Why Aren’t Gene Editing Treatments Available Yet For People With Genetic Disorders? 
Lynn Julian Crisci, 40, is an actress, a singer-songwriter, and an ambassador for the U.S. Pain Foundation. She is also a Boston Marathon bombing survivor. Crisci has a genetic disorder called Ehlers-Danlos syndrome (EDS), which has magnified the impact of the traumatic brain injury she sustained as a result of the attack that occurred almost five years ago. Having EDS means that her brain tissue is weaker and more prone to injury.
"I would love to learn more about gene editing and the possibilities of using it to lessen the symptoms of EDS, or cure it completely."
"EDS is a genetic tissue disorder that forces the body to make defective collagen," Crisci told LeapsMag. Since collagen is the main component of connective tissue (bones, blood vessels, the gastrointestinal tract, skin, cartilage, etc.), and is the most abundant protein in mammals, EDS can affect virtually every part of the body. "This results in widespread joint pain, usually due to hypermobility, sometimes along with digestive issues such as inflammatory bowel disease, and prolapsed organs."
If life was difficult with Ehlers-Danlos syndrome alone, the addition of the brain injury has made Crisci's life feel unbearable at times. Amidst her week's back-to-back doctor's visits, Crisci said that she would "love to learn more about gene editing and the possibilities of using it to lessen the symptoms of Ehlers-Danlos syndrome, or cure it completely."
With all of the excitement these days around CRISPR, a precise and efficient way to edit DNA that has taken the world by storm, such treatments seem tantalizingly within reach. But is it fair to present the hope of such cures to those with life-limiting genetic disorders?
"From the experience that we've had from gene therapy — we're 20, almost 30 years past some of the initial gene therapy stuff — and there's still not a huge number of applications for it," said Scott Weissman, founder of Chicago Genetic Consultants, a company that provides genetic counseling services to patients. "Unfortunately, we have to wait and see if this is something that's truly viable, or if it's really just hype."
"I expect five years from now we'll look back and say, 'Wow, we were just scratching the surface.'"
Defining Our Terms
The terms "gene therapy" and "gene editing" are often used interchangeably, but not everyone agrees with this usage.
According to Editas Medicine, a leader in CRISPR technology, gene therapy involves the transfer of a new gene into a patient's cells to augment a defective gene, instead of using drugs or surgery to treat a condition. After a teenager's death in 1999 effectively shut down gene therapy research in the U.S., subsequent studies helped the field make a comeback, and the first such treatment for an inherited disease was approved by the FDA just a few weeks ago, for a rare form of vision loss. Called Luxturna, it is for treatment of patients with RPE65-mediated inherited retinal disease (IRD).
Since those with RPE65-mediated IRD typically become blind in childhood and have no pharmacologic treatment options, the FDA's approval of Luxturna is "a significant moment for patients," said Jeffrey Marrazzo, the chief executive officer of the company behind the product, Spark Therapeutics. Two other gene therapy treatments were also approved in the last five months, both for specific cancers.
Gene editing, on the other hand, refers to a group of technologies that enables scientists to precisely and directly change an organism's genes by adding, removing, or altering particular segments of DNA. Gene editing tools include Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and CRISPR/Cas9. The first treatment using ZFNs happened in November in California, when a 44-year-old man with a metabolic ailment called Hunter syndrome was injected with gene editing tools. Results are not yet known.
Dr. David Valle, director of the Institute of Genetic Medicine at Johns Hopkins, said that gene therapy's "significant therapeutic misadventures" have actually been beneficial. They've helped us learn to "be rigorous in our thinking about what we can do and what we can't do with CRISPR" and other gene editing tools.
"It appears like we are really beginning to have, for the first time, some meaningful and good results from gene therapy — it's moving into the clinic now in a meaningful way," Valle said. "I expect five years from now we'll look back and say, 'Wow, we were just at this point in 2017 — we were just scratching the surface.'"
Over 2300 gene therapy clinical trials are planned, ongoing, or have been completed so far. As for gene editing, no treatments are commercially available anywhere in the world. The expectation, however, is that many treatments that are "currently in or soon to enter clinical trials will come up for approval in coming years," according to a November 2016 report by the American Society of Gene & Cell Therapy.
CRISPR Therapeutics of Cambridge, Massachusetts will begin a European gene editing trial this year, with the hopes of creating a treatment for beta thalassemia, an inherited blood disorder. The company will also request approval from the FDA to begin a clinical trial using CRISPR for sickle-cell disease. And Stanford University School of Medicine researchers are planning a similar CRISPR clinical trial for sickle-cell disease. They hope to begin their trial in 2019.
Jim Burns, the president and chief executive officer of Casebia Therapeutics, told Leapsmag that the company will start animal research this year using CRISPR to treat autoimmune diseases, hemophilia A, and retinal diseases. They expect to begin clinical research in humans in 2019 or 2020. [Disclosure: Casebia Therapeutics is a novel joint venture between CRISPR Therapeutics and Leapsmag's founder, Leaps by Bayer, though Leapsmag is editorially independent of Bayer.]
Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside.
The Technology Isn't There Yet
Unlike germline gene editing — when egg and sperm cell DNA is edited in an embryo — somatic cell gene editing in adults is not very controversial, because the edits are not heritable. Since somatic cells contribute to the various tissues of the body but not to eggs or sperm cells, changes made to somatic cells are limited to the treated individual.
The number one reason that gene therapy and gene editing treatments are not yet widely available to the adult population is that the technology is not advanced enough. But it's getting there. Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside — especially in the case of monogenic diseases.
Roughly 10,000 genetic illnesses are monogenic, meaning that they result from a disease-causing variant in a single gene. Some monogenic diseases that have gene editing treatments currently in development for use in clinical trials include cystic fibrosis, Huntington's disease, Tay-Sachs disease, and sickle cell anemia.
Marrazzo of Spark Therapeutics told LeapsMag that his company is working on gene therapies for monogenic diseases that affect the eye, like the retinal disease that Luxturna targets, as well as neurodegenerative and liver diseases.
But most illnesses are polygenic, meaning that they result from multiple gene mutations that have a combined influence on disease progression. Polygenic diseases, like high blood pressure and diabetes, would therefore be more challenging to treat with genome-targeted interventions. As a result, most research is currently focused on monogenic diseases.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured."
A major hurdle of gene editing is the risk of off-target effects. Editing the genome "can have unpredictable effects on gene expression and unintended effects on neighboring genes," wrote Morgan Maeder and Charles Gersbach in a March 2016 article in Molecular Therapy. One such unintended effect is the development of leukemia when a new gene unintentionally activates a cancer gene.
And since there are roughly 37 trillion cells in the adult human body, getting the gene editing machinery to enough cells or target tissues to create a lasting and significant change is a daunting task.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured," said Weissman, the genetic counseling expert. If you take an adult patient with known BRCA1 or BRCA2 mutations, for example, how do you then "get the [gene editing] system in the breast so that it accurately cuts out the mutation in every single breast cell that could potentially turn into breast cancer, or in every single ovarian cell that could turn into ovarian cancer? We don't know how to target it like that, and I think that's the biggest reason you're not seeing it more somatically at this point in time."
Approval and Access
Debra Mathews, assistant director for science programs for the Johns Hopkins Berman Institute of Bioethics, told LeapsMag that pre-existing regulatory frameworks surrounding gene therapy have been sufficient for addressing ethical and regulatory concerns surrounding gene editing. A bigger concern, she said, centers around access to future genome-targeted treatments.
"We know more about the genetics of Caucasian populations than other populations," Mathews explained, due to how genomic data is gathered. This "could lead to problems not just of financial but of biological access to new therapies." In other words, she said, "if you're of European ancestry, there may be a greater chance that there's a relevant genetically-targeted therapy for you than if you're of non-European ancestry."
Ensuring that genome-targeted treatments are accessible to all will require increased cooperation and data-sharing among key stakeholders around the world, as well as increased public engagement that is inclusive of a wide range of voices.
"It's important to be realistic in our predictions to the public."
The Coming Wave of Gene Editing Treatments
Ehlers-Danlos syndrome alone has 13 monogenic subtypes, each with its own genetic basis and set of clinical criteria. Though several of the gene mutations causing EDS subtypes have been identified, the genetic basis for the most common subtype that Lynn Julian Crisci has — hypermobile EDS — remains unknown. What this means, according to Valle, the doctor from Johns Hopkins, is that a gene therapy or gene editing approach "really cannot be contemplated because we don't know what we're trying to fix" yet. This is the case for many genetic illnesses.
Efforts are ongoing in gene discovery by organizations such as the Baylor-Hopkins Center for Mendelian Genomics, of which Valle is the principal investigator. "Our objective," he said, "is to identify the genes and variants responsible" in monogenic disorders.
While Valle is optimistic about the coming wave of commercially available gene therapy and gene editing treatments, he also thinks that "it's important to be realistic in our predictions to the public." As eager as physicians are to offer cures to their patients, "we have to make sure that we're rigorous in our thinking and our ideas are well-buttressed with results."
Estimates vary for how long Crisci and others with genetic illnesses will have to wait for genome-targeted treatment options. Depending on the illness, viable gene editing treatments could hit the market within the next ten years. Though patients have already waited a long while, the revolutionary technology allowing us to fix nature's mistakes could make up for lost time and lost hope.
MILESTONE: Doctors have transplanted a pig organ into a human for the first time in history
Surgeons at Massachusetts General Hospital made history last week when they successfully transplanted a pig kidney into a human patient for the first time ever.
The recipient was a 62-year-old man named Richard Slayman who had been living with end-stage kidney disease caused by diabetes. While Slayman had received a kidney transplant in 2018 from a human donor, his diabetes ultimately caused the kidney to fail less than five years after the transplant. Slayman had undergone dialysis ever since—a procedure that uses an artificial kidney to remove waste products from a person’s blood when the kidneys are unable to—but the dialysis frequently caused blood clots and other complications that landed him in the hospital multiple times.
As a last resort, Slayman’s kidney specialist suggested a transplant using a pig kidney provided by eGenesis, a pharmaceutical company based in Cambridge, Mass. The highly experimental surgery was made possible with the Food and Drug Administration’s “compassionate use” initiative, which allows patients with life-threatening medical conditions access to experimental treatments.
The new frontier of organ donation
Like Slayman, more than 100,000 people are currently on the national organ transplant waiting list, and roughly 17 people die every day waiting for an available organ. To make up for the shortage of human organs, scientists have been experimenting for the past several decades with using organs from animals such as pigs—a new field of medicine known as xenotransplantation. But putting an animal organ into a human body is much more complicated than it might appear, experts say.
“The human immune system reacts incredibly violently to a pig organ, much more so than a human organ,” said Dr. Joren Madsen, director of the Mass General Transplant Center. Even with immunosuppressant drugs that suppress the body’s ability to reject the transplant organ, Madsen said, a human body would reject an animal organ “within minutes.”
So scientists have had to use gene-editing technology to change the animal organs so that they would work inside a human body. The pig kidney in Slayman’s surgery, for instance, had been genetically altered using CRISPR-Cas9 technology to remove harmful pig genes and add human ones. The kidney was also edited to remove pig viruses that could potentially infect a human after transplant.
With CRISPR technology, scientists have been able to prove that interspecies organ transplants are not only possible, but may be able to successfully work long term, too. In the past several years, scientists were able to transplant a pig kidney into a monkey and have the monkey survive for more than two years. More recently, doctors have transplanted pig hearts into human beings—though each recipient of a pig heart only managed to live a couple of months after the transplant. In one of the patients, researchers noted evidence of a pig virus in the man’s heart that had not been identified before the surgery and could be a possible explanation for his heart failure.
So far, so good
Slayman and his medical team ultimately decided to pursue the surgery—and the risk paid off. When the pig organ started producing urine at the end of the four-hour surgery, the entire operating room erupted in applause.
Slayman is currently receiving an infusion of immunosuppressant drugs to prevent the kidney from being rejected, while his doctors monitor the kidney’s function with frequent ultrasounds. Slayman is reported to be “recovering well” at Massachusetts General Hospital and is expected to be discharged within the next several days.Niklas Anzinger is the founder of Infinita VC based in the charter city of Prospera in Honduras. Infinita focuses on a new trend of charter cities and other forms of alternative jurisdictions. Healso hosts a podcast about how to accelerate the future by unblocking “stranded technologies”.This spring he was a part of the network city experiment Zuzalu spearheaded by Ethereum founder Vitalik Buterin where a few hundred invited guests from the spheres of longevity, biotechnology, crypto, artificial intelligence and investment came together to form a two-monthlong community. It has been described as the world’s first pop-up city. Every morning Vitalians would descend on a long breakfast—the menu had been carefully designed by famed radical longevity self-experimenter Bryan Johnson—and there is where I first met Anzinger who told me about Prospera. Intrigued to say the least, I caught up with him later the same week and the following is a record of our conversation.
Q. We are sitting here in the so-called pop-up network state Zuzalu temporarily realized in the village of Lusticia Bay by the beautiful Mediterranean Sea. To me this is an entirely new concept: What is a network state?
A. A network state is a highly aligned online community that has a level of in-person civility; it crowd-funds territory, and it eventually seeks diplomatic recognition. In a way it's about starting a new country. The term was coined by the crypto influencer and former CTO of Coinbase Balaji Srinivasan in a book by the same title last year [2022]. What many people don't know is that it is a more recent addition or innovation in a space called competitive governance. The idea is that you have multiple jurisdictions competing to provide you services as a customer. When you have competition among governments or government service providers, these entities are forced to provide you with a better service instead of the often worse service at higher prices or higher taxes that we're currently getting. The idea went from seasteading, which was hardly feasible because of costs, to charter cities getting public/private partnerships with existing governments and a level of legal autonomy, to special economic zones, to now network states.
Q. How do network states compare to charter cities and similar jurisdictions?
A. Charter cities and special economic zones were legal forks from other existing states. Dubai, Shenzhen in China, to some degree Hong Kong, to some degree Singapore are some examples. There's a host of other charter cities, one of which I'm based in myself, which is Prospera located in Honduras on the island Roatán. Charter cities provide the full stack of governance; they provide new laws and regulations, business registration, tax codes and governance services, Estonia style: you log on to the government platform and you get services as a citizen.
When conceptualizing network states, Balagi Srinivasan turns the idea of a charter city a bit on its head: he doesn't want to start with this full stack because it's still very hard to get these kinds of partnerships with government. It's very expensive and requires lots of experience and lots of social capital. He is saying that network states could instead start as an online community. They could have a level of alignment where they trade with each other; they have their own economy; they meet in person in regular gatherings like we're doing here in Zuzulu for two months, and then they negotiate with existing governments or host cities to get a certain degree of legal autonomy that is centered around a moral innovation. So, his idea is: don't focus on building a completely new country or city; focus on a moral innovation.
Q. What would be an example of such a moral innovation?
A. An example would be longevity—life is good; death is bad—let's see what we can do to foster progress around that moral innovation and see how we can get legal forks from the existing system that allow us to accelerate progress in that area. There is an increasing realization in the science that there are hallmarks of aging and that aging is a cause of other diseases like cancer, ALS or Alzheimer's. But aging is not recognized as a disease by the FDA in the United States and in most countries around the world, so it's very hard to get scientific funding for biotechnology that would attack the hallmarks of aging and allow us potentially to reverse aging and extend life. This is a significant shortcoming of existing government systems that groups such as the ones that have come together here in Montenegro are now seeking alternatives too. Charter cities and now network states are such alternatives.
Q. Would it not be better to work within the current systems, and try to improve them, rather than abandon them for new experimental jurisdictions?
A. There are numerous failures of public policies. These failures are hard, if not impossible, to reverse, because as soon as you have these policies, you have entrenched interests who benefit from the regulations. The only way to disrupt incumbent industries is with start-ups, but the way the system is set up makes it excessively hard for such start-ups to become big companies. In fact, larger companies are weaponizing the legal system against small companies, because they can afford the lawyers and the fixed cost of compliance.
I don't believe that our institutions in many developed countries are beyond hope. I just think it's easier to change them if you could point at successful examples. ‘Hey, this country or this zone is already doing it very successfully’; if they can extend people’s lifespan by 10 years, if they can reduce maternal mortality, and if they have a massive medical tourism where people come back healthier, then that is just very embarrassing for the FDA.
Q. Perhaps a comparison here would be the relationship between Hong Kong and China?
A. Correct, so having Hong Kong right in front of your door … ‘Hey, this capitalism thing seems to work, why don't we try it here?’ It was due to the very bold leadership by Deng Xiaoping that they experimented with it in the development zone of Shenzhen. It worked really well and then they expanded with more special economic zones that also worked.
Próspera is a private city and special economic zone on the island of Roatán in the Central American state of Honduras.
Q. Tell us about Prospera, the charter city in Honduras, that you are intimately connected with.
A. Honduras is a very poor country. It has a lot of crime, never had a single VC investment, and has a GDP per capita of 2,000 per year. Honduras has suffered tremendously. The goal of these special economic zones is to bring in economic development. That's their sole purpose. It's a homegrown innovation from Honduras that started in 2009 with a very forward-thinking statesman, Octavio Sanchez, who was the chief of staff to the president of Honduras, and then president. He had his own ideas about making Honduras a more decentralized system, where more of the power lies in the municipalities.
Inspired by the ideas of Nobel laureate economist Paul Romer, who gave a famous Ted Talk in 2009 about charter cities, Sanchez initiated a process that lasted for years and eventually led to the creation of a special economic zone legal regime that’s anchored in the Hunduran constitution that provides the highest legal autonomy in the world to these zones. There are today three special economic zones approved by the Honduran government: Prospera, Ciudad Morazan and Orchidea.
Q. How did you become interested and then involved in Prospera?
A. I read about it first in an article by Scott Alexander, a famous rationalist blogger, who wrote a very long article about Prospera, and I thought, this is amazing! Then I came to Prospera and I found it to be one of the most if not the most exciting project in the world going on right now and that it also opened my heart to the country and its people. Most of my friends there are Honduran, they have been working on this for 10 or more years. They want to remake Honduras and put it on the map as the place in the world where this legal and governance innovation started.
Q. To what extent is Prospera autonomous relative to the Honduran government?
A. What's interesting about the Honduran model is that it's anchored within the Honduran constitution, and it has a very clear framework for what's possible and what's not possible, and what's possible ensures the highest degree of legal autonomy anywhere seen in the world. Prospera has really pushed the model furthest in creating a common law-based polycentric legal system. The idea is that you don't have a legislature, instead you have common law and it's based on the best practice common law principles that a legal scholar named Tom W. Bell created.
One of the core ideas is that as a business you're not obligated to follow one regulatory monopoly like the FDA. You have regulatory flexibility so you can choose what you're regulated under. So, you can say: ‘if I do a medical clinic, I do it under Norwegian law here’. And you even have the possibility to amend it a bit. You're still required to have liability insurance, and have to agree to binding arbitration in case there's a legal dispute. And your insurance has to approve you. So, under that model the insurance becomes the regulator and they regulate through prices. The limiting factor is criminal law; Honduran criminal law fully applies. So does immigration law. And we pay taxes.
Q. Is there also an idea of creating a kind of healthy living there, and encourage medical tourism?
A. Yes, we specifically look for legal advantages in autonomy around creating new drugs, doing clinical trials, doing self-medication and experimentation. There is a stem cell clinic here and they're doing clinical trials. The island of Roatán is very easily accessible for American tourists. It's a beautiful island, and it's for regulatory reasons hard to do stem cell therapies in the United States, so they're flying in patients from the United States. Most of them are very savvy and often have PhDs in biotech and are able to assess the risk for themselves of taking drugs and doing clinical trials. We're also going to get a wellness center, and there have been ideas around establishing a peptide clinic and a compound pharmacy and things like that. We are developing a healthcare ecosystem.
Q. This kind of experimental tourism raises some ethical issues. What happens if patients are harmed? And what are the moral implications for society of these new treatments?
A. As a moral principle we believe in medical freedom: people have rights over their bodies, even at the (informed) risk of harm to themselves if no unconsenting third-parties are harmed; this is a fundamental right currently not protected effectively.
What we do differently is not changing ethical norms around safety and efficacy, we’re just changing the institutional setup. Instead of one centralized bureaucracy, like the FDA, we have regulatory pluralism that allows different providers of safety and efficacy to compete under market rules. Like under any legal system, common law in Prospera punishes malpractice, fraud, murder etc. This system will still produce safe and effective drugs, and it will still work with common sense legal notions like informed consent and liability for harm. There are regulations for medical practice, there is liability insurance and things like that. It will just do so more efficiently than the current way of doing things (unless it won’t, in which case it will change and evolve – or fail).
A direct moral benefit ´to what we do is that we increase accessibility. Typical gene therapies on the market cost $1 million dollars in the US. The gene therapy developed in Prospera costs $25,000. As to concern about whether such treatments are problematic, we do not share this perspective. We are for advancing science responsibly and we believe that both individuals and society stand to gain from improving the resiliency of the human body through advanced biotechnology.
Q. How does Prospera relate to the local Honduran population?
A. I think it's very important that our projects deliver local benefits and that they're well anchored in local communities. Because when you go to a new place, you're seen as a foreigner, and you're seen as potentially a danger or a threat. The most important thing for Prospera and Ciudad Morazan is to show we're creating jobs; we're creating employment; we're improving people's lives on the ground. Prospera is directly and indirectly employing 1,100 people. More than 2/3 of the people who are working for Prospera are Honduran. It has a lot of local service workers from the island, and it has educated Hondurans from the mainland for whom it's an alternative to going to the United States.
Q. What makes a good Prosperian citizen?
A. People in Prospera are very entrepreneurial. They're opening companies on a small scale. For example, Vehinia, who is the cook in the kitchen at Prospera, she's from the neighboring village and she started an NGO that is now funding a school where children from the local village can go to instead of a school that's 45 minutes away. There's very much a spirit of ‘let's exchange and trade with each other’. Some people might see that as a bit too commercial, but that's something about the culture that people accept and that people see as a good thing.
Q. Five years from now, if everything goes well, what do we see in Prospera?
A. I think Prospera will have at least 10,000 residents and I think Honduras hopefully will have more zones. There could be zones with a thriving industrial sector and sort of a labor-intensive economy and some that are very strong in pharmaceuticals, there could also be other zones for synthetic biology, and other zones focused on agriculture. The zones of Prospera, Ciudad Morazan and Orchidea are already showing the results we want to see, the results that we will eventually be measured by, and I'm tremendously excited about Honduras.