Three Stages to COVID-19 Brain Damage, New Review Suggests

A new review outlines a three-stage classification of the impact of COVID-19 on the central nervous system and recommends hospitalized patients with the virus all undergo MRI to flag potential neurologic damage and inform postdischarge monitoring.

In stage 1, viral damage is limited to epithelial cells of the nose and mouth, and in stage 2 blood clots that form in the lungs may travel to the brain, leading to stroke. In stage 3, the virus crosses the blood–brain barrier and invades the brain.

“Our major take-home points are that patients with COVID-19 symptoms, such as shortness of breath, headache, or dizziness, may have neurological symptoms that, at the time of hospitalization, might not be noticed or prioritized, or whose neurological symptoms may become apparent only after they leave the hospital,” lead author Majid Fotuhi, MD, PhD, medical director of NeuroGrow Brain Fitness Center, McLean, Virginia, told Medscape Medical News.

“Hospitalized patients with COVID-19 should have a neurological evaluation and ideally a brain MRI before leaving the hospital; and, if there are abnormalities, they should follow up with a neurologist in 3 to 4 months,” said Fotuhi, who is also affiliate staff at Johns Hopkins Medicine in Baltimore, Maryland.

The review was published online June 8 in the Journal of Alzheimer’s Disease.

Wreaks CNS Havoc

It has become “increasingly evident” that SARS-CoV-2 can cause neurologic manifestations, including anosmia, seizures, stroke, confusion, encephalopathy, and total paralysis, the authors write.

The authors note that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) that facilitates the conversion of angiotensin II to angiotensin. After ACE2 has bound to respiratory epithelial cells, and then to epithelial cells in blood vessels, SARS-CoV-2 triggers the formation of a “cytokine storm.”

These cytokines, in turn, increase vascular permeability, edema, and widespread inflammation, as well as triggering “hypercoagulation cascades,” which cause small and large blood clots that affect multiple organs.

If SARS-CoV-2 crosses the blood–brain barrier, directly entering the brain, it can contribute to demyelination or neurodegeneration.

“We very thoroughly reviewed the literature published between January 1 and May 1, 2020 about neurological issues [in COVID-19] and what I found interesting is that so many neurological things can happen due to a virus which is so small,” said Fotuhi.

“This virus’ DNA has such limited information, and yet it can wreak havoc on our nervous system because it kicks off such a potent defense system in our body that damages our nervous system,” he said.

Three-Stage Classification

Stage 1

The extent of SARS-CoV-2 binding to the ACE2 receptors is limited to the nasal and gustatory epithelial cells, with the cytokine storm remaining “low and controlled.” During this stage, patients may experience smell or taste impairments, but often recover without any interventions.

Stage 2

A “robust immune response” is activated by the virus, leading to inflammation in the blood vessels, increased hypercoagulability factors, and the formation of blood clots in cerebral arteries and veins. The patient may therefore experience either large or small strokes.

Additional stage 2 symptoms include fatigue, hemiplegia, sensory loss, double vision, tetraplegia, aphasia, or ataxia.

Stage 3

The cytokine storm in the blood vessels is so severe that it causes an “explosive inflammatory response” and penetrates the blood–brain barrier, leading to the entry of cytokines, blood components, and viral particles into the brain parenchyma and causing neuronal cell death and encephalitis.

This stage can be characterized by seizures, confusion, delirium, coma, loss of consciousness, or death.

“Patients in stage 3 are more likely to have long-term consequences, because there is evidence that the virus particles have actually penetrated the brain, and we know that SARS-CoV-2 can remain dormant in neurons for many years,” said Fotuhi.

“Studies of coronaviruses have shown a link between the viruses and the risk of multiple sclerosis or Parkinson’s disease even decades later,” he added.

“Based on several reports in recent months, between 36% to 55% of patients with COVID-19 that are hospitalized have some neurological symptoms, but if you don’t look for them, you won’t see them,” Fotuhi noted.

As a result, patients should be monitored over time after discharge, as they may develop cognitive dysfunction down the road.

Additionally, “it is imperative for patients [hospitalized with COVID-19] to get a baseline MRI before leaving the hospital so that we have a starting point for future evaluation and treatment,” said Fotuhi.

“The good news is that neurological manifestations of COVID-19 are treatable,” and “can improve with intensive training,” including lifestyle changes—such as a heart-healthy diet, regular physical activity, stress reduction, improved sleep, biofeedback, and brain rehabilitation,” Fotuhi added.

Routine MRI Not Necessary

Kenneth Tyler, MD, chair of the Department of Neurology at the University of Colorado School of Medicine, disagreed that all hospitalized patients with COVID-19 should routinely receive an MRI.

“Whenever you are using a piece of equipment on patients who are COVID-19 infected, you risk introducing the infection to uninfected patients,” he told Medscape Medical News.

Instead, “the indication is in patients who develop unexplained neurological manifestations — altered mental status or focal seizures, for example —because in those cases, you do need to understand whether there are underlying structural abnormalities,” said Tyler, who was not involved in the review.

Also commenting on the review for Medscape Medical News, Vanja Douglas, MD, associate professor of clinical neurology, University of California San Francisco, described the review as “thorough” and suggested it may “help us understand how to design observational studies to test whether the associations are due to severe respiratory illness or are specific to SARS-CoV-2 infection.”

Douglas, who was not involved in the review, added that it is “helpful in giving us a sense of which neurologic syndromes have been observed in COVID-19 patients, and therefore which patients neurologists may want to screen more carefully during the pandemic.”

The study had no specific funding. Fotuhi has disclosed no relevant financial relationships. Coauthor Cyrus Raji reports consulting fees as a member of the scientific advisory board for Brainreader ApS and reports royalties for expert witness consultation in conjunction with Neurevolution LLC. Tyler and Douglas have disclosed no relevant financial relationships.

J Alzheimers Dis. Published online June 10, 2020. Full text

https://www.medscape.com/viewarticle/933131#vp_1

Monopar Therapeutics files for US patent for COVID-19 treatment

Monopar Therapeutics (MNPR +7.8%) and NorthStar Medical Radioisotopes submits a provisional patent application for precision radioimmunotherapeutic targeting Urokinase Plasminogen Activator Receptor (uPAR) for the treatment of COVID-19.

Earlier, Monopar and NorthStar inked a collaboration to couple Monopar’s MNPR-101 uPAR targeting monoclonal antibody to a therapeutic radioisotope provided by NorthStar.

https://seekingalpha.com/news/3587473-monopar-therapeutics-files-for-us-patent-for-covidminus-19-treatment

Takeda’s Morabito on the science behind plasma-based Covid treatments

Although vaccine efforts against COVID-19 are moving at breakneck speed, experts caution that the 12- to 18-month time frame suggested by government officials is “overly optimistic.” Therapeutics from antivirals and antibody cocktails to drugs focused on specific symptoms will act as a “bridge” while the world waits for a vaccine.

One of those approaches is well-known: convalescent plasma, or using the plasma of recovered patients to give others antibodies against a virus. It’s been used in various epidemics from measles and mumps to influenza. Today, Takeda, CSL Behring and an alliance of plasma specialists are working on a hyperimmune globulin, a purified version of this treatment, for COVID-19 infection.

“We know that passive immunotherapies work from historical experience,” said Chris Morabito, Ph.D., head of R&D for Takeda’s Plasma-Derived Therapies unit. “With coronaviruses, there is experience with SARS and MERS that hyperimmune approaches are effective, though none was developed for either disease because the disease stopped having pandemic potential before development could be completed.”

Hyperimmune globulins work by giving patients a mix of antibodies produced by different kinds of immune cells, so they have multiple different antibodies against multiple different antigens on the virus. Morabito called it a “shotgun approach” that could help patients fight off SARS-CoV-2, the virus that causes COVID-19, while researchers are still learning about the disease and how the virus interacts with the body.

The treatments are made by purifying antibodies from donated plasma, giving them some advantages over plain old convalescent plasma.

“[They are] a standard product, a drug produced from pooled plasma,” said Morabito, who authored a paper on the promise of plasma-based treatments against COVID-19. “We will know what the batch-to-batch consistency , what the neutralizing titer [of antibodies] is like. It’s a stable, homogeneous mixture, so we can give specific dosing instructions.”

Having worked on hyperimmune globulins against the H1N1 influenza pandemic in 2009, Takeda is confident it can quickly develop a treatment for COVID-19. Although vaccines are moving “very, very quickly,” Morabito reckons a hyperimmune treatment could come faster.

“It’s really accessible. In the pandemic, we are seeing the number of convalescent patients is increasing exponentially, as transmission was increasing exponentially,” he said. “With proper campaigning—which we have initiated—we should be able to get convalescent patients in to donate plasma and use that plasma for the production of the hyperimmune treatment.”

That’s part of why Takeda has teamed up with other plasma players as well as companies like Uber and Microsoft. It initially started work on its own program, TAK-888, but quickly realized it would need all the help it could get.

“We came to the conclusion quickly that at every step of the way we would need some help to mitigate the risks of developing this thing … The scale needed to do it quickly would require multiple partnerships. We abandoned the ghost and signed up with this coalition for plasma collection,” Morabito said..

The group, dubbed the CoVIg-19 Plasma Alliance, is pooling know-how and resources to develop a single, unbranded medicine. That includes collecting plasma, manufacturing the treatment and conducting clinical trials.

One potential hurdle is a “dearth of plasma” from which to produce the treatment. Over time, recovered patients will have fewer antibodies circulating in their blood as they’re no longer fighting infection.

“There will be a time coming in the next year—maybe sooner—at which collecting plasma from those particular convalescent patients will not produce a robust hyperimmune,” Morabito said.

“There is a limited period of time to work quickly to collect enough plasma to make this drug,” he added.

That said, Morabito thinks the group is working quickly enough that it won’t be an issue: “We do anticipate we will have the drug available before the end of the calendar year based on how well things are going with collections, manufacturing and the anticipated start of the clinical trial this summer,” he said.

The alliance will work with the National Institute of Allergy and Infectious Diseases to test the safety and efficacy of the treatment in adults with COVID-19. The global study will lay the groundwork for a regulatory submission for the treatment.

https://www.fiercebiotech.com/biotech/covid-closeup-takeda-s-chris-morabito-science-behind-plasma-based-treatments

Biopharma tackles COVID-19, HIV and other viruses with gene and cell therapies

When Celularity spun out of Celgene in 2018 with $250 million and a plan to develop cell therapies from placenta to treat cancer, the science was still several years away from translating into marketable products. Then the COVID-19 pandemic exploded, and Celularity’s researchers raced to apply the science behind their cell therapies to fighting the new virus.

What emerged was CYNK-001, an off-the-shelf therapy made from immune cells in placenta called natural killer (NK) cells. It’s similar to the cell therapies Celularity is developing for cancer, explained founder and CEO Robert Hariri, M.D., Ph.D., in an interview.

“We learned that the way natural killer cells identify cancer cells is by recognizing the expression of stress antigens,” which are immune-stimulating molecules on the cells’ surfaces, Hariri said. “Well, it turns out virally infected cells express similar stress antigens.”

A few months of preclinical work was enough to persuade the FDA to allow the company to launch a clinical trial of CYNK-001, and it’s now recruiting COVID-19 patients in New Jersey and Washington.

CYNK-001 is among a rapidly growing collection of gene and cell therapies now in development to treat and prevent a wide range of viruses.

Biopharma companies and academic researchers have created engineered immune cells, CRISPR-edited gene products and more to combat not just COVID-19 but also influenza and HIV, the virus that causes AIDS. Though many challenges have to be overcome before these therapies are ready for widespread use against viruses, early signals suggest they could offer a promising new strategy.

Harnessing immunity from recovered patients

Another company that made a quick pivot to address COVID-19 is AlloVir, which launched back in 2013 with a plan to develop T-cell therapies to treat viruses.

When the pandemic hit, the company was busy with phase 2 trials of Viralym-M, a T-cell treatment for six viruses common in immunocompromised people, including cystitis and cytomegalovirus. Allovir started looking at COVID-19 along with its research partners at Baylor College of Medicine.

AlloVir’s development platform centers on taking T cells from people who’ve recovered from viral illnesses, separating them from other cells that could spark a rejection response, expanding them and then making them available off-the-shelf to patients fighting those illnesses. The company is applying the same approach to COVID-19, hoping to get a product into clinical trials by the end of the year.

“There’s new evidence every day that COVID patients with acute problems have deficits in their T cells,” said Ann Leen, Ph.D., co-founder and chief scientific officer of AlloVir, in an interview.

“We’ve been looking at the immune response from people who naturally control this virus without needing hospitalization,” she said. “We are learning lessons about the important antigens or protein targets within the virus. And these donors—what I call ‘natural controllers’—will also serve as the source of our virus-specific T cells.”

Gene therapy is also yielding new ways to fight viral illness. Stanford University researchers developed a CRISPR gene editing approach to crippling viruses by destroying nucleotide sequences in their genomes. In June, they reported that the system (called PAC-MAN), could be used to attack the H1N1 flu strain in human lung cells. Now, they’re working on adapting the technology to COVID-19.

And a team led by Harvard University’s Massachusetts General Hospital is working on a COVID-19 vaccine designed to touch off an immune response by delivering fragments of SARS-CoV-2 into the body with an adeno-associated virus (AAV) vector. It’s similar to gene-therapy technology used in FDA-approved products like Novartis’ Zolgensma to treat spinal muscular atrophy. In fact, Novartis agreed in May to manufacture the Mass General vaccine, should it be approved.

“The fact that there’s an established industry out there around AAV made it easy for us to step into the existing [manufacturing] capacity, rather than having to build it,” said Luk Vandenberghe, Ph.D., an associate professor at Harvard Medical School, in an interview. Mass General was also able to speed up preclinical development by teaming with gene-therapy pioneers at the University of Pennsylvania.

Deploying CRISPR against hidden HIV reservoirs

Excision BioTherapeutics is applying both CRISPR and AAV delivery toward solving a different but equally vexing problem in antiviral drug development: HIV. Even though antiretroviral drugs can tamp down the virus to the point where it’s no longer detectable in the blood, it can hide out in “reservoirs” and emerge later.

Excision licensed gene-editing technology developed at Temple University that uses CRISPR to cut out several pieces of the HIV genome. “If you just make a single cut, the virus can mutate around it. We make multiple cuts to deactivate the viral genome,” CEO Daniel Dornbusch said in an interview. A recent trial in nonhuman primates showed the CRISPR version reached every tissue in the body where HIV reservoirs reside, Dornbusch said.

Excision is working on similar treatments for other viruses, including herpes and hepatitis B, and with the proper funding, it could even address COVID-19, he added. But the company’s priority is to gain FDA approval to start human testing of the HIV treatment by the end of this year.

Sangamo Therapeutics is also working on eliminating HIV reservoirs with gene editing, using a technology developed by scientists at Case Western University. The technique, called zinc finger nuclease gene editing, uses engineered proteins to knock a particular gene—CCR5, which shuttles HIV into host cells—out of T cells. In an ongoing clinical trial, 20 patients are receiving the T-cell therapy and 10 a placebo.

The researchers hope to show that the treatment will boost levels of CD4+ T cells, which work to eliminate HIV reservoirs, said Rafick-Pierre Sékaly, Ph.D., a professor at Case Western, in an interview. “You have to confront the virus with more than one mechanism. Drugs target only one component,” he said. “They don’t rescue the immune response and they don’t restore CD4 numbers. HIV eradication can’t be a single-component issue.”

Hurdles ahead

Developers of gene and cell therapies are facing plenty of challenges, to be sure. They’ll need ample safety trials to demonstrate their products stimulate the immune system without causing unintended side effects, for example. And ultimately, they’ll have to demonstrate the value of choosing these new therapies over older and often less expensive treatments, like antiviral drugs.

In the current moment, they also face a pandemic that’s grown increasingly politicized.

Celularity’s Hariri found himself in the crosshairs of critics who thought he was hyping the potential of cell therapy in COVID-19 after he appeared on a podcast in late March with Rudy Giuliani, President Donald Trump’s attorney. Hariri said the attention from a government official shouldn’t lead anyone to assume the biopharmaceutical industry is cutting corners to get COVID-19 remedies on the market.

“It was an informative discussion. It was not about politics whatsoever,” Hariri said.

Hariri hopes the biopharma industry will put politics and rivalries aside and focus instead on working together to solve the logistical challenges of tackling viruses with gene and cell therapies.

“The critical issue in my mind is that for any therapy to impact the force of the pandemic, we have to be ready to have a scalable process that can produce millions of doses,” he said. “That’s going to require coordination between many organizations.”

https://www.fiercebiotech.com/biotech/biopharma-tackles-covid-19-hiv-and-other-viruses-gene-and-cell-therapies