaled, the nanoparticles contained within each droplet enter the cells and instruct it to make a particular protein from mRNA,” Patel says.
The researchers found that 24 hours after the mice inhaled the mRNA, lung cells were producing the bioluminescent protein. The amount of protein gradually fell over time as the mRNA was cleared. The researchers were able to maintain steady levels of the protein by giving the mice repeated doses, which may be necessary if adapted to treat chronic lung disease.
Broad distribution
Further analysis of the lungs revealed that mRNA was evenly distributed throughout the five lobes of the lungs and was taken up mainly by epithelial lung cells, which line the lung surfaces. These cells are implicated in cystic fibrosis, as well as other lung diseases such as respiratory distress syndrome, which is caused by a deficiency in surfactant protein. In her new lab at Imperial College London, Patel plans to further investigate mRNA-based therapeutics.
In this study, the researchers also demonstrated that the nanoparticles could be freeze-dried into a powder, suggesting that it may be possible to deliver them via an inhaler instead of nebulizer, which could make the medication more convenient for patients.
TranslateBio, a company developing mRNA therapeutics, partially funded this study and has also begun testing an inhalable form of mRNA in a Phase 1/2 clinical trial in patients with cystic fibrosis. Other sources of funding for this study include the United Kingdom Engineering and Physical Sciences Research Council and the Koch Institute Support (core) Grant from the National Cancer Institute.
Story Source:
Materials provided by Massachusetts Institute of TechnologyNote: Content may be edited for style and length.

Journal Reference:
  1. Asha Kumari Patel, James C. Kaczmarek, Suman Bose, Kevin J. Kauffman, Faryal Mir, Michael W. Heartlein, Frank DeRosa, Robert Langer, Daniel G. Anderson. Inhaled Nanoformulated mRNA Polyplexes for Protein Production in Lung EpitheliumAdvanced Materials, 2019; 1805116 DOI: 10.1002/adma.201805116