Broad Institute star scientist Feng Zhang is back in the spotlight, adapting CRISPR technology in a shift from permanently editing DNA to revising RNA — temporarily if needed. And he illustrated the promise of this approach by deactivating APOE4, which may be a ticking time bomb for people at risk of developing Alzheimer’s. CRISPR/Cas9 gene editing tech has taken the lab by storm, in part because of the work Zhang and his one-time colleagues Jennifer Doudna and Emmanuelle Charpentier accomplished. They’re still scrapping over the patents to the original Cas9 work. But Zhang, who founded Beam Therapeutics with David Liu and Keith Joung, has moved on in search of better tech, and in a paper published in Science, says they have made real progress in switching from DNA to RNA editing.
They call this new advance RESCUE: RNA Editing for Specific C to U Exchange. And it builds on REPAIR: RNA Editing for Programmable A to I. Using Cas13, Zhang’s team was able to take the APOE4 gene — believed to carry the added risk of spurring Alzheimer’s — and changed it to a benign APOE2. The RNA editors converted “the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine, or C to U.”
But there are also ways to achieve a temporary change that could benefit patients without creating potential risks. In a separate cell experiment, Zhang and his group were able to orchestrate a transitory spike in β-catenin activation and cell growth. That kind of temporary impact could erase threats of cancer, associated with uncontrolled cell growth while treating wounds.
“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” says Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT.
It’s an intriguing experiment, but don’t look for the experiment in cells to make the leap into practice anytime soon. MIT’s Jonathan Gootenberg summed it up for WBUR:
“It’s a first step in a very large journey. We’re still at the base of the mountain, you might say.”
New research reported at the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles suggests healthy lifestyle choices — including healthy diet, exercise, and cognitive stimulation — may decrease risk of cognitive decline and dementia. Researchers also found lifestyle modifications may reduce risk even in the face of other risk factors, including genetics and pollution, and provide maximum memory benefit when combined.
Five research studies reported at AAIC 2019 suggest:
Adopting four or five healthy lifestyle factors reduced risk of Alzheimer’s dementia by 60% compared to adopting none or only one factor.
Adherence to a healthy lifestyle may counteract genetic risk for Alzheimer’s disease.
Having a higher cognitive reserve, built through formal education and cognitive stimulation, may benefit the aging brain by reducing risk of dementia among people exposed to high levels of air pollution.
Confirmation that early adult to mid-life smoking may be associated with cognitive impairment at mid-life, as early as one’s 40s.
Alcohol use disorder significantly increased risk of dementia in older women.
“While there is no proven cure or treatment for Alzheimer’s, a large body of research now strongly suggests that combining healthy habits promotes good brain health and reduces your risk of cognitive decline,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “The research reported today at AAIC gives us attainable, actionable recommendations that can help us all live a healthier life.”
Tuscan Holdings Corp II, the second blank check company led by Stephen Vogel targeting the cannabis industry, raised $150 million by offering 15 million units at $10. The company originally planned to raise $125 million.
Each unit consists of one share of common stock and one-half of one warrant, with each whole warrant entitling the holder to purchase one share at a price of $11.50.
Tuscan Holdings Corp II plans to list on the Nasdaq under the symbol THCAU. EarlyBirdCapital acted as lead manager on the deal.
BioArctic AB (publ) (Nasdaq Stockholm: BIOA B) announced today that presentations related to BAN2401 will be given at the Alzheimer’s Association International Conference® 2019 (AAIC®) to be held July 14-18 in Los Angeles, USA.
In addition to the presentations, BioArctic’s partner Eisai will sponsor an interactive satellite symposium focusing on the rationale and opportunities for drug development in preclinical Alzheimer’s disease – clinically normal people with increased cerebral amyloid deposition who are at risk for developing Alzheimer’s disease. The symposium will take place Tuesday, July 16.
The past decade of Alzheimer’s disease research has been fraught with disappointment.
Years of focus on one hallmark of the disease ultimately resulted in no progress toward treatment or prevention.
But this week, when top scientists gather in Los Angeles at the Alzheimer’s Association International Conference, an annual meeting, many will present research on a different target: inflammation.
“The big breakthrough is that neuroinflammation is the target. It’s killing the bulk of the nerve cells that leads to dementia,” said Rudolph Tanzi, a professor of neurology at Harvard University and the director of neurology at Massachusetts General Hospital.
Moving beyond plaques
Early research into Alzheimer’s disease pointed toward a conspicuous target: clumps of protein in the brain called amyloid plaques. When scientists studied the brains of people with Alzheimer’s disease who died, they noticed the brain tissue was full of these plaques, which are still considered a hallmark of the disease.
But although research has shown time and time again that amyloid plaques may play a role in Alzheimer’s, it’s not the singular key to a cure.
Indeed, on Thursday, pharmaceutical companies Amgen and Novartis announced their trial of a drug meant to help block the production of amyloid plaques had failed. In fact, patients who received the drug got worse. The Alzheimer’s Association called the outcome “disappointing.”
But according to Tanzi, going after the plaques after they’ve formed means you’re too late. That’s because amyloid develops very early in the Alzheimer’s disease process — even 20 years before the first symptoms appear. Attacking amyloid in patients who already have dementia is like trying to stop a forest fire by blowing out a match, he said. It’s inflammation that’s allowing the fire to rage out of control.
“If you want to hit the plaques, you have to do so early on with early detection,” Tanzi said. “I believe that will be the future for preventing Alzheimer’s disease. But for now, how do we help the 5 million patients in this country? You have to put out the forest fire.”
Putting out the inflammation fire
Tanzi is working with a Boston-based company called AZTherapies to find drugs already in existence that can tackle that neuroinflammation. Tanzi serves as director of the company’s scientific advisory board, and has financial ties to the company.
On the left, healthy brain tissue is full of nerve cells, highlighted in green. On the right, brain tissue with signs of inflammation.Dr. Joseph Park, Dr. Rudy Tanzi
Part of AZTherapies’ research involves a drug used to treat asthma, called Cromolyn, which targets inflammation in the lungs. The company altered the medication so that it reaches the brain, and is testing it in combination with ibuprofen.
“This is one of the first trials to take a relatively safe drug … reformulate it, and then ask if we turn off neuroinflammation, can we put out the forest fire and, just like a forest, allow it to grow back?” Tanzi said.
AZTherapies has enrolled almost 600 patients for that trial, and expects results within the next year or two. Still, it’s far too early to suggest people take anti-inflammatory medications to help stave off dementia. Drugs on the market now either don’t reach the brain, or come with other risks associated with long-term use, like increased risk for heart attack, stroke and stomach ulcers.
AZTherapies is not the only company moving away from amyloid research and into areas that target inflammation.
Neurotrope will present research at next week’s Alzheimer’s Association conference about its drug, bryostatin-1.
Originally tested as a cancer drug, bryostatin-1 works by activating a protein involved with the “wiring”of the brain.
“It induces the regeneration of wiring and synaptic networks that are lost. It prevents neuronal death. And also it is very significantly anti-inflammatory,” Dr. Daniel Alkon, Neurotrope’s president, said.
Alkon told NBC News that in early studies of Alzheimer’s patients, those taking bryostatin-1 showed cognitive improvement that was sustained for at least a month after treatment.
“To us, this is consistent with new networks being formed,” Alkon said. “We think the ways we have been using anti-inflammatories as part of an overall pro-survival approach to the brain networks could be a breakthrough for the field.”
Moving forward
That inflammation plays a role in Alzheimer’s is not a new idea — scientists have been studying its role for some time. In 2013, researchers at Massachusetts General Hospital and Mayo Clinic published a study that looked at post-mortem brains. All of the brains had evidence of amyloid plaques and another Alzheimer’s hallmark, tau tangles.
But only half of the patients had dementia when they were alive. The others were cognitively normal.
“The only thing that differentiated them was an inflammatory response. There were more inflammatory cells in the brain … in the people who had clinical dementia versus those who were clinically normal, again suggesting that inflammation is a key mediator here,” Dr. Ronald Petersen, a neurologist and director of Mayo Clinic’s Alzheimer’s Disease Research Center, said.
The hunt for an effective treatment for Alzheimer’s disease will remain critical as the number of patients — estimated as 5.8 million in the U.S. alone — is projected to swell to 14 million by 2050, according to the Alzheimer’s Association. It is the sixth leading cause of death in the U.S.
Memory loss associated with Alzheimer’s can be mild in the early stages of the disease. But over time, patients develop more serious confusion and memory loss, as well as mood and behavior changes, disorientation and difficulty speaking, swallowing and walking.
There is no cure for Alzheimer’s disease. Available treatments can only improve quality of life and temporarily slow a person’s decline.
I feel like we’re finally seeing a light at the end of the tunnel.
Maria Carrillo, chief science officer at the Alzheimer’s Association, is not ready to call the last decade of research on amyloid a waste. On the contrary, she said it’s helped scientists understand that it’s not only amyloid and tau that matter.
“Today’s science tells us there might be as many as four or five other proteins that are going wrong, contributing to the cell death we experience in Alzheimer’s dementia,” Carrillo said.
“It’s important that we understand what those are and how to tackle all of them with pharmaceuticals. That’s where we need to go, a combination approach that may also include lifestyle changes, just like other diseases do,” she said.
Tanzi agrees. He suggests an approach he calls SHIELD, an acronym for lifestyle factors that appear to help reduce the risk of developing Alzheimer’s. They include:
developing good sleep habits
getting a handle on stress
interacting with friends
exercising daily
learning new skills
eating a healthy diet
“It’s never too early to start thinking about how to protect your brain,” he said. He is hopeful those lifestyle changes, plus research into neuroinflammation, will make a marked impact on Alzheimer’s disease.
“I feel like we’re finally seeing a light at the end of the tunnel,” said Tanzi. “We’ve made mistakes, but those mistakes have taught us where we need to get to next.”
Last week was a quiet one for the biotech space with the exception of a few clinical trial readouts.
Pharma and biotech stocks took comfort in a ruling by a federal judge that went against President Donald Trump’s initiative that would require drug companies to reveal the sticker price of their drugs in TV ads.
The following are some key catalysts for the biotech stocks in the unfolding week.
Conferences
28th European Diabetes Congress: July 17-18 in Edinburgh, Scotland
23rd Annual American Association of Cancer Research, or AACR, Workshop on Molecular Biology in Clinical Oncology: July 20-27 in Snowmass Village, Colorado
PDUFA Dates
The FDA is set to issue its verdict on Merck & Co., Inc. MRK 1.56%‘s NDA for a combination of relebactam with imipenem/cilastatin in treating complicated urinary tract infections and complicated intra-abdominal infections. The PDUFA date is set for Tuesday, July 16.
Clinical Trial Readouts
TapImmune Inc. MRKR 0.34% will present Phase 1/2 data for its pancreatic cancer immunotherapy multi TAA-specific T cells at the AACR workshop on Saturday, July 20.
Earnings
Tuesday, July 16
Johnson & Johnson JNJ 4.14% (before the market open)
Seattle Genetics, Inc. SGEN 2.16% (after the market close)
Wednesday, July 17
Abbott Laboratories ABT 2.16% (before the market open)
Thursday, July 18
Intuitive Surgical, Inc. ISRG 1.82% (after the market close)
IPOs
Mirum Pharmaceuticals, which develops therapies for rare cholestatic liver diseases, will offer 5 million shares priced between $14 and $16. The company seeks to list the shares on the Nasdaq under the ticker symbol “MIRM.”
Fulcrum Therapeutics proposes to offer 4.5 million shares in an IPO, with the estimated price in the range of $16-$18. The company seeks to list its shares on the Nasdaq under the ticker symbol “FULC.”
Danish biotech GENMAB A/S/S ADR GMXAY 4.32% has filed to offer 27.8 million ADSs, representing 2.78 million of its ordinary shares. The company has applied to list the ADS on the Nasdaq under the ticker symbol “GMAB.”
