New Hope for Organ Transplantation: Life Without Anti-Rejection Drugs
Rob Waddell dreaded getting a kidney transplant. He suffers from a genetic condition called polycystic kidney disease that causes the uncontrolled growth of cysts that gradually choke off kidney function. The inherited defect has haunted his family for generations, killing his great grandmother, grandmother, and numerous cousins, aunts and uncles.
But he saw how difficult it was for his mother and sister, who also suffer from this condition, to live with the side effects of the drugs they needed to take to prevent organ rejection, which can cause diabetes, high blood pressure and cancer, and even kidney failure because of their toxicity. Many of his relatives followed the same course, says Waddell: "They were all on dialysis, then a transplant and ended up usually dying from cancers caused by the medications."
When the Louisville native and father of four hit 40, his kidneys barely functioned and the only alternative was either a transplant or the slow death of dialysis. But in 2009, when Waddell heard about an experimental procedure that could eliminate the need for taking antirejection drugs, he jumped at the chance to be their first patient. Devised by scientists at the University of Louisville and Northwestern University, the innovative approach entails mixing stem cells from the live kidney donor with that of the recipient to create a hybrid immune system, known as a chimera, that would trick the immune system and prevent it from attacking the implanted kidney.
The procedure itself was done at Northwestern Memorial Hospital in Chicago, using a live kidney donated by a neighbor of Waddell's, who camped out in Chicago during his recovery. Prior to surgery, Waddell underwent a conditioning treatment that consisted of low dose radiation and chemotherapy to weaken his own immune system and make room for the infusion of stem cells.
"The low intensity chemo and radiation conditioning regimen create just enough space for the donor stem cells to gain a foothold in the bone marrow and the donor's immune system takes over," says Dr. Joseph Levanthal, the transplant surgeon who performed the operation and director of kidney and pancreas transplantation at Northwestern University Feinberg School of Medicine. "That way the recipient develops an immune system that doesn't see the donor organ as foreign."
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis."
A week later, Waddell had the kidney transplant. The following day, he was infused with a complex cellular cocktail that included blood-forming stem cells derived from his donor's bone marrow mixed what are called tolerance inducing facilitator cells (FCs); these cells help the foreign stem cells get established in the recipient's bone marrow.
Over the course of the following year, he was slowly weaned off of antirejection medications—a precaution in case the procedure didn't work—and remarkably, hasn't needed them since. "I felt better than I had in decades because my kidneys [had been] degrading," recalls Waddell, now 54 and a CPA for a global beverage company. And what's even better is that this new approach offers hope for one of his sons who has also inherited the disorder.
Kidney transplants are the most frequent organ transplants in the world and more than 23,000 of these procedures were done in the United States in 2019, according to the United Network for Organ Sharing. Of this, about 7,000 operations are done annually using live organ donors; the remainder use organs from people who are deceased. Right now, this revolutionary new approach—as well as a similar strategy formulated by Stanford University scientists--is in the final phase of clinical trials. Ultimately, this research may pave the way towards realizing the holy grail of organ transplantation: preventing organ rejection by creating a tolerant state in which the recipient's immune system is compatible with the donor, which would eliminate the need for a lifetime of medications.
"As a surgeon, I saw what my patients had to go through—taking 25 pills a day, dying at an early age from heart disease, or having a 35% chance of dying every year on dialysis," says Dr. Suzanne Ildstad, a transplant surgeon and director of the Institute for Cellular Therapeutics at the University of Louisville, whose discovery of facilitator cells were the basis for this therapeutic platform. Ildstad, who has spent more than two decades searching for a better way, says, "This is something I have worked for my entire life."
The Louisville group uses a combination of chemo and radiation to replace the recipient's immune and blood forming cells with that of the donor. In contrast, the Stanford protocol involves harvesting the donor's blood stem cells and T-cells, which are the foot soldiers of the immune system that fight off infections and would normally orchestrate the rejection of the transplanted organ. Their transplant recipients undergo a milder form of "conditioning" that only radiates discrete parts of the body and selectively targets the recipient's T-cells, creating room for both sets of T-cells, a strategy these researchers believe has a better safety profile and less of a chance of rejection.
"We try to achieve immune tolerance by a true chimerism," says Dr. Samuel Strober, a professor of medicine for immunology and rheumatology at Stanford University and a leader of this research team. "The recipients immune system cells are maintained but mixed in the blood with that of the donor."
Studies suggest both approaches work. In a 2018 clinical trial conducted by Talaris Therapeutics, a Louisville-based biotech founded by Ildstad, 26 of 37 (70%) of the live donor kidney transplant recipients no longer need immunosuppressants. Last fall, Talaris began the final phase of clinical tests that will eventually encompass more than 120 such patients.
The Stanford group's cell-based immunotherapy, which is called MDR-101 and is sponsored by the South San Francisco biotech, Medeor Therapeutics, has had similar results in patients who received organs from live donors who were either well matched, such as one from siblings, meaning they were immunologically identical, or partially matched; Talaris uses unrelated donors where there is only a partial match.
In their 2020 clinical trial of 51 patients, 29 were fully matched and 22 were a partial match; 22 of the fully matched recipients didn't need antirejection drugs and ten of the partial matches were able to stop taking some of these medications without rejection. "With our fully matched, roughly 80% have been completely off drugs up to 14 years later," says Strober, "and reducing the number of drugs from three to one [in the partial matches] means you have far fewer side effects. The goal is to get them off of all drugs."
But these protocols are limited to a small number of patients—living donor kidney recipients. As a consequence, both teams are experimenting with ways to broaden their approach so they can use cadaver organs from deceased donors, with human tests planned in the coming year. Here's how that would work: after the other organs are removed from a deceased donor, stem cells are harvested from the donor's vertebrae in the spinal column and then frozen for storage.
"We do the transplant and give the patient a chance to recover and maintain them on drugs," says Ildstad. "Then we do the tolerance conditioning at a later stage."
If this strategy is successful, it would be a genuine game changer, and open the door to using these protocols for transplanting other cadaver organs, including the heart, lungs and liver. While the overall procedure is complex and costly, in the long run it's less expensive than repeated transplant surgeries, the cost of medications and hospitalizations for complications caused by the drugs, or thrice weekly dialysis treatments, says Ildstad.
And she adds, you can't put a price tag on the vast improvement in quality of life.
They received retinal implants to restore their vision. Then the company turned its back on them.
The first thing Jeroen Perk saw after he partially regained his sight nearly a decade ago was the outline of his guide dog Pedro.
“There was a white floor, and the dog was black,” recalls Perk, a 43-year-old investigator for the Dutch customs service. “I was crying. It was a very nice moment.”
Perk was diagnosed with retinitis pigmentosa as a child and had been blind since early adulthood. He has been able to use the implant placed into his retina in 2013 to help identify street crossings, and even ski and pursue archery. A video posted by the company that designed and manufactured the device indicates he’s a good shot.
Less black-and-white has been the journey Perk and others have been on after they were implanted with the Argus II, a second-generation device created by a Los Angeles-based company called Second Sight Medical Devices.
The Argus II uses the implant and a video camera embedded in a special pair of glasses to provide limited vision to those with retinitis pigmentosa, a genetic disease that causes cells in the retina to deteriorate. The camera feeds information to the implant, which sends electrical impulses into the retina to recapitulate what the camera sees. The impulses appear in the Argus II as a 60-pixel grid of blacks, grays and whites in the user’s eye that can render rough outlines of objects and their motion.
Smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Ross Doerr, a retired disability rights attorney in Maine who received an Argus II in 2019, describes the field of vision as the equivalent of an index card held at arm’s length. Perk often brings objects close to his face to decipher them. Moreover, users must swivel their heads to take in visual data; moving their eyeballs does not work.
Despite its limitations, the Argus II beats the alternative. Perk no longer relies on his guide dog. Doerr was uplifted when he was able to see the outlines of Christmas trees at a holiday show.
“The fairy godmother department sort of reaches out and taps you on the shoulder once in a while,” Doerr says of his implant, which came about purely by chance. A surgeon treating his cataracts was partnered with the son of another surgeon who was implanting the devices, and he was referred.
Doerr had no reason to believe the shower of fairy dust wouldn’t continue. Second Sight held out promises that the Argus II recipients’ vision would gradually improve through upgrades to much higher pixel densities. The ability to recognize individual faces was even touted as a possibility. In the winter of 2020, Doerr was preparing to travel across the U.S. to Second Sight’s headquarters to receive an upgrade. But then COVID-19 descended, and the trip was canceled.
The pandemic also hit Second Sight’s bottom line. Doerr found out about its tribulations only from one of the company’s vision therapists, who told him the entire department was being laid off. Second Sight cut nearly 80% of its workforce in March 2020 and announced it would wind down operations.
Ross Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market.
Jan Doerr
Second Sight’s implosion left some 350 Argus recipients in the metaphorical dark about what to do if their implants failed. Skeleton staff seem to have rarely responded to queries from their customers, at least based on the experiences of Perk and Doerr. And some recipients have unfortunately returned to the actual dark as well, as reports have surfaced of Argus II failures due to aging or worn-down parts.
Product support for complex products is remarkably uneven. Although the iconic Ford Mustang ceased production in the late 1960s, its parts market is so robust that it’s theoretically possible to assemble a new vehicle from recently crafted components. Conversely, smartphone and computer manufacturers typically stop issuing software upgrades to their devices after two or three years, eventually rendering them bricks. Consumers have accepted both extremes.
But is the smartphone approach acceptable for a device that helps restore the most crucial sense a human being possesses?
Margaret McLean, a senior fellow at the Markkula Center for Applied Ethics at Santa Clara University in California, notes companies like Second Sight have a greater obligation for product support than other consumer product ventures.
“In this particular case, you have a great deal of risk that is involved in using this device, the implant, and the after care of this device,” she says. “You cannot, like with your car, decide that ‘I don’t like my Mustang anymore,’ and go out and buy a Corvette.”
And, whether the Argus II implant works or not, its physical presence can impact critical medical decisions. Doerr’s doctor wanted him to undergo an MRI to assist in diagnosing attacks of vertigo. But the physician was concerned his implant might interfere. With the latest available manufacturer advisories on his implant nearly a decade old, the procedure was held up. Doerr spent months importuning Second Sight through phone calls, emails and Facebook postings to learn if his implant was contraindicated with MRIs, which he never received. Although the cause of his vertigo was found without an MRI, Doerr was hardly assured.
“Put that into context for a minute. I get into a serious car accident. I end up in the emergency room, and I have a tag saying I have an implanted medical device,” he says. “You can’t do an MRI until you get the proper information from the company. Who’s going to answer the phone?”
Second Sight’s management did answer the call to revamp its business. It netted nearly $78 million through a private stock placement and an initial public offering last year. At the end of 2021, Second Sight had nearly $70 million in cash on hand, according to a recent filing with the Securities and Exchange Commission.
And while the Argus II is still touted at length on Second Sight’s home page, it appears little of its corporate coffers are earmarked toward its support. These days, the company is focused on obtaining federal approvals for Orion, a new implant that would go directly into the recipient’s brain and could be used to remedy blindness from a variety of causes. It obtained a $6.4 million grant from the National Institutes of Health in May 2021 to help develop Orion.
Presented with a list of written questions by email, Second Sight’s spokesperson, Dave Gentry of the investor relations firm Red Chip Companies, copied a subordinate with an abrupt message to “please handle.” That was the only response from a company representative. A call to Second Sight acting chief executive officer Scott Dunbar went unreturned.
Whether or not the Orion succeeds remains to be seen. The company’s SEC filings suggest a viable and FDA-approved device is years away, and that operational losses are expected for the “foreseeable future.” Second Sight reported zero revenue in 2020 or 2021.
Moreover, the experiences of the Argus II recipients could color the reception of future Second Sight products. Doerr notes that his insurer paid nearly $500,000 to implant his device and for training on how to use it.
“What’s the insurance industry going to say the next time this crops up?” Doerr asks, noting that the company’s reputation is “completely shot” with the recipients of its implants.
Perk, who made speeches to praise the Argus II and is still featured in a video on the Second Sight website, says he also no longer supports the company.
Jeroen Perk, an investigator for the Dutch customs service, cried for joy after partially regaining his sight, but he no longer trusts Second Sight, the company that provided his implant.
Nanda Perk
Nevertheless, Perk remains highly reliant on the technology. When he dropped an external component of his device in late 2020 and it broke, Perk briefly debated whether to remain blind or find a way to get his Argus II working again. Three months later, he was able to revive it by crowdsourcing parts, primarily from surgeons with spare components or other Argus II recipients who no longer use their devices. Perk now has several spare parts in reserve in case of future breakdowns.
Despite the frantic efforts to retain what little sight he has, Perk has no regrets about having the device implanted. And while he no longer trusts Second Sight, he is looking forward to possibly obtaining more advanced implants from companies in the Netherlands and Australia working on their own products.
Doerr suggests that biotech firms whose implants are distributed globally be bound to some sort of international treaty requiring them to service their products in perpetuity. Such treaties are still applied to the salvage rights for ships that sunk centuries ago, he notes.
“I think that in a global tech economy, that would be a good thing,” says McLean, the fellow at Santa Clara, “but I am not optimistic about it in the near term. Business incentives push toward return on share to stockholders, not to patients and other stakeholders. We likely need to rely on some combination of corporately responsibility…and [international] government regulation. It’s tough—the Paris Climate Accord implementation at a slow walk comes to mind.”
Unlike Perk, Doerr has mostly stopped using his Argus II, the result of combination of fear of losing its assistance from wear and tear and disdain for the company that brought it to market. At 70, Doerr says he does not have the time or energy to hold the company more accountable. And with Second Sight having gone through a considerable corporate reorganization, Doerr believes a lawsuit to compel it to better serve its Argus recipients would be nothing but an extremely costly longshot.
“It’s corporate America at its best,” he observes.
Rehabilitating psychedelic drugs: Another key to treating severe mental health disorders
Lori Tipton's life was a cascade of trauma that even a soap opera would not dare inflict upon a character: a mentally unstable family; a brother who died of a drug overdose; the shocking discovery of the bodies of two persons her mother had killed before turning the gun on herself; the devastation of Hurricane Katrina that savaged her hometown of New Orleans; being raped by someone she trusted; and having an abortion. She suffered from severe PTSD.
“My life was filled with anxiety and hypervigilance,” she says. “I was constantly afraid and had mood swings, panic attacks, insomnia, intrusive thoughts and suicidal ideation. I tried to take my life more than once.” She was fortunate to be able to access multiple mental health services, “And while at times some of these modalities would relieve the symptoms, nothing really lasted and nothing really address the core trauma.”
Then in 2018 Tipton enrolled in a clinical trial that combined intense sessions of psychotherapy with limited use of Methylenedioxymethamphetamine, or MDMA, a drug classified as a psychedelic and commonly known as ecstasy or Molly. The regimen was arduous; 1-2 hour preparation sessions, three sessions where MDMA was used, which lasted 6-8 hours, and lengthy sessions afterward to process and integrate the experiences. Two therapists were with her every moment of the three-month program that totaled more than 40 hours.
“It was clear to me that [the therapists] weren't going to heal me, that I was going to have to do the work for myself, but that they were there to completely support my process,” she says. “But the effects of MDMA were really undeniable for me. I felt embodied in a way that I hadn't in years. PTSD had robbed me of the ability to feel safe in my own body.”
Tipton doesn’t think the therapy completely cured her PTSD. “But when I completed the trial in 2018, I no longer qualified for the diagnosis, and I still don't qualify for the diagnosis today,” she told an April workshop on psychedelics as mental health treatment by the National Academies of Sciences, Engineering and Medicine, or NASEM.
A Champion
Rick Doblin has been a catalyst behind much of the contemporary research into psychedelics. Prior to the DEA clamp down, the Boston psychotherapist had seen that MDMA and other psychedelics could benefit some of his patients where other measures had failed. He immediately organized efforts to question the drug rescheduling but to little avail. In 1986, he created the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS), which slowly laid the scientific foundation for clinical trials, including the one that Tipton joined, using psychedelics to treat mental health conditions.
Now, only slowly, have researchers been able to explore the power of these drugs to treat a broad spectrum of severely debilitating mental health conditions, including trauma, depression, and PTSD, where other available treatments proved inadequate.
“Psychedelic psychotherapy is an attempt to go after the root causes of the problems with just a relatively few administrations, as contrasted to most of the psychiatric drugs used today that are mostly just reducing symptoms and are meant to be taken on a daily basis,” Doblin said in a 2019 TED Talk. Most of these drugs can have broad effect but “some are probably more effective than others for certain conditions,” he added in a recent interview with Leaps.org. Comparative head-to-head studies of psychedelic therapies simply have not been conducted.
Their mechanisms of action are poorly understood and can vary between drugs, but it is generally believed that psychedelics change the activity of neurons so that the brain processes information differently, says Katrin Preller, a neuropsychologist at the University of Zurich. A recent important study in Nature Medicine by Richard Daws and colleagues used functional magnetic resonance imaging (fMRI) of the brain and found that “functional networks became more functionally interconnected and flexible after psilocybin treatment…implying that psilocybin's antidepressant action may depend on a global increase in brain network integration.”
Rosalind Watts, a clinical investigator at the Imperial College in London, believes there is “an overestimation of the importance of the drug and an underestimation of the importance of the [therapeutic] context” in psychedelic research. “It is unethical to provide the drug without the other,” she says. Doblin notes that “psychotherapy outcomes research demonstrates that the therapeutic alliance between the therapist and the patients is the single most predictive factor of outcomes. [It is] trust and the sense of safety, the willingness to go into difficult spaces” that makes clinical breakthroughs possible with the drug.
Excitement and Challenges
Recurrent themes expressed at the NASEM workshop were exciting glimpses of the potential for psychedelics to treat mental health conditions combined with the challenges of realizing those potentials. A recent review paper found evidence that using psychedelics can help with treating a variety of common mental illnesses, but the paper could identify only 14 clinical trials of classic psychedelics published since 1991. Much of the reason is that the drugs are not patentable and so the pharmaceutical industry has no interest in investing in expensive clinical trials to bring them to market. MAPS has raised about $135 million over its 36-year history to conduct such research, says Doblin, the vast majority of it from individual donors and none from foundations.
The workshop participants’ views also were colored by the history of drug crackdowns and a fear that research might easily be shut down in the future. There was great concern that use of psychedelics should be confined to clinical trials with high safety and ethical standards, instead of doctors and patients experimenting on their own. “We need to get it right this time,” says Charles Grob, a psychiatrist at the UCLA School of Medicine. But restricting access to psychedelics will become even more difficult now that Oregon and several cities have acted to decriminalize possession and use of many of these drugs.
The experience with ketamine also troubled Grob. He is hoping to “mitigate the rush of rapid commercialization” that occurred with that drug. Ketamine technically is not a psychedelic though it does share some of their potentially euphoric properties. In 2019, soon after the FDA approved a form of ketamine with a limited label indication to treat depression, for profit clinics sprang up promoting off label use of the drug for psychiatric conditions where there was little clinical evidence of efficacy. He fears the same thing will happen when true psychedelics are made available.
If these therapies are approved, access to them is likely to be a problem. The drugs themselves are cheap but the accompanying therapy is not, and there is a shortage of trained psychotherapists. Mental health services often are not adequately covered by health insurance, while the poor and people of color suffer additional burdens of inadequate access. Doblin is committed to health care equity by training additional providers and by investigating whether some of the preparatory and integration sessions might be handled in a group setting. He says it is important that the legal aspects of psychedelics also be addressed so that patients “don't have to go underground” in order to receive this care.