As a new mother, she didnt know to look for blue-tinged lips. She could just tell her babys color was off. On a chest X-ray, the clean, white-against-dark curves of his ribs were obscured, clouded by fluid. Pneumonia. That tipped Ray Ballards physicians off: He had a form of severe combined immunodeficiency SCID, for short a genetic mutation that hampered the growth of crucial immune cells, leaving him utterly vulnerable to infection.
The best fix was a transplant of his mothers bone marrow. The attitude was that in three to six months, you should be able to go back to normal life, recalled his mom, Barb Ballard.
That was true at least sort of. He got two more booster transplants before he hit 10. An antibiotic left him with hearing loss, and a virus with digestive tract damage. His lack of B cells meant he needed regular injections of other peoples antibodies, and his T cell counts were never ideal. But he was healthy enough to go to public school, to move through the hallways high-fiving half the guys, to slowly inhale and take aim during rifle team practice.
His T cells had to be working well enough that he wasnt coming down with everything that walked into the classroom, Ballard said.
Then, when Ray was around 18, his immunity began to wane. For him, it came in the form of a norovirus he couldnt shake. For others with the same rare disease, it appears as pneumonia or gastrointestinal trouble or an unexpected T cell decline. Over the last 10 years, the trend has become increasingly clear: The bone marrow transplants that kept certain babies with SCID alive sometimes stop working after years or decades of providing fairly reliable immune defenses.
Now, to patient advocates, this has become an urgent lesson in the language people use to talk about treatment and not just for SCID. They see their communitys experience as a cautionary tale for anyone developing or receiving a therapy thats marketed as potentially curative.
Theres an expectation and a hope: When they hear about bone marrow transplants, it sounds like a lifetime deal, a forever fix, said John Boyle, president and CEO of the Immune Deficiency Foundation. Weve discovered, as a result of this issue, that bone marrow transplant ended up not being the forever fix we thought it was.
Experts have known for years that some of these transplants wouldnt provide full immune protection over the course of a SCID patients entire life. They say clinicians should have avoided the word cure. But even scientific papers that hinted at such complications called the treatment curative. Just this year, an Immune Deficiency Foundation employee was given the unenviable task of sifting through the organizations thousands of pages of online material, scrubbing out every cure that popped up. It was only there a handful of times sometimes in quotes from clinicians, Boyle said but it was there and it needed to be removed.
The language patients hear can sometimes even change their outcomes. Weve heard of cases where, years later, they realized their immune system isnt as healthy as they thought, but nobody was tracking that because they hadnt maintained a relationship with the physician, or the physician didnt maintain a relationship with them, explained Ballard. The word cure, it gives them a false sense of security.
At a time when seemingly every biotech is promoting the idea of one-and-done therapies and setting prices accordingly these advocates hope companies, too, will be more wary. One of the things Im trying to make them very aware of is the need for lifelong follow-up, said Heather Smith, who runs the SCID Angels for Life foundation. For her, its personal: This summer, her son took part in a clinical trial for a gene therapy in the hope that it would provide the immune protection that his decades-old bone marrow transplant no longer could. My son will be followed for 15 years, she said. But what about after that?
Part of the issue with bone marrow transplants from one person to another is the natural genetic variation between us, particularly in the proteins that help our bodies distinguish its own cells from foreign ones. Receiving cells from someone whose proteins dont match yours could cause a civil war within you. Thats why bone marrow transplants began back in the 1950s with identical twins: Sharing those genes meant increasing the likelihood of harmony between the body and the graft.
But the vast majority of people dont have a protein-matched sibling, let alone an identical twin. So researchers set about figuring out how to transplant bone marrow from a parent to a child in spite of only sharing half of their genes and from a matched unrelated donor to a stranger. Like cooks intent on refining recipes to their taste, the doctors who adapted the technique for SCID often did so slightly differently from one another. Over the past 35 years, those idiosyncrasies have hardened into habits. Right now, everybody transplants their patients their way, said Dr. Sung-Yun Pai, an immune deficiency researcher and co-director of the gene therapy program at Boston Childrens Hospital.
Perhaps the most vociferous controversy has been about whether to use chemotherapy to wipe out the existing stem cells within a recipients bone marrow to make room for the donors. The doctors who do use chemo before a transplant might prescribe different doses; others forego it entirely.
The arguments were sound on both sides. On the one hand, the toxic drugs could clean out the niches within our bone and increase the chances that the donors cells take root. On the other, these chemicals could hamper growth, brain development, and fertility, could make an infant who was already sick even sicker, and could increase the likelihood of certain cancers later in life. Its like being exposed to a bunch of X-rays and sunlight, or other DNA-damaging agents, Pai explained.
Because SCID is so rare the most common subtype is thought to occur in 1 out of every 50,000 to 100,000 newborns and because every hospital was doing transplants slightly differently, it was hard for physicians to systematically study what was working best. But even early on, they could tell that some of the infants whod gotten no chemo were developing incomplete immune systems. They didnt produce their own B cells, for instance, and so needed regular injections of antibodies collected from other peoples blood.
In healthy infants, stem cells migrate from the crevices of the skeleton to an organ in the chest called the thymus, where theyre trained to become T cells. In these infants, the T cell counts grew after transplant but it wasnt necessarily because the sludge was securely taking hold in the niches of their bones. Rather, immunologists say, the donors progenitor cells were only transient. Some were able to head toward the thymus for schooling. Some graduated and started fighting off infections. But as those populations were depleted with age, there werent robust reserves of stem cells in the bone marrow that could arrive to produce more. To Pai, its like trying to fill a kindergarten class in a neighborhood where no ones having babies.
You and I continue to have a slow trickle of new T cells coming out, said Dr. Harry Malech, a senior investigator at the National Institutes of Health, who sits on the board of a gene therapy company, Orchard Therapeutics (ORTX), but does not receive any financial compensation. Instead of a torrent becoming slower, in these patients it goes from a trickle to practically nothing.
Thats why immunity starts to wane in kids like Ray Ballard. To many immunologists, it isnt a surprise, though they still arent sure why chemo-less transplants last longer for some of these kids than others. They can also understand how some families and clinicians might have viewed this treatment as a lifetime fix.
As Malech put it, If I said to you, Your child, instead of dying in infancy, will likely get to adulthood, go to school, have a normal life, you might think the word cure in your mind.
Even for parents who knew the protection might not last forever, the failure of a long-ago bone marrow transplant puts them in a bind. If they do nothing, their child will once again be vulnerable to any passing infection, which could prove fatal. They can try another round of the same procedure, though booster transplants sometimes come with added complications. Or they can try getting their child into a research trial for gene therapy, which comes with the risks of any experimental treatment.
Some feel an irrational guilt when the bone marrow they donated to their child stops functioning. Its your cells, and if it doesnt work, you failed them, said Ballard, who lives in Clifton, Va., about a 40-minute drive from Washington, D.C. Her son Ray had already had three transplants as a child. When his immune system started to fail again in early adulthood, gene therapy at the NIH seemed like the only reasonable choice.
That would involve researchers removing cells from his bone marrow, using an engineered virus as a kind of molecular syringe to slip in a healthy copy of the gene in which he had a defect, and then threading these corrected cells back into his veins a bone marrow transplant to himself. But preparing a virus can be tricky, and there were delays.
Meanwhile, Rays condition was getting worse. His norovirus was preventing him from absorbing much nutrition, and as Ballard put it, his bone structure was just crumbling at that point. His doctors told her he had the skeleton of an 85-year-old.
He died this past February, at 25 years old. One friend got his birth and death dates tattooed onto her shoulder. Another painted a portrait of him for Ballard, in which his arms are crossed, his lips pressed together in a wry smile.
At Boston Childrens, Pai is now helping to lead a randomized trial to better understand what dose of chemo works best for SCID patients receiving transplants. Over the last decade or so, she, Malech, and many other clinicians have also teamed up to track the long-term results of immune deficient patients whove received someone elses bone marrow.
Pai is hopeful that knowing about the phenomenon of waning immunity will give gene therapies a better shot at becoming a durable fix. They probably have a better chance of achieving a one-time, lifelong cure, but its never wrong to be humble, she said. Only after decades more and hundreds or thousands of patients will we know for sure.
Patient advocates point out that even then, these patients will still have the capacity of passing on their SCID-causing gene to future generations, and so the word cure is overly optimistic. Thats why I like the word remission, said Smith. That still gives you the hope. If you were given a cancer diagnosis, you wouldnt go through treatment and then just forget about it for the rest of your life.
As Boyle put it, Weve seen the promise and then weve seen the reality. Everyone who is looking at a transformational therapy should be optimistic, but also realistic, and not assume that this is truly one and done. (Boyles foundation has received financial support from Orchard Therapeutics, which is developing a gene therapy for a form of SCID.)
To Amy Saada, of South Windsor, Conn., that isnt theoretical. Her son Adam is now 12, and the immunity from the bone marrow transplant he got as a baby is wearing off. He isnt yet sick, but his parents know they need to decide between gene therapy or another transplant soon. She has a very clear memory of how long and uncertain the recovery from treatment felt. In some ways, she wishes she didnt know quite as much as she does; that way, she would feel less trepidation about what lies ahead.
Your heart kind of sinks, she said. Youve already been through it once, and it was hell. Its harder the second time.
- gene therapy | Description, Uses, Examples, & Safety ... - February 24th, 2020
- Gene therapy - Mayo Clinic - February 24th, 2020
- How does gene therapy work? - Genetics Home Reference - NIH - February 24th, 2020
- Nationwide Childrens among hospitals leading the way in gene therapy - The Columbus Dispatch - February 24th, 2020
- BioMarin gene therapy won't need an AdComm as it nabs speedy FDA review - FierceBiotech - February 24th, 2020
- Gene therapy to halt rare form of sight loss - BBC News - February 24th, 2020
- With supply tight, Novartis readies gene therapy plant for production - BioPharma Dive - February 24th, 2020
- New Gene Therapies Institute Aims to Address Regulatory Barriers - HealthITAnalytics.com - February 24th, 2020
- Bluebird's gene therapy hits another delay, this time in the US - BioPharma Dive - February 24th, 2020
- First patient undergoes Luxturna gene therapy on NHS - PharmaTimes - February 24th, 2020
- First Patients Begin Gene Therapy Treatment for Blindness through NHS - Interesting Engineering - February 24th, 2020
- Spark R&D chief High exits in wake of Roche takeover - FierceBiotech - February 24th, 2020
- Why So Many Biotechs Are Scrambling to Develop a Drug for the Same Rare Disease - The Motley Fool - February 24th, 2020
- 3 Cancer Treatment Stocks to Buy Right Now - The Motley Fool - February 24th, 2020
- The Most Important Stock to Own Over the Next Decade - Nasdaq - February 24th, 2020
- FDA Continues Strong Support of Innovation in Development of Gene Therapy Products - FDA.gov - February 2nd, 2020
- Interpreting Sameness Gene Therapy Products Orphan Drug Regulations - FDA.gov - February 2nd, 2020
- Pfizer lays out gene therapy aspirations - BioPharma Dive - February 2nd, 2020
- Global Gene Therapy Industry Outlook 2020-2024 - Strong Product Pipeline Gives Rise to Lucrative Growth Opportunities - P&T Community - February 2nd, 2020
- FDA guidance on gene therapies development and manufacturing - BioPharma-Reporter.com - February 2nd, 2020
- Devastation, then hope: Platteville baby first in state treated for rare condition after screening - Madison.com - February 2nd, 2020
- Studies target unilateral gene therapy injection - Ophthalmology Times - February 2nd, 2020
- Otonomy Presents Preclinical Results for GJB2 Gene Therapy Collaboration and Cisplatin Otoprotection Program - Yahoo Finance - February 2nd, 2020
- Eyeing a trio of trial initiations, Jim Wilson's gene therapy startup woos Bruce Goldsmith from Deerfield as CEO - Endpoints News - February 2nd, 2020
- The FDA unveils a new regulatory framework to speed along gene therapies, rewarding the leading players - Endpoints News - February 2nd, 2020
- Gene Therapies Make it to Clinical Trials - Discover Magazine - December 31st, 2019
- Experimental Gene Therapy Shows Promise for Preventing and Treating Lou Gehrig's Disease in Mice - BioSpace - December 31st, 2019
- 2019: The year gene therapy came of age - INQUIRER.net - December 31st, 2019
- BLA Submitted for Gene Therapy to Treat Hemophilia A - Monthly Prescribing Reference - December 31st, 2019
- First Alzheimer's Disease Gene Therapy Human Study Provided by Maximum Life Foundation, Offers 10 Free Therapies for Qualifying Patients - Benzinga - December 31st, 2019
- Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research - News18 - December 31st, 2019
- Gene therapy to conquering hepatitis C: A decade of medical breakthroughs - Business Standard - December 31st, 2019
- What were the biggest biopharma stories of 2019? - MedCity News - December 31st, 2019
- Global Gene Therapy Market 2019 Revenue, Opportunity, Forecast and Value Chain 2025 - Market Research Sheets - December 31st, 2019
- Manufacturing: the next breakthrough in gene therapy - STAT - December 23rd, 2019
- Novartis in talks with patients upset about lottery-like gene therapy giveaway - Reuters - December 23rd, 2019
- Ring Therapeutics Launches to Expand Gene Therapy Viral Vector Options - Xconomy - December 23rd, 2019
- Gene Therapy for Sickle-Cell Anemia Looks Promisingbut It's Riddled With Controversy - Singularity Hub - December 23rd, 2019
- Making advanced therapies takes industrializing personalization - STAT - December 23rd, 2019
- Dyno Therapeutics Launches to Improve Viral Vectors for Gene Therapy - BioSpace - December 23rd, 2019
- New Gene Therapy Method May Open BRAVE New World in Parkinson's - Parkinson's News Today - December 23rd, 2019
- Pharma's gene and cell therapy ambitions will kick into high gear in 2020despite some major hurdles - FiercePharma - December 23rd, 2019
- Viewpoint: EU should take a lead in enforcing the corporate social responsibility of gene therapy manufacturers - Science Business - December 23rd, 2019
- Takeda Presents Data for Hemophilia A and B Gene Therapy Optimization - Hemophilia News Today - December 23rd, 2019
- GenScript Biotech to Host Global Forum on Cell and Gene Therapy and the Booming China Market During JPM Week - PRNewswire - December 23rd, 2019
- The gene therapy research that could save a family of four - News - The University of Sydney - December 23rd, 2019
- Would you pay $1M to partake in an anti-aging gene therapy trial? - Fox Business - December 13th, 2019
- Pfizer to bring gene therapy production in-house - BioPharma-Reporter.com - December 13th, 2019
- Buyer beware of this $1 million gene therapy for aging - MIT Technology Review - December 13th, 2019
- Dr. James Wilson, a scientific pioneer, on the future of gene therapy - STAT - December 13th, 2019
- The Rise Of Patent Wars In Europe's Gene Therapy Space - Law360 - December 13th, 2019
- Pfizer cites competitiveness of inhouse gene therapy - Bioprocess Insider - BioProcess Insider - December 13th, 2019
- Investment in UK cell and gene therapy manufacturing set to continue - European Pharmaceutical Review - December 13th, 2019
- Biomanufacturing and Supply Chain Standardization Key to Success in Cell and Gene Therapy Industry Boom - BioBuzz - December 13th, 2019
- Research targets gene therapy for exudative AMD patients - Modern Retina - December 13th, 2019
- Magenta Therapeutics Demonstrates First-ever Successful Gene Therapy Transplant Without Chemotherapy in Primates Using a Single Dose of Antibody-drug... - December 13th, 2019
- GenEdit and Editas Medicine Enter into Exclusive License and Collaboration Agreement for Nanoparticle Gene Therapy Delivery - Business Wire - December 13th, 2019
- First 2 Adults with Severe Hemophilia A Respond Well to Gene Therapy BAY 2599023 in Clinical Trial - Hemophilia News Today - December 13th, 2019
- New Anti-Aging Clinical Trial Begins. For $1 Million, You Can Be a Participant. - Livescience.com - December 13th, 2019
- Watch out, Keytruda. Ferring's bladder cancer gene therapy rival has new dataand they look competitive - FiercePharma - December 13th, 2019
- Solid Biosciences Stock Crashes Over Safety Concerns About Its Gene Therapy - Barron's - November 13th, 2019
- Solid's Duchenne gene therapy trial halted after patient suffers toxicity - STAT - November 13th, 2019
- Gene Therapy in Neurology: 2019 Overview & Forecast Report - Yahoo Finance - November 13th, 2019
- How Gene Therapy Is Evolving to Tackle Complex... - Labiotech.eu - November 13th, 2019
- Lonza taps Cryoport to bolster cell and gene therapy delivery - BioPharma Dive - November 13th, 2019
- Pfizer's 'brainstorming' payment deals as gene therapies advance, exec tells Bloomberg - FiercePharma - November 13th, 2019
- Next generation cell and gene therapies: fine tuning the promise - Business Weekly - November 13th, 2019
- Vertex invests in gene therapy manufacturing - BioPharma-Reporter.com - November 13th, 2019
- Scientists are using gene therapy to treat a heart disease in dogs. Could humans be next? - 10News - November 13th, 2019
- Updated Alta Trial Results Support SB-525 Gene Therapy for Hemophilia A - Hemophilia News Today - November 13th, 2019
- Sangamo Announces Gene Therapy and Ex Vivo Gene-Edited Cell Therapy Data Presentations at the American Society of Hematology Annual Meeting - Business... - November 13th, 2019
- Modified Protein Enhances the Accuracy of CRISPR Gene Therapy - DocWire News - November 13th, 2019
- Triple-Gene Announces Completion of Enrollment and Dosing in Phase 1 Trial of INXN4001, First Multigenic Investigational Therapeutic Candidate for... - November 13th, 2019
- Five benefits of gene therapies - Echo Live - September 19th, 2019
- Reprogramming the Human Computer: Silicon Valley Meets Cell and Gene Therapy - BioBuzz - September 19th, 2019
- FDA approves 2nd gene therapy cancer drug from Durham's Precision Bio for clinical trial - WRAL Tech Wire - September 19th, 2019
- 7-Year-Old Receives New FDA-Approved Retina Gene Therapy - University of Michigan Health System News - September 19th, 2019
- First Patient Dosed in Trial of Fabry Gene Therapy Candidate FLT190 - Fabry Disease News - September 19th, 2019
- Bluebird bio reveals further encouraging data for CALD gene therapy - PMLiVE - September 19th, 2019
- Joseph M. Sanzari Childrens Hospital and John Theurer Cancer Center Launch Clinical Trial Evaluating Gene Therapy for Severe Sickle Cell Disease in... - September 19th, 2019