Time for Miracles

“Even miracles take a little time.”   --Fairy Godmother, Cinderella 

Hope can be hard to find in the healthcare system.

It’s hard to find for parents watching their child wither away, as Spinal Muscular Atrophy (SMA) robs their motor neurons of the SMN protein needed for movement, breathing, swallowing, survival. Growing older, they grow weaker, slowly losing the ability to walk, then stand, then sit, until finally they are confined to a life where others make the movements for them, positioning their bodies in beds or adjusting them in chairs that force those bodies to stay upright. Those diagnosed with type 1 face an even grimmer fate, likely never standing or sitting, missing every milestone their parents had so eagerly awaited, eventually needing a feeding tube and facing the collapse of their lungs. Ninety percent of those diagnosed with type 1 won’t live to celebrate their second birthday. And as of today, there is no cure for this devastating genetic disorder.

It's hard to find for families told Wilson disease was discovered too late to prevent or reverse toxic levels of copper from accumulating in the liver, brain and vital organs. Slowly, silently, the copper had gathered in the liver leading, in time, to inflammation, cirrhosis, and eventually liver failure. Ultimately, the damage will prove too great to repair without a liver transplant, the transplant list too long and their loved one too low on the priority rankings to be saved. For some, it will reveal itself instead in the brain, bringing anxiety, depression, mood changes and potentially psychosis with it. It may seep into the central nervous system, causing problems with speech and coordination, stiff muscles, tremors. Others will see it spill into the kidneys, the endocrine system, even the heart before being caught, perhaps with time to spare their life but certainly with symptoms and complications made permanent along the way. While there is no cure, Wilson disease is treatable if uncovered early enough, but with an occurrence of just 1 in 30,000 people, few in the medical community are looking and this genetic disorder continues to steadily destroy and kill.

It’s hard to find for individuals living with Glycogen Storage Disease (GSD), left—through the lack or failure of an enzyme—unable to convert excess glucose into glycogen to be stored in the liver and muscles until called forth to sustain the energy needs of the body. Without this glycogen storage, those with the disease face dangerously low levels of blood sugar and ultimately death. For much of history, GSD was a death sentence regardless of type, but in 1971, medical researchers discovered that a continuous source of glucose stopped the “metabolic derangements” and spared lives. For most of the ten identified types, this has meant a return to the expectation of a normal life span through a heavily regimented diet stripped of all simple carbohydrates; fruit, vegetables and dairy with high concentrations of natural sugars; and sugars of any kind that require liver metabolism. The addition of doses of uncooked cornstarch consumed every 4-5 hours throughout the day, including overnight, helped to stabilize this condition. It is a life tied to the clock and vastly limited in dietary options, but it is still a life of meaning and purpose. For the two most severe types—Pompe’s disease and Anderson’s disease, types II and IV respectively—dietary restrictions and a constant source of steady glucose offered by uncooked cornstarch will not be enough. These are still often fatal. And as of today, there is no cure. 

It's hard to find, too, for the medical professionals who are left, once again, to utter the three-letter word that feels like a four-letter word: yet. We don’t have a cure. Yet. We don’t have an answer. Yet. We don’t even have hope. Yet. And to watch family after family and patient after patient live out a heroic battle against unimaginable odds, with nothing that science and medicine can yet offer to offset those odds. 

What is a life worth when it is your son or daughter, your mother or father, your partner and lifelong love fighting those unimaginable odds? What wouldn’t you do to give back mobility to those held hostage by bodies unable to move independently? What wouldn’t you sacrifice to put a stop to organs shutting down, one by one, collapsing under any number of genetic toxicities? What wouldn’t you try to be free of the crushing pain of sickle-shaped cells and the fear of repeat hospitalizations? What wouldn’t you give to restore sight, hearing, health, life?

And then suddenly, unexpectedly, hope is injected into a situation once deemed hopeless. Whispers begin of a biotechnology that can alter the code of life, our DNA, by replacing, repairing or removing the faulty code holding our health hostage. As the whispers grow louder, talk of miracles begins. Jimi Olaghere, recalling a life that had been “bleak,” now smiles as he holds his 9-month-old daughter at home, describing a life beyond the frequent hospitalizations and debilitating pain brought on by sickle cell disease. He utters the word we are searching for: cure.

There, too, are Shante and Jammell Stagg, parents of Jammell Jr. who was born with aromatic L-amino acid decarboxylase deficiency (AADC), an “ultra-rare” genetic disorder that leaves the brain without the dopamine and serotonin needed for cognition and movement. Following an injection of gene therapy “deep within the brain where these cells reside,” the junior Jammell is living without seizures and with his head held high. That he is sitting up, playing with toys, and fully aware is “nothing short of a miracle,” says his adoring and grateful mother.

And, smiling and chasing her brother, is Maddy Smith who was born with SMA. Just before her second birthday, she could only scoot, lacking the strength to walk or crawl despite having been diagnosed at birth and receiving drug therapy from day two. Then came the 2019 FDA approval of gene therapy drug Zolgenzma, aimed at treating the root cause of this genetic disorder. Now, she and her brother are “little tornadoes together,” reports her exhausted, but equally grateful, mother Angie Bryce.

If these stories and others like them aren’t enough, here too comes the new #1 New York Times Bestseller Life Force by powerhouse of empowerment, Tony Robbins, proclaiming in bold font that “gene therapy is a chance for us to literally eliminate disease, not treat it but cure it completely.” After reviewing examples from a “cure” for blindness to the repair of heart damage and a “jackpot gene” to protect against Alzheimer’s disease, Robbins concludes that “if you are or someone in your family is one of the 30 million Americans living with a rare genetic disease, there has never been a better time to have hope that a treatment—or, even better, a cure—lies around the corner. Thanks to gene editing and gene therapy, diseases that have historically had no available treatments are now on the cusp of breakthroughs.”

The announcement in 2020 by Goran K. Hansson, then secretary general of the Royal Swedish Academy of Sciences, that the Nobel prize-winning CRISPR-Cas9 system of genome editing would enable us to “rewrite the code of life” nicely sums up the hope felt by many in the medical community and the roughly 30 million people in the United States now fighting a rare genetic disease. What was broken might now be fixed. What was written poorly might be edited, rewritten. In so doing, human lives destined to be limited or cut short might be granted a new, longer, more meaningful story.

Hope is a powerful thing. Necessary, particularly for those facing unimaginable odds. But too often, hope is all we speak of in the press surrounding gene editing in general and especially CRISPR. We have an obligation to the already burdened not to heap false hope on them as well, not to mistake possibility for proof, not to take “ought to” work over evidence that it does. We owe it to those already in the fray of genetic disease to share the full story.

There are a multitude of sources that have set out to explain the science behind gene editing and CRISPR biotechnologies. Britannica does a detailed and accessible job of describing gene editing; co-creator of the CRISPR-Cas9 process, Jennifer Doudna, nicely explains its development and functions in her TED talk while Harvard offers a more comprehensive understanding of this “game changing genetic engineering technique”; the gene editing digital media kit offered by the National Institutes of Health offers a broader understanding of the full range of gene editing research and its intents; and yourgenome.org describes the types and techniques of gene therapy, among others. 

But how it works at a scientific level may be a less pressing concern than the matters of whether it works, how well it works, and for whom. To speak only of hope and possibility is to deny that lives have been lost, and are still being lost, in the search for answers.

The most memorable of these cases was also one of the earliest. In 1999, Jesse Gelsinger was just entering adulthood. After graduating high school and gaining a part-time position at a local supermarket, Jesse looked for other ways to have an impact and found his opportunity in a safety study through the University of Pennsylvania, a study his doctor had recommended. In safety studies, the knowledge gained through the study is used to create treatments that will benefit others, in this case newborns with ornithine transcarbamoylase (OTC) disorder, but is not intended to improve the health or condition of the participants themselves. 

Jesse was born with a milder version of OTC, a condition where ammonia builds up to lethal levels in the blood. While Jesse had not been diagnosed until the age of two and had lived to adulthood with the help of a strict non-protein diet and upwards of 50 pills a day, children with the more severe form generally fall into a coma and experience brain damage within 72 hours of birth. Half of them won’t live to see their first birthday. Of the remaining 50 percent, half of those will die before age five. 

Jesse wanted to give hope to the families of children with OTC, so he volunteered to be part of the gene therapy study developing a fix for the OTC gene. Had he been told, as required, that some of the 17 earlier participants had experienced severe adverse reactions to the treatment or that three monkeys had died after developing a clotting disorder and severe liver inflammation following the injection, he might have reconsidered. But on September 13, 1999, Jesse entered the medical facility and was injected with the corrected OTC gene encased in an adenovirus. Within a day, he developed a severe inflammatory response and a serious blood clotting disorder. The days following brought on a cascade of organ failures: kidney, liver, lungs. By day four, Jesse was dead.

The death of this “relatively healthy” volunteer rocked the nation. The Washington Post reported at the time that “The death is the latest in a series of setbacks for a promising approach that has so far failed to deliver its first cure and that has been criticized as moving too quickly from the laboratory bench to the bedside.” But while gene therapy research quieted for a time following Jesse’s death, it came roaring back with billions in investments over the more than 20 years since and an explosion of new funding after the introduction of the CRISPR method, deemed more precise, more efficient, and more cost effective. This is an industry predicted to reach $20.47 billion by 2030.

After the formal review of the Gelsinger case, the FDA and NIH revealed that 691 volunteers in gene therapy experiments had died or become ill in the seven years leading up to Jesse’s death but that only 39 of those incidents had been properly reported. And while study controls and monitoring were tightened at the federal level and a new system for reporting serious adverse events was created, the explosion of private investments into proprietary studies outside the scope and reach of the NIH and FDA is once again raising concerns that patient safety will be compromised in the rush to produce a miracle treatment.

Those fears may be well founded. While there is no standard database for a public review of the outcomes from the 2500+ clinical trials that have been approved, are in progress, or have been completed (though Innovative Genomics Institute has compiled a list summarizing some of the key trials underway as of 2022), an online search reveals a number of headlines featuring lives lost in gene therapy trials. Among them is an October 2021 report from the Wall Street Journal on several serious events and deaths that have clouded “one of biotech’s most promising technologies and hottest sectors.” Under fire were a study by Japan’s Astellas Pharma Inc. attempting a gene therapy treatment for the rare neuromuscular disease X-Linked myotubular myopathy. Since the summer of 2020, four boys have died in that study, the most recent death coming in September 2022, as reported by MedCityNews. The study had only recently resumed after a review of the three earlier deaths. Also caught in the crosshairs was BioMarin Pharmaceutical Inc. with reports showing that cancer had been discovered in mice that had received the treatment for the phenylketonuria (PKU) gene therapy. Regulators placed a long-term hold on that study pending additional nonclinical trials, a further setback to a company already struggling after the FDA refused approval on their gene-editing therapy for hemophilia, stating that they needed to see more detailed feedback over a longer term before granting approval. 

Then came word of another death in a gene-editing study. On August 17th, 2022, Cure Rare Disease founder Richard Horgan announced that the FDA had given him the green light to move forward with his first-of-its-kind CRISPR-based treatment for a rare form of muscular dystrophy, a form so rare that his brother, Terry Horgan, was likely to be the only one ever to receive that treatment. After three years of development with a team of scientists from Charles River Laboratories, UMass Chan Medical School, Yale University and other institutions and with their new seal of approval from the FDA, the brothers were “cautiously optimistic.” Then came word of Terry’s death in October 2022 with the caveat that the cause of that death may take up to four months to find. Calling his brother a “medical pioneer whose courage and unflinching determination has paved the way for increased focus and attention on funding and developing new therapies for patients with rare and ultra-rare conditions,” Richard Horgan pledged to “continue to fight for patients like him who are running out of time and options.”

There is hope to be found in the seemingly miraculous ability to alter the human genome, fixing errors in the code of life that so restrict or abbreviate the lives of those unfortunate enough to carry those errors. But these deaths, and others unmentioned in the press, should certainly be a cautionary tale, one that asks us to be more thoughtful about the speed at which we advance these technologies, about how we design each human study to ensure the greatest learning gathered with the least amount of risk to participants, about who and how many we choose as participants, and about how we fairly and fully inform them of those risks. As co-creator of the CRISPR-Cas9 technology, Jennifer Doudna, said in 2015, “I hope that we don’t get ahead of ourselves with this technology. As exciting as it is, I really would like to see…people take a very measured and responsible path forward, where there’s careful vetting along the way.”

That measured path must include a consideration of not only the safety and reliability of these treatments, in both the short and long term, but also the accessibility of them to those in most critical need. As the New York Times reported following Jesse Gelsinger’s death, “biotech companies have poured millions into research—not for rare hereditary disorders but for big-profit illnesses like cancer, heart disease, and AIDS. As of August [1999], the government had reviewed 331 gene-therapy protocols involving more than 4,000 patients. Just 41 were for the ‘monogenic,’ or single-gene, defect diseases whose patients so desperately hoped gene therapy would be their salvation.” That trend has not reversed course in the more than 20 years since that article was written. The faces of gene therapy are Jesse Gelsinger and Terry Horgan, Maddy Smith and Jammell Stagg, Jr. Those with rare genetic disorders who, lacking an available treatment, will struggle with maintenance, likely decline, probably face a premature death. Those are the patients the industry was developed for. Those are the patients that researchers are willing to pursue radical treatments to save. Or so the story goes. In truth, the majority of human gene-editing studies continue to center on HIV, cancer, heart disease, high cholesterol, and even urinary tract infections. That is the reality of the research underway.

Verve Therapeutics is one of those working to permanently lower cholesterol using CRISPR technologies to “turn off a troublesome gene.” Allison Gatlin of Investor’s Business Daily says that “while most companies in the space are taking on rare genetic conditions, Verve is sprinting to the starting block with a huge, potential use case.” High cholesterol affects a large population of Americans, to be sure. The CDC estimates that population at nearly 12% of people aged 20 or over in the United States. And yet, as the Mayo Clinic notes, “High cholesterol can be an inherited disorder, but it’s often the result of unhealthy lifestyle choices.” The population of those with a genetic component to their high cholesterol, and thus eligible for gene editing, is significantly smaller than 12% of the population. And even for those, there are effective treatments already available. The Mayo Clinic sums up the simplicity of treating most cases by saying that “A healthy diet, regular exercise, and sometimes medication can help reduce cholesterol.” 

Verve and others argue that treatment is not a cure, saying “it’s not like the problem is solved because treatments are available,” but if safe, effective and, most importantly, proven treatments hold the condition at bay, prevent damage to vital organs, and allow the person to live a long, healthy, happy life, do we need to try a technology that has not yet proven itself in the human genome just to have a “one-and-done” treatment? As biotech analyst Rob Toczycki said, “if the only benefit is that it’s a one-and-done treatment, that’s fantastically ridiculous.”

We need to rationally consider the evidence of gene editing efficacy before we allow its use in our bodies. We need to realistically consider the need for such treatments in disorders that can be effectively treated through other means. Gene editing cannot, and should not, save us from ourselves, filling in for our own unwillingness to eat what is healthy and healing for our own bodies, take the supplements and/or medications needed for those bodies to function effectively, and take advantage of less risky medical marvels currently available to us.

For those facing rare, fatal genetic disorders, gene therapy may be their only hope. It is these patients who should be the priority for medical researchers, but those researchers (and the institutions and corporations funding them) must take care with the lives being placed in their hands, carefully setting the boundaries of their studies and carefully considering a core concern for the rare genetic disease community: whether those treatments will be priced in a way that allows access to those who need it most.

To date, that has not been the case. For the few gene therapy drugs designed to treat rare genetic diseases, nearly all are priced in the millions for their one-time treatment. In the case of VERVE-101, Verve Therapeutics’ gene-editing drug designed to lower cholesterol by “turning off” the PCSK9 gene in the liver, a price has not yet been set given the infancy of its human trials (a single patient in New Zealand has received the injection, but reports on that patient’s outcomes and the treatment’s effectiveness in that single case are not due until early 2023). It is expected to be priced comparably to others within the industry, and the prices for those are breathtaking.

There are currently six gene therapies approved by the FDA. Hemgenix, a treatment for the genetic blood clotting disorder Hemophilia B, is priced at $3.5 million. Luxterna, designed to treat Leber Congenital Amaurosis, a genetic disease causing vision loss in youth, is $850,000. Pediatric Congenital Athymia, a rare immune disorder in which sufferers are born without a thymus, leaving them unable to fend off infections, is being treated with Rethymic which touts a wholesale cost of $2.7 million. Biotechnology company bluebird bio holds two of the six approvals; Skysona is used to treat the devastating and fatal disorder cerebral adrenoleukodystrophy, which destroys the myelin around nerve cells leaving them unable to communicate with the brain and leads to coma and ultimately death, and Zynteglo, meant to treat adults and children with B-thalassemia, a genetic blood disorder that leaves those afflicted with reduced levels of hemoglobin and requires regular red blood cell (RBC) transfusions. Currently, Skysona is priced at $3 million and Zynteglo at $2.8 million. The final FDA-approved treatment, Zolgensma, which treats SMA in those under two years of age, will cost those seeking to save their child $2.1 million. And, at this point, insurance is not covering those costs.

Can we truly count this as hope if the treatment we pledge will work, a treatment that has shown promise in other patients (if not proof of long-term cure without unintended consequences), is beyond their financial reach? If we loudly and persistently proclaim an answer but set the cost of that answer beyond a family’s ability to pay, who is that answer serving? Certainly not those who have already sold off assets and exhausted their bank accounts just to keep their loved ones alive long enough for a cure to come. 

In what has been deemed “one of the greatest scientific feats in history,” the Human Genome Project spent more than 12 years and some $3 billion mapping out the human genome (the sequences of all DNA in the human body). When the first draft of that genetic map was announced in June of 2000, the international consortium responsible for this effort declared that it had mapped 90% of the human genome, with 150,000 unknown DNA sequences remaining. The second draft, in April 2003, improved that to 92% of the human genome known with fewer than 400 unknown sequences. Then, on March 31, 2022, came news from the Telomere-to-Telomere (T2T) consortium that all unknown sequences had been identified and we now knew the entire human code of life.

This effort will, in time, bring hope to those born with flawed DNA and those that love and care for them. It will, in time, bring revolutionary new treatments and biomedical miracles to those in greatest need. CRISPR and other gene editing technologies may, in time, play a crucial role in those miracles. But it is critical to keep in mind that the entire human code of life has been known for just nine short months. They have now identified all 3 billion base pairs of DNA in the human genome. What we don’t yet have is a full understanding of how all those base pairs work, how they work together as an intricate system, and how they change over time. We don’t yet fully understand what happens to the rest of the genome when we make changes—through cutting, deleting, altering, or inserting—to a DNA sequence. There is much to learn, and we need to allow medical researchers the time needed to gain that foundational knowledge before demanding a jump to treatments and clinical trials.

 James M. Wilson, lead researcher in the Jesse Gelsinger case, reflected on the causes of the “hyperaccelerated transition to the clinic” that occurred in gene therapy in the 1990s in an article for Science. Those causes were, first, “a straightforward, if ultimately simplistic, theoretical indication that the approach ‘ought to’ work”; second, “a large population of patients with disabling or lethal diseases and their affiliated foundations harboring fervent hopes that this novel therapy could help them”; third, the “unbridled enthusiasm of some scientists in the field, fueled by uncritical media coverage”; and, fourth, “commercial development by the biotechnical industry during an era in which value and liquidity could be achieved almost entirely on promise, irrespective of actual results.” 

All of those factors are still at play in the gene editing and CRISPR conversations of today. We are repeating the errors of the past that led to deadly outcomes and the near destruction of a promising industry. We need to pause, reflect, learn. As the National Institutes of Health panel that was convened to review the Gelsinger case ultimately concluded, “only a minority” of clinical studies were being designed in ways that would yield “useful basic information.” Their recommendation, that “researchers get back to basics and develop a more robust understanding” is more important than ever in the CRISPR era.

Jesse Gelsinger gave his life for the cause of finding a cure. So, too, did Terry Horgan and others. Let us not treat these deaths casually by repeating the error of rushing to clinical trials and gene-editing drug distribution without a firm foundational knowledge of the intricacies of the human genome and the nuances of its interactions. Let us give Jesse, Terry and others this final gift of restraint.

Written by Marcia Young.