An Investigational Drug Offers Hope to Patients with a Disabling Neuromuscular Disease
Robert Thomas was a devoted runner, gym goer, and crew member on a sailing team in San Diego when, in his 40s, he noticed that his range of movement was becoming more limited.
He thought he was just getting older, but when he was hiking an uphill trail in Lake Tahoe, he kept tripping over rocks. "I'd never had this happen before," Robert says. "I knew something was wrong but didn't know what it was."
It wasn't until age 50 when he was diagnosed with Charcot-Marie-Tooth disease. The genetic disorder damages the peripheral nerves, which connect the brain and spinal cord to the rest of the body. This network of nerves is responsible for relaying information and signals about sensation, movement, and motor coordination. Over time, the disease causes debilitating muscle weakness and the loss of limb control.
Charcot-Marie-Tooth usually presents itself in childhood or in a person's teens, but in some patients, like Robert, onset can be later in life. Symptoms may include muscle cramping, tingling, or burning. Many patients also have high foot arches or hammer toes — toes that curl from the middle joint instead of pointing forward. Those affected often have difficulty walking and may lose sensation in their lower legs, feet, hands, or forearms. One of the most common rare diseases, it affects around 130,000 people in the United States and 2.8 million worldwide.
Like many people with Charcot-Marie-Tooth, or CMT, Robert wears corrective braces on his legs to help with walking. Now 61, he can't run or sail anymore because of the disease, but he still works out regularly and can hike occasionally. CMT also affects his grip, so he has to use special straps while doing some exercises.
For the past few years, Robert has been participating in a clinical trial for an investigational CMT drug. He takes the liquid formulation every morning and evening using an oral syringe. Scientists are following patients like Robert to learn if their symptoms stabilize or improve while on the drug. Dubbed PXT300, the drug was designed by French biopharmaceutical company Pharnext and is the farthest along in development for CMT. If approved, it would be the first drug for the disease.
Currently, there's no cure for CMT, only supportive treatments like pain medication. Some individuals receive physical and occupational therapy. A drug for CMT could be a game-changer for patients whose quality of life is severely affected by the disease.
Genetic Underpinnings
CMT arises from mutations in genes that are responsible for creating and maintaining the myelin sheath — the insulating layer around nerves. Pharnext's drug is meant to treat patients with CMT1A, the most common form of the disease, which represents about half of CMT cases. Around 5% of those with CMT1A become severely disabled and end up in wheelchairs. People with CMT1A have an extra copy of the gene PMP22, which makes a protein that's needed to maintain the myelin sheath around peripheral nerves.
Typically, an individual inherits one copy of PMP22 from each parent. But a person with CMT1A receives a copy of PMP22 from one parent and two copies from a parent with the disease. This extra copy of the gene results in excess protein production, which damages the cells responsible for preserving and regenerating the myelin sheath, called Schwann cells.
The myelin sheath helps ensure that a signal from the brain gets carried to nerves in the muscles so that a part of the body can carry out a particular action or movement. This sheath is like the insulation on an electrical cord and the action is like a light bulb. If the insulation is fine, the light bulb turns on. But if the insulation is frayed, the light will flicker.
"The same happens to these patients," says David Horn Solomon, CEO of Pharnext. "The signal to their muscle is weak and flickers." Over time, their muscles become weaker and thinner.
The PMP22 gene has proven difficult to target with a drug because it's located in a protected space — the Schwann cells that make up the insulation around nerves. "There's not an easy way to tamp it down," Solomon says.
Another company, Acceleron Pharma of Cambridge, Massachusetts, was developing an injectable CMT drug meant to increase the strength of leg muscles. But the company halted development last year after the experimental drug failed in a mid-stage trial. While the drug led to a statistically significant increase in muscle volume, it didn't translate to improvements in muscle function or quality of life for trial participants.
Made by Design
Pharnext's drug, PXT3003, is a combination of three existing drugs — baclofen, a muscle relaxant; naltrexone, a drug that decreases the desire for alcohol and opioids; and sorbitol, a type of sugar alcohol.
The company designed the drug using its artificial intelligence platform, which screened 20,000 existing drugs to predict combinations that could inhibit the PMP22 gene and thereby lower protein production. The AI system narrowed the search to several hundreds of combinations and Pharnext tested around 75 of them in the lab before landing on baclofen, naltrexone, and sorbitol. Individually, the drugs don't have much effect on the PMP22 gene. But combined, they work to lower how much protein the gene makes.
"How the drug inside the cell reduces expression isn't quite clear yet," says Florian Thomas, director of the Hereditary Neuropathy Center, and founding chair and professor in the department of neurology at Hackensack University Medical Center and Hackensack Meridian School of Medicine in New Jersey (no relation to Robert Thomas, the CMT patient). "By reducing the amount of protein being produced, we hopefully can stabilize the nerves."
In rodents genetically engineered to have the PMP22 gene, the drug reduced protein levels and delayed onset of muscle weakness when given to rats. In another animal study, the drug increased the size of the myelin sheath around nerves in rats.
"Like humans with CMT, one of the problems the animals have is they can't grip things, their grip strength is poor," Solomon says. But when treated with Pharnext's drug, "the grip strength of these animals improves dramatically even over 12 weeks."
Human trials look encouraging, too. But the company ran into a manufacturing issue during a late-stage trial. The drug requires refrigeration, and as a result of temperature changes, crystals formed inside vials containing the high dose of the drug. The study was a double-blind trial, meaning neither the trial participants nor investigators were supposed to know who received the high dose of the drug, who received the low dose, and who received a placebo. In these types of studies, the placebo and experimental drug should look the same so that investigators can't tell them apart. But because only the high dose contained crystals, not the low dose or placebo, regulators said the trial data could be biased.
Pharnext is now conducting a new randomized, double-blind trial to prove that its drug works. The study is recruiting individuals aged 16 through 65 years old with mild to moderate CMT. The company hopes to show that the drug can stop patients' symptoms from worsening, or in the best case scenario, possibly even improve them. The company doesn't think the drug will be able to help people with severe forms of the disease.
"In neurologic disease, you're looking for plasticity, where there's still the possibility of stabilization or reversal," Solomon says. Plasticity refers to the ability of the nervous system to change and adapt in response to stimuli.
Preventing Disability
Allison Moore, a CMT patient and founder and CEO of the Hereditary Neuropathy Foundation, has been following drug development for CMT since she founded the organization in 2001. She says many investigational drugs haven't moved forward because they've shown little success in animals. The fact that Pharnext's drug has made it to a late-stage human trial is promising, she says.
"It's really exciting," Moore says. "There's a chance that if you take the drug early before you're very severe, you'll end up not developing the disease to a level that's super disabling."
CMT has damaged Moore's peroneal nerve, a main nerve in the foot. As a result, she has foot drop, the inability to lift the front part of her foot, and needs to wear leg braces to help her walk. "The idea that you could take this early on and that it could stop progression, that's the hope that we have."
Thomas, the neurologist, says a drug doesn't have to be a cure to have a significant impact on patients. "If I have a CMT patient who's 50 years old, that patient will be more disabled by age 60," he says. "If I can treat that person with a drug, and that person is just as disabled at age 60 as they were at age 50, that's transformative in my mind."
While Robert Thomas says he hasn't noticed a dramatic improvement since he's been on the drug, he does think it's helping. Robert is now in an open-label study, which means he and his health provider are aware that he's receiving the drug.
When the COVID-19 pandemic hit, manufacturing and supply chain disruptions meant that Robert was without the trial drug for two months. When his medication ran out, his legs felt unstable again and walking was harder. "There was a clear distinction between being on and off that medication," he says.
Pharnext's current trial will take about a year and a half to complete. After that, the FDA will decide on whether to approve the drug for CMT patients.
As scientists learn more about the PMP22 gene and the more than 100 other genes that when mutated cause CMT, more precise treatments could be possible. For instance, scientists have used the gene-editing tool CRISPR to correct a CMT-causing mutation in human cells in the lab. The results were published August 16 in the journal Frontiers in Cell and Developmental Biology.
Pharnext is also interested in pursuing genetic treatments for CMT, but in the meantime, repurposed drugs may be the best shot at helping patients until more advanced treatments are available.
CandyCodes could provide sweet justice against fake pills
When we swallow a pill, we hope it will work without side effects. Few of us know to worry about a growing issue facing the pharmaceutical industry: counterfeit medications. These pills, patches, and other medical products might look just like the real thing. But they’re often stuffed with fillers that dilute the medication’s potency or they’re simply substituted for lookalikes that contain none of the prescribed medication at all.
Now, bioengineer William Grover at the University of California, Riverside, may have a solution. Inspired by the tiny, multi-colored sprinkles called nonpareils that decorate baked goods and candies, Grover created CandyCodes pill coatings to prevent counterfeits.
The idea was borne out of pandemic boredom. Confined to his home, Grover was struck by the patterns of nonpareils he saw on candies, and found himself counting the number of little balls on each one. “It’s random, how they’re applied,” he says. “I wondered if it ever repeats itself or if each of these candies is unique in the entire world.” He suspected the latter, and some quick math proved his hypothesis: Given dozens of nonpareils per candy in a handful of different colors, it’s highly unlikely that the sprinklings on any two candies would be identical.
He quickly realized his finding could have practical applications: pills or capsules could be coated with similar “sprinkles,” with the manufacturer photographing each pill or capsule before selling its products. Consumers looking to weed out fakes could potentially take a photo with their cell phones and go online to compare images of their own pills to the manufacturer’s database, with the help of an algorithm that would determine their authenticity. Or, a computer could generate another type of unique identifier, such as a text-based code, tracking to the color and location of the sprinkles. This would allow for a speedier validation than a photo-based comparison, Grover says. “It could be done very quickly, in a fraction of a second.”
Researchers and manufacturers have already developed some anti-counterfeit tools, including built-in identifiers like edible papers with scannable QR codes. But such methods, while functional, can be costly to implement, Grover says.
It wouldn’t be paranoid to take such precautions. Counterfeits are a growing problem, according to Young Kim, a biomedical engineer at Purdue University who was not involved in the CandyCodes study. “There are approximately 40,000 online pharmacies that one can access via the Internet,” he says. “Only three to four percent of them are operated legally.” Purchases from online pharmacies rose dramatically during the pandemic, and Kim expects a boom in counterfeit medical products alongside it.
The FDA warns that U.S. consumers can be exposed to counterfeits through online purchases, in particular. The problem is magnified in low- to middle-income nations, where one in 10 medical products are counterfeit, according to a World Health Organization estimate. Cost doesn’t seem to be a factor, either; antimalarials and antibiotics are most often reported as counterfeits or fakes, and generic medications are swapped as often as brand-name drugs, according to the same WHO report.
Counterfeits weren’t tracked globally until 2013; since then, there have been 1,500 reports to the WHO, with actual incidences of counterfeiting likely much higher. Fake medicines have been estimated to result in costs of $200 billion each year, and are blamed for more than 72,000 pneumonia- and 116,000 malaria-related deaths.
Researchers and manufacturers have already developed some anti-counterfeit tools, including built-in identifiers like edible papers with scannable QR codes or barcodes that are stamped onto or otherwise incorporated into pills and other medical products. But such methods, while functional, can be costly to implement, Grover says.
CandyCodes could provide unique identifiers for at least 41 million pills for every person on the planet.
William Grover
“Putting universal codes on each pill and each dosage is attractive,” he says. “The challenge is, how can we do it in a way that requires as little modification to the existing manufacturing process as possible? That's where I hope CandyCodes have an edge. It's not zero modification, but I hope it is as minor a modification of the manufacturing process as possible.”
Kim calls the concept “a clever idea to introduce entropy for high-level security” even if it may not be as close to market as other emerging technologies, including some edible watermarks he’s helped develop. He points out that CandyCodes still needs to be tested for reproducibility and readability.
The possibilities are already intriguing, though. Grover’s recent research, published in Scientific Reports, predicts that unique codes could be used for at least 41 million pills for every person on the planet.
Sadly, CandyCodes’ multicolored bits probably won’t taste like candy. They must be made of non-caloric ingredients to meet the international regulatory standards that govern food dyes and colorants. But Grover hopes CandyCodes represent a simple, accessible solution to a heart-wrenching issue. “This feels like trying to track down and go after bad guys,” he says. “Someone who would pass off a medicine intended for a child or a sick person and pass it off as something effective, I can't imagine anything much more evil than that. It's fun and, and a little fulfilling to try to develop technologies that chip away at that.”
Waste smothering our oceans is worth billions – here’s what we can do with all that sh$t
There’s hardly a person out there who hasn’t heard of the Great Pacific Garbage Patch. That type of pollution is impossible to miss. It stares you in the face from pictures and videos of sea turtles with drinking straws up their noses and acres of plastic swirling in the sea.
It demands you to solve the problem—and it works. The campaign to raise awareness about plastic pollution in the oceans has resulted in new policies, including bans on microplastics in personal care products, technology to clean up the plastic, and even new plastic-like materials that are better for the environment.
But there’s a different type of pollution smothering the ocean as you read this. Unfortunately, this one is almost invisible, but no less damaging. In fact, it’s even more serious than plastic and most people have no idea it even exists. It is literally under our noses, destroying our oceans, lakes, and rivers – and yet we are missing it completely while contributing to it daily. In fact, we exacerbate it multiple times a day—every time we use the bathroom.
It is the way we do our sewage.
Most of us don’t think much about what happens after we flush the toilet. Most of us probably assume that the substances we flush go “somewhere” and are dealt with safely. But we typically don’t think about it beyond that.
Most of us also probably don’t think about what’s in the ocean or lakes we swim in. Since others are swimming, jumping in is just fine. But our waterways are far from clean. In fact, at times they are incredibly filthy. In the US, we are dumping 1.2 trillion of gallons of untreated sewage into the environment every year. Just New York City alone discharges 27 billion gallons into the Hudson River basin annually.
How does this happen? Part of it is the unfortunate side effect of our sewage system design that dates back to over a century ago when cities were smaller and fewer people were living so close together.
Back then, engineers designed the so-called “combine sewer overflow systems,” or CSOs, in which the storm water pipes are connected to the sanitary sewer pipes. In normal conditions, the sewage effluent from homes flows to the treatment plants where it gets cleaned and released into the waterways. But when it rains, the pipe system becomes so overwhelmed with water that the treatment plant can’t process it fast enough. So the treatment plant has to release the excess water through its discharge pipes—directly, without treatment, into streams, rivers and the ocean.
The 1.2 trillion gallons of CSO releases isn’t even the full picture. There are also discharges from poorly maintained septic systems, cesspools and busted pipes of the aging wastewater infrastructure. The state of Hawaii alone has 88,000 cesspools that need replacing and are currently leaking 53 million gallons of raw sewage daily into their coastal waters. You may think twice about swimming on your Hawaii vacations.
Overall, the US is facing a $271 billion backlog in wastewater infrastructure projects to update these aging systems. Across the Western world, countries are facing similar challenges with their aging sewage systems, especially the UK and European Union.
That’s not to say that other parts of the planet are in better shape. Out of the 7+ billion people populating our earth, 4.2 billion don’t have access to safe sanitation. Included in this insane number are roughly 2 billion people who have no toilet at all. Whether washed by rains or dumped directly into the waterways, a lot of this sludge pollutes the environment, the drinking water, and ultimately the ocean.
Pipes pour water onto a rocky shore in Jakarta, Indonesia.
Tom Fisk
What complicates this from an ocean health perspective is that it’s not just poop and pee that gets dumped into nearby waterways. It is all the things we put in and on our bodies and flush down our drains. That vicious mix of chemicals includes caffeine, antibiotics, antidepressants, painkillers, hormones, microplastics, cocaine, cooking oils, paint thinners, and PFAS—the forever chemicals present in everything from breathable clothing to fire retardant fabrics of our living room couches. Recent reports have found all of the above substances in fish—and then some.
Why do we allow so much untreated sewage spill into the sea? Frankly speaking, for decades scientists and engineers thought that the ocean could handle it. The mantra back then was “dilution is the solution to pollution,” which might’ve worked when there were much fewer people living on earth—but not now. Today science is telling us that this old approach doesn’t hold. That marine habitats are much more sensitive than we had expected and can’t handle the amount of wastewater we are discharging into them.
The excess nitrogen and phosphorus that the sewage (and agricultural runoff) dumps into the water causes harmful algal blooms, more commonly known as red or brown tides. The water column is overtaken by tiny algae that sucks up all the oxygen from the water, creating dead zones like the big fish kills in the Gulf of Mexico. These algae also cause public health issues by releasing gases toxic to people and animals, including dementia, neurological damage, and respiratory illness. Marshes and mangroves end up with weakened root systems and start dying off. In a wastewater modeling study I published last year, we found that 31 percent of salt marshes globally were heavily polluted with human sewage. Coral reefs get riddled with disease and overgrown by seaweed.
We could convert sewage into high-value goods. It can be used to generate electricity, fertilizer, and drinking water. The technologies not only exist but are getting better and more efficient all the time.
Moreover, by way of our sewage, we managed to transmit a human pathogen—Serratia marcescens, which causes urinary, respiratory and other infections in people—to corals! Recent reports from the Florida Keys are showing white pox disease popping up in elk horn corals caused by S.marcescens, which somehow managed to jump species. Many recent studies have documented just how common this type of pollution is across the globe.
Yet, there is some good news in that abysmal sewage flow. Just like with plastic pollution, realizing that there’s a problem is the first step, so awareness is key. That’s exactly why I co-founded Ocean Sewage Alliance last year—a nonprofit that aims to “re-potty train the world” by breaking taboos in talking about the poop and pee problem, as well as uniting experts from various key sectors to work together to end sewage pollution in coastal areas.
To end this pollution, we have to change the ways we handle our sewage. Even more exciting is that by solving the sewage problem we can create all sorts of economic benefits. In 2015, human poop was valued at $9.5 billion a year globally, which today would be $11.5 billion per year.
What would one do with that sh$t?
We could convert it into high-value goods. Sewage can be used to generate electricity, fertilizer, and drinking water. The technologies not only exist but are getting better and more efficient all the time. Some exciting examples include biodigesters and urine diversion (or peecycling) systems that can produce fertilizer and biogas, essentially natural gas. The United Nations estimates that the biogas produced from poop could provide electricity for 138 million homes. And the recovered and cleaned water can be used for irrigation, laundry and flushing toilets. It can even be refined to the point that it is safe for drinking water – just ask the folks in Orange County, CA who have been doing so for the last few decades.
How do we deal with all the human-made pollutants in our sewage? There is technology for that too. Called pyrolysis, it heats up sludge to high temperatures in the absence of oxygen, which causes most of the substances to degrade and fall apart.
There are solutions to the problems—as long as we acknowledge that the problems exist. The fact that you are reading this means that you are part of the solution already. The next time you flush your toilet, think about where this output may flow. Does your septic system work properly? Does your local treatment plant discharge raw sewage on rainy days? Can that plant implement newer technologies that can upcycle waste? These questions are part of re-potty training the world, one household at a time. And together, these households are the force that can turn back the toxic sewage tide. And keep our oceans blue.