Induced pluripotent stem cells reprogrammed from human skin (California Institute for Regenerative Medicine)
29 April 2016. A challenge offered through InnoCentive is seeking new methods of harnessing adult stem cells for regenerative medicine. The competition has a total purse of $15,000 and a 24 June 2016 deadline for submissions. The sponsor of the challenge, pharmaceutical company Boehringer Ingelheim, also seeks research plans related to the challenge proposals, with funding amounts negotiated separately.
The competition is conducted by InnoCentive in Waltham, Massachusetts that conducts open-innovation, crowdsourcing competitions for corporate and organization sponsors. Free registration is required to see details of the competition. In November 2015, Boehringer Ingelheim revealed that it plans to make more use of crowdsourcing for R&D ideas through InnoCentive and others.
From the competition, Boehringer Ingelheim hopes to uncover new processes that further the promise of endogenous, or adult, stem cells for regenerative medicine. Adult stem cells are those inhabiting human tissue, as opposed to embryonic stem cells that can transform into any cells in the body. Adult stem cells, however, may be more readily available with patients, and do not carry the ethical baggage of embryonic stem cells with some people.
Adult stem cells maintain and repair the tissue in which they reside, and like embryonic stem cells transform or differentiate into some or all of their representative tissue cells. Current methods for differentiating adult stem cells into functioning tissue cells, in most cases, first require genetically reprogramming stem cells into a state similar to embryonic cells. These induced pluripotent stem cells are already proving to be valuable tools in drug development, and eventually for transplantation.
Boehringer Ingelheim is seeking new molecular mechanisms and processes for collecting, stimulating, and differentiating adult stem cells for regenerative cell-replacement therapies. The solutions should address, direct, or enhance the built-in capabilities of adult stem cells to maintain human tissue.
InnoCentive calls this type of competition an ideation challenge, which requires a brief (two-page) proposal. Ideation proposals can contain ideas originating from the participants, the public domain where no restrictions are applied, or third-parties where participants have the rights to propose solutions with those ideas. Participants are asked not to submit confidential information in their proposals.
Boehringer Ingelheim says it plans to award the entire $15,000 challenge purse, with at least one award being no smaller than $5,000 and no award being smaller than $1,000. The sponsor also indicates that submitting a proposal grants the sponsor a non-exclusive, perpetual, and royalty-free license to use any information in the proposal. An exclusive transfer of intellectual property rights to the sponsor, however, is not required.
Participants in the competition with their own research facilities can apply for funding to carry out the research plan in their challenge proposals. Boehringer Ingelheim says delivery schedules and funding amounts for these research plans will be negotiated separately from the challenge awards. The company says the optional research proposals will also be considered separately from the challenge submissions, but still have a 24 June 2016 deadline.
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Katie Brenner (Bryce Richter, Univ. of Wisconsin-Madison)
29 April 2016. A new company is taking shape that aims to make it easier for women to get pregnant, based on research at a biochemistry lab at University of Wisconsin. BluDiagnostics, in Madison, founded by postdoctoral research Katie Brenner in the lab of biochemistry professor Douglas Weibel, a co-founder of the company, already raised $1.2 million in seed funding.
Brenner’s interest in the topic is more than academic. In her own experiences to start a family, Brenner discovered the difficulty and unreliability of finding the optimal ovulation time that today uses a combination of urine and blood tests to measure levels of hormone indicators. “We looked at how many women struggle to become pregnant,” says Brenner in a university statement, “and they don’t know if it’s something about their body, their partner’s body, or just poor timing. It’s hard to find information at a time when you want a lot of information and control.”
At Wisconsin, Brenner applies her bioengineering doctorate to practical microbiology issues. In this case, she and Weibel devised a process where women wet a paper strip with saliva, a more readily available bodily fluid than blood or urine. The paper strip is infused with reagents that test for the hormones progesterone and estrogen, where changes in levels are indicators of ovulation.
Hormone level measurements from the paper strip are sent to a smartphone app called Fertility Finder that records the readings and tracks the daily measurements over time. Brenner adds that “nobody wants to take a blood test every day, so we developed one using saliva instead.” She and Weibel filed a patent application for their technology.
BluDiagnostics started officially in 2012 with life sciences business consultant Jodi Schroll joining Brenner and Weibel as co-founder, but real activity with the company began only last year. In the space of three months, June through August 2015, BluDiagnostics won three business contests in Wisconsin, including the Governor’s Business Plan Competition. These wins helped the company attract loans of $1.2 million as seed funding in January and February of 2016.
BluDiagnostics aims to gain FDA approval for its device, and reach the market in 2017. Brenner believes its basic technology can be extended to improve reporting on other women’s health issues. “Most studies collect self-reported data on menstrual cycles: what you ate, your mood and exercise, and try to reach medical conclusions,” she notes. “For the first time, we will marry that data with cold, hard numbers to support a better understanding of relationships between hormonal trends and underlying disorders.”
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Microsatellite nodes in lab before launch (NASA)
28 April 2016. A start-up satellite imaging provider and agency of the United Nations are partnering on new ways to use satellite imaging to further the UN’s humanitarian, peace-keeping, and climate change mitigation missions. Financial terms between BlackSky Global LLC in Seattle and the United Nations Institute for Training and Research, or Unitar, were not disclosed.
BlackSky Global, founded in 2013 and that began operations in June 2015, is offering high-resolution satellite imaging on a fee-for-image model, which the company says will deliver images faster and at a fraction of the cost of current providers. The company plans to launch 6 satellites this year, with its full fleet of 60 satellites in orbit by 2019, which will enable BlackSky to provide a 30-square kilometer image for less than $100, about one-tenth of the current industry average, in 2 hours or less.
In their agreement, BlackSky and Unitar will jointly explore and develop new applications for satellite imagery that support the UN’s work in humanitarian relief and sustainable development. A division of Unitar known as Unosat already provides services with geographic information systems and satellite imagery for UN agencies and member states, as well as other international agencies and non-government organizations.
Unitar and Unosat are particularly interested in BlackSky’s professed ability to deliver images with a resolution of 1 square meter and fast turn-around. “The combination of detailed 1 meter resolution imagery with frequent revisit times and near real-time delivery,” says Unosat manager Einar Bjorgo in a Unitar statement, “will open new applications areas and further strengthen existing services we provide to the UN family and developing countries.”
Unitar and BlackSky plan to explore applications for the company’s satellite services to support the UN’s work in humanitarian relief and early recovery, peace-keeping missions, climate change adaptation, disaster risk reduction, cultural heritage protection, environmental monitoring, and sustainable development.
To compete with current providers of high-resolution satellite images, BlackSky plans to launch a fleet of microsatellites, mainly in mid-latitudes, that provide frequent revisiting rates over 95 percent of the world’s population. Those satellites will provide still images and 1-frame-per-second video, supported by a software program for customers to request and receive images via the Internet.
The company expects to launch its first 6 satellites by the end of 2016, with commercial services starting in 2017. BlackSky is an independent subsidiary of Spaceflight Industries. The company says it raised $28.5 in financing over the past 2 years, and has 20 employees.
Following is an example of Unosat images currently provided, in this case showing damage from the recent earthquake in Ecuador.
Satellite-detected damaged structures in Chone area in Manabi Province, Ecuador, located about 175 km south west of the 16 April 2016 Muisne earthquake main shock epicenter. Click on image for full-size display. (Unosat)
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Acute myeloid leukemia cells (Cancer Genome Atlas, NIH)
28 April 2016. A clinical trial shows engineered immune-system cells transplanted in patients with one form of leukemia achieves a 93 percent remission rate. Results of the trial, at the Fred Hutchinson Cancer Research Center in Seattle, were reported in the 25 April issue of The Journal of Clinical Investigation.
Fred Hutchinson Center researchers were testing the cancer-fighting ability of T-cells, white blood cells in the immune system, engineered with added synthetic molecules known as chimeric antigen receptors. Without these added weapons, cancerous cells evade the immune system, allowing tumors to grow unchecked. The chimeric antigen receptors added to T-cells, called CAR-Ts, were designed in this case to attack cancer cells identified with specific CD19 proteins. These CD19 molecules act as indicators of weakened B-cells in the immune system found with blood-related cancers.
The CAR-T technology developed at the Fred Hutchinson Center is licensed to a spin-off company Juno Therapeutics, founded in 2013 with researchers at Memorial Sloan-Kettering Cancer Center in New York, and Seattle Children’s Research Institute. Juno is a sponsor of this clinical trial, with several of the authors supported by or with equity stakes in the company.
In the CAR-T process, blood cells are extracted from cancer patients and their T-cells with the required genetic sequences in the cells’ DNA are separated for enrichment. The T-cells are then grown in the lab into dosage quantities for infusion back into the patient. In the body, the engineered T-cells multiply in the presence of targeted proteins, in this case CD19 proteins, and attack their corresponding tumor cells.
The clinical trial recruited 32 patients with relapsing or persistent B cell acute lymphoblastic leukemia, a cancer of blood and bone marrow that progresses quickly, making an overabundance of immature lymphocytes, a type of white blood cell. It is also the most common type of cancer among children, although it can also affect adults. Two of the individuals developed complications from prior treatments, leading to one death. The 30 remaining participants received a form of chemotherapy that enhances immune-system response against cancerous cells, before receiving the engineered T-cells.
Of the 30 individuals, 29 still had leukemia cells in their bone marrow following the chemotherapy and CAR-T treatments. After 3 weeks, 27 of these 29 participants had no detectable leukemia in their bone marrow, according to flow cytometry tests that use lasers to identify fluorescent-labeled cells. This remission of leukemia occurred at all dosage levels tested. The treatments also removed cancer that spread to other parts of the participants’ bodies.
The results, however, were not uniformly favorable. Five of the 27 remission patients later relapsed, some of which did not respond to a second CAR-T therapy. In addition, many of the participants experienced cytokine release syndrome that occurs when enzymes are emitted from cells targeted by treatments, which can cause flu-like symptoms such as fevers, nausea, and muscle pain, as well as neurological symptoms including hallucinations and delirium.
The research team plans to follow-up with the patients over a 15-year period, as required by FDA for gene therapies. Further trials testing CAR-T therapies with other forms of acute lymphoblastic leukemia, non-Hodgkin lymphoma, and chronic lymphocytic leukemia are also recruiting patients.
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27 April 2016. Drug maker Sanofi is partnering with two research institutes to harness big data analytics for predicting how people with type 2 diabetes will take their medications. Sanofi’s U.S. division in Bridgewater, New Jersey announced the collaborations today with Duke Clinical Research Institute in Durham, North Carolina and Center for Assessment Technology and Continuous Health, or Catch, at Massachusetts General Hospital in Boston.
Prescribing medications for chronic diseases like type 2 diabetes does not guarantee those drugs will be taken as prescribed, nor will the prescription be refilled. Among older individuals, those age 65 and over, non-adherence to medications for chronic diseases ranges from 40 to 75 percent, with reasons for not taking or continuing medications attributed to cost, number of medicines, or adverse effects, as well as personal conditions including vision loss or depression. In addition, non-adherence to medications is associated with increased hospitalization, progression of disease, and higher mortality.
Sanofi is collaborating with the two research groups to help improve patient health outcomes, drug development, clinical trial design, and quality of care. The company aims to take advantage of work at Duke and Mass. General using big data analytics to derive insights from the institutes’ large-scale collections of anonymized electronic patient health records. Those insights, says Sanofi, can help identify patterns of medication adherence down to individual patients, and generate tailored treatment strategies.
Among the insights sought from the data are ways of identifying cohorts or communities where adherence rates are lower and where more outreach and engagement with patients may be needed. The goal would be to extend those findings to individual drugs and conditions, which can help improve patient outcomes, and better design clinical trials for new treatments.
Duke Clinical Research Institute is a division of Duke University’s medical school. The institute carries out clinical trials, manages patient registries, conducts health outcomes research. It is also home to the Duke Databank for Cardiovascular Diseases, which the institute says is the largest institutional cardiovascular database, in operation for 40 years.
Catch is a collaboration between Mass. General — affiliated with Harvard Medical School — and MIT that discovers new ways of measuring health and disease. The center’s goals are earlier identification of conditions, better treatments targeted to the individual, and where possible prevent disease entirely. In March, Catch released GlucoSuccess, an iPhone app created to help researchers study type 2 diabetes. The app allows patients to track health behaviors important for controlling type 2 diabetes, such as physical activity, diet, and medication adherence.
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27 April 2016. A project now underway in Europe plans to develop techniques for smartphones and wearable devices to monitor people with depression, epilepsy, and multiple sclerosis. The 5-year, €22 million ($US 25 million) initiative known as Remote assessment of disease and relapse – Central Nervous System, or Radar-CNS, is funded by the Innovative Medicines Initiative, a joint program of the European Union and European pharmaceutical industry.
Radar-CNS aims to improve the quality of life for people with major depressive disorder, epilepsy, and multiple sclerosis, who often have periods when symptoms are under control, but also episodes of deterioration and relapse. Surveys of people with these conditions cited by Radar-CNS indicate a need to better predict when these episodes will occur and provide treatments to prevent them from happening.
The initiative, led by Kings College London and the pharmaceutical company Janssen Pharmaceutica, says smartphones and wearable devices offer the opportunity to follow people with epilepsy, depression, and multiple sclerosis at a level of detail which was unachievable before. “It may be that this sort of data can improve clinical care simply by providing more accurate information,” says Matthew Hotopf, director of Maudsley Biomedical Research Centre, affiliated with Kings College London, in a university statement. “Better still, it may be possible to spot when a patient is getting into trouble before their clinic visit.”
Hotopf, co-leader of Radar-CNS, offers an example where “in depression, someone’s behavior may change even before they have noticed they are struggling. Their sleep may get worse, or they may stop doing so much in the weeks leading up to a relapse.”
Radar-CNS project teams are expected to identify characteristic bio-signatures that track different states of these disorders and predict relapse, develop algorithms for collecting and an infrastructure for analyzing the data collected, propose privacy and usability factors that encourage remote assessments, and identify solutions with the technologies that fit the workflows of caregivers and physicians, as well as meet requirements of regulatory authorities.
The project anticipates involving people with these disorders from the beginning to identify key symptoms, and implement these technologies in a way that engages the individuals, while safeguarding their privacy and security. The researchers plan to use available and inexpensive technologies to the extent possible, and design solutions that can be transferred to similar disorders.
In addition to Kings College London and Janssen Pharmaceutica, a division of Johnson & Johnson, some 22 other institutions, pharmaceutical, medical device, and software companies in Europe and the U.S. are taking part in Radar-CNS.
Disclosure: The author owns shares in Johnson & Johnson.
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Brain wiring illustration (Courtesy, Human Connectome Project and NIH)
26 April 2016. A pharmaceutical company in Sweden is collaborating with University of Pennsylvania’s medical school in preclinical studies of a new drug that protects against long term damage caused by traumatic brain injury. Financial terms of the agreement between NeuroVive Pharmaceutical AB in Lund, Sweden and the university were not disclosed.
NeuroVive develops drugs based on cyclosporine, a common compound used largely to suppress the immune system for preventing rejection in organ transplants. The company’s work extends another property of cyclosporine, to protect mitochondria in nerve cells following traumatic injuries. Mitochondria are components in cells that provide energy for the cells at large.
Traumatic brain injuries are caused by a blow to the head or penetrating head wound, such as a gun shot, that disrupt the normal functioning of the brain. The effects can be minor and temporary, such as concussions, but some can cause extended loss of consciousness. Centers for Disease Control and Prevention say 138 people in the U.S. die every day from traumatic brain injuries, accounting for 30 percent of all injury deaths.
One of NeuroVive’s lead products is NeuroStat, for protecting nerve cells in the brain from deterioration following traumatic brain injury. The drug is designed to prevent the deterioration of brain cells beyond the immediate injury caused by biochemical reactions, including calcium overload, inflammation, and oxidative damage. NeurStat is given as an infusion after patients with severe head injuries are stabilized.
While NeuroStat is undergoing an intermediate-stage clinical trial with traumatic brain injury or TBI patients, the company is engaging Penn’s medical school to test additional treatment options for the drug. Professor of bioengineering Susan Margulies and Todd Kilbaugh, a professor of anesthesiology and critical care, will lead the preclinical studies. Findings from the preclinical studies are expected to support the company’s regulatory submissions.
“We have been working for several years to develop clinically relevant experimental models of TBI,” says Margulies in a NeuroVive statement, “and believe that the testing of novel pharmaceutical treatments in our models, such as NeuroStat, will facilitate and improve the future clinical development of TBI.”
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Wheat stem rust (John Innes Center)
26 April 2016. Plant scientists in the U.K. developed genetic engineering techniques that quickly clone resistance to plant diseases affecting wheat, soybeans, and potatoes. The techniques are described in articles appearing in the 25 April issue of the journal Nature Biotechnology (paid subscription required).
Teams from the John Innes Centre and Sainsbury Laboratory in Norwich — with colleagues from academic and industrial labs in the U.S., Australia, Malaysia, and Brazil — are seeking faster and more reliable tools to build resistance to plant diseases in crops, which take high toll on growers’ yields. While disease-resistance traits can be transferred to crop plants, finding resistant genes in large plant genomes and breeding new varieties is a long and laborious process. The alternative for growers in many cases is to use chemicals to kill the blight.
The researchers, led by Brande Wulff at John Innes Centre and Sainsbury Lab, devised a 3-step technique they call MutRenSeq that quickly identifies genes in wild type plants resistant to disease. In their papers, the researchers then apply the technique to develop new blight-resistant varieties in the lab for wheat, soybeans, and potatoes. The authors say this technology can reduce the time for breeding new varieties to 2 years, a process that now takes 10 to 15 years.
The key to the technique is finding a minimal set of genes in wild-type varieties with natural resistance to blight, which in the past was an extended and difficult task. “With MutRenSeq,” says Wulff in a joint statement, “we can find the needle in the haystack: we can reduce the complexity of finding resistance genes by zeroing in from 124,000 genes, to just a single candidate gene.”
MutRenSeq begins with creating mutations in wild-type plants resistant to blight, resulting in a variety without that resistance, using ethyl methane sulfonate, a chemical known for causing genetic variations. The researchers then sequence the genomes of the original wild-type plant and mutated version, followed by matching the two genomes to identify the differences responsible for blight resistance.
The team first applied MutRenSeq to wheat stem rust, a fungal disease that according to 2Blades Foundation, a sponsor of the research, causes devastating epidemics leading to losses of 50 to 100 percent of yields. Using MutRenSeq, the team cloned a variety of wheat with resistant genes Sr22 and Sr45 identified in the genomic analysis, with another resistant gene Sr33. The researchers say Sr33 was already known for its resistance to blight, but scientists were not able before to isolate the two other genes.
Another team used MutRenSeq to develop a variety of soybeans resistant to Asian soybean rust, a fungus that affects soybean crops in North and South America, as well as Asia, causing yield losses of up to 80 percent. Asian soybean rust is so far treatable only with fungicides, and no resistant genes have yet been cloned. The researchers used MutRenSeq to identify a resistant gene, CcRpp1, in pigeonpeas, a close relative, which was cloned into commercial soybean varieties. Lab tests show the cloned variety is fully resistant to Asian soybean rust.
A third team applied the MutRenSeq technique to potato blight, known historically for wiping out the Irish potato crop in the 1840s and still a serious problem for growers. The researchers added single-molecule real-time or SMRT sequencing to their tools to identify the resistant gene Rpi-amr3 in American black nightshade plants, a relative of potato. Rpi genes, say the researchers, are known to be resistant to potato blight fungi, but breeding resistant varieties up to now is difficult and slow. The researchers report successfully cloning a potato variety with the Rpi-amr3 gene.
Institutions and individual researchers filed patent applications for the technologies in these papers.
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Ian Shakil, Augmedix Inc. CEO, with Google Glass. (Augmedix Inc.)
25 April 2016. A company building a system that allows doctors to automatically create patient notes with Google Glass added $17 million in its second full round of venture funding. Augmedix Inc., a 2 year-old enterprise in San Francisco, says the new financing will enable the company to scale-up its service across the country to more health systems and private clinics.
Augmedix harnesses Google Glass, Google’s wearable camera mounted on eyeglasses, to capture interactions between doctors and patients for electronic health records. Google first introduced Google Glass as a consumer product, which received mixed reviews at best, including being banned for privacy intrusions at a number of restaurants, and the U.S. Navy base and prison at Guantánamo Bay, Cuba. In January 2015, Google ended its Explorer early adopter program for consumers, to focus on developers that integrate Glass into larger systems.
One of those developers is Augmedix, which says it’s the first and largest Google Glass start-up of any kind. Google Glass, worn by clinicians, monitors and records interactions with patients in real time, then converts the conversation to text and formatted into a note for the patient’s electronic health record. The eyeglass display on Google Glass enables the clinician to see data and visuals from the patient’s health record, such as electrocardiogram, while interacting with the patient.
Augmedix ran a pilot test of its system with 3 family practice physicians at Dignity Health, a not-for-profit health system in California, and reported results in June 2014. The pilot test showed the Augmedix system enabled the physicians to increase the proportion of their work days for direct patient care from 35 to 70 percent. At the same time, their time devoted to electronic health record keeping declined from 53 percent before using the system to 15 percent of their work days.
The company says it now serves hundreds of primary care physicians, as well as surgeons and specialists in most states, recording interactions with some 5,000 patients a day. Augmedix so far raised a total of $40 million in venture funds, beginning with a seed round in March 2014, and now employs nearly 400 employees.
The financing round was led by Redmile Group in San Francisco, a hedge fund that also makes venture investments in life sciences, biotechnology, and medical device companies. Current institutional investors Emergence Capital and DCM Ventures joined the round.
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25 April 2016. Clinical trials are planned to assess experimental treatments and new diagnostics for inherited forms of Alzheimer’s disease. The new studies, which extend earlier trials of drugs to treat inherited Alzheimer’s disease, are funded by a $4.3 million grant from Alzheimer’s Association in Chicago.
Like the earlier trials, the new round of studies will evaluate treatments for dominantly inherited Alzheimer’s disease that results from a genetic mutation. People with this type of Alzheimer’s disease tend to develop symptoms, such as loss of memory or cognitive abilities, earlier — during their 30s, 40s, or 50s — than sporadic, age-related Alzheimer’s disease that often forms after age 65. While people with dominantly inherited Alzheimer’s disease make up about 1 percent of all people with the disorder, the earlier and predictable age of onset makes it possible to test drugs before symptoms appear.
The trials are expected as well to help develop treatments for age-related Alzheimer’s disease. Because the progression of Alzheimer’s in people with the mutation is similar to individuals with age-related Alzheimer’s, treatments shown effective in slowing or preventing degeneration of cognitive functions in people with the mutation may also work with individuals having the sporadic, age-related type of the disorder.
A consortium of pharmaceutical companies and Washington University in St. Louis in 2012 began clinical trials to test drug candidates with people found having dominantly inherited Alzheimer’s disease. The trials, known as Dominantly Inherited Alzheimer’s Network Trials Unit or DIAN-TU, assess the engineered antibodies solanezumab and gantenerumab, made by Eli Lilly and Company and Roche respectively, to slow the progression or prevent symptoms from occurring. The studies, still underway, recruited 210 participants at 26 sites.
The new set of trials, named DIAN-TU Next Generation, plan to test experimental treatments designed to prevent the accumulation of amyloid brain plaques, deposits of amyloid-beta protein fragments that build up between nerve cells in the brain and are often found in people with Alzheimer’s disease. In addition, the trials will evaluate new diagnostics for Alzheimer’s that aim to detect the disorder earlier in its formation:
– Positron emission tomograph or PET imaging that spots tangles of tau, abnormal collections of twisted and misfolded protein threads. The tau tangles attract large deposits of phosphate molecules that disrupt the healthy functioning of nerve cells, and damage the ability of nerve cells to communicate with each other.
– Increased home-based cognitive testing to detect subtle changes in symptoms of Alzheimer’s disease earlier on. If these tests are shown to predict the onset of Alzheimer’s they could be used as part of a treatment program with drugs to slow or prevent the development of symptoms.
The DIAN-TU Next Generation trials will recruit people with the characteristic gene mutation for dominantly inherited Alzheimer’s disease, but with mild or no symptoms. Participants will be randomly assigned to receive the test drug or a placebo for four years. Study teams will evaluate participants with cognitive tests given before, during, and after the trials, as well as with PET imaging scans and tests for characteristic biomarkers of Alzheimer’s disease. The researchers plan to expand the number of sites beyond the current 26 locations in North America, Europe, and Australia, to others in Europe, South America, and Asia.
Much of the funding for the trial is donated to Alzheimer’s Association by the investment firm Edward Jones. “The single greatest threat to financial security late into life,” says Jim Weddle, Managing Partner at Edward Jones in an Alzheimer’s Association statement, “is contracting a long-lasting disease that destroys a person’s savings and leaves them dependent upon their children or Medicaid. The most expensive of those chronic diseases, in both financial and emotional costs, is Alzheimer’s.”
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