March 2019

Essays

Elizabeth Finkel

Chasing the miracle of gene therapy

Isla and Jude Donnell. Photograph by Sammy Elsom

For Megan Donnell’s family, the DNA-altering revolution cannot come soon enough

To look at Megan Donnell, you wouldn’t think this vibrant and cheerful 44-year-old Sydney woman is living a nightmare. But her children, Isla, 9, and Jude, 7, are afflicted with a terminal genetic illness known as Sanfilippo syndrome. Both were healthy at birth; their symptoms started to manifest when they were toddlers. The expected course of events is that they will become progressively paralysed, unable to walk, talk or eat, and will die in their teens.

It’s impossible to fathom the depth of Donnell’s grief. What sustains her is her sense of mission. She is looking to gene therapy, a fantastical technology that after three decades of false starts is starting to produce miraculous results.

For inherited rare genetic diseases – think cystic fibrosis, Duchenne muscular dystrophy, Tay-Sachs – the treatment options are limited or non-existent. Some are so rare – in the case of Sanfilippo there’s an estimated 75–100 cases in Australia and 2000 babies born worldwide each year – it has made little economic sense for drug companies to enter this space. The path has largely been forged by savvy, dogged parents like Donnell. “It’s people like Megan that inspire me to keep going,” says Ian Alexander, head of the Gene Therapy Research Unit at Sydney’s Children’s Hospital at Westmead, who has helped pioneer the field of gene therapy over the last 30 years.

When her children were diagnosed in 2013, the take-home message was “do not hold any false hope”. Donnell demurred. She formed the Sanfilippo Children’s Foundation (Alexander now chairs the scientific advisory board), funded research and ensured trials were carried out in Australia. Whether or not her own children actually benefit, a big part of her drive comes from knowing that she is doing her part to banish the nightmare for others. “I want Isla and Jude to have a legacy, that their lives have not been for nothing.”

The results of the trials so far are encouraging. So much so that last year the company conducting the trial, Abeona Therapeutics Inc, was granted Regenerative Medicine Advanced Therapy status for the treatment, allowing for a more streamlined approval by the US Food and Drug Administration (FDA). The FDA also allowed babies as young as six months to be enrolled.

Meanwhile, the results of gene therapy for other diseases are firing parental hope. In 2017 the New England Journal of Medicine reported a dazzling result for the fatal neurodegenerative disease spinal muscular atrophy (SMA). Thanks to a single infusion delivered in the first few months of life, toddlers who were supposed to have become paralysed and died by the age of two were alive. Most were sitting and rolling; some were walking and talking. “Everyone on the planet saw that gene therapy works!” says Alexander. “It was almost biblical.”

The FDA is doing what it can to meet these products halfway, says Janet Lynch, CEO of the US-based Alliance for Regenerative Medicine, which represents industry, not-for-profits, academia and patient groups. “They see the clinical promise is so dramatic they want to work hand in glove, making sure that safe and effective products are brought to market as soon as they can.”

The treatments, however, command record-breaking prices – US$4–5 million for SMA, according to one recent estimate.

Just how to turn the miracle into a market reality is the question of the moment.


Gene therapy is a wonderfully simple concept. A person is born with a glitch in a piece of their DNA code or is missing that piece altogether. Correct or add that piece of DNA code – the gene – and the problem is fixed. How is it possible to correct or add DNA? Nature has ferries designed to do just that: viruses. They not only infect your bloodstream, they can infiltrate the DNA of your very cells. The idea is to include in that viral payload some human DNA that carries instructions to fix the genetic anomaly.

This was first tried in 1990, to treat a child with “bubble boy syndrome”, or severe combined immunodeficiency (SCID), where the immune system is faulty for lacking a functional version of the gene called ADA.

The researchers were able to use a virus to transfer the missing gene to the child’s blood cells in a test tube and then to give those cells back to the child. It worked, though not well enough to have a significant therapeutic effect, says Alexander. Nevertheless, the race was on to bring gene therapy into the clinic.

Racing was a bad idea. Nine years later, 18-year-old Jesse Gelsinger paid the price. The teenager carried a genetic glitch known as “ornithine transcarbamylase deficiency” that had impaired his ability from birth to rid his body of ammonia, produced when proteins are broken down. His condition had been kept under control through a low-protein diet and medication. Four days after volunteering for a gene therapy trial at the University of Pennsylvania he was dead, his body wracked by an immune storm instigated by trillions of particles of adenovirus, the same type that causes the common cold.

In 2003, a second tragedy struck the field. In trials led by French and British researchers, 20 children with “bubble boy syndrome”, in this case a type known as X-linked SCID, were successfully treated using gene therapy involving a so-called retrovirus. Several years later, five of them developed leukaemia. The retrovirus had inserted its payload into their DNA, so curing their immune deficiency, but it had also inadvertently activated a nearby cancer-causing gene.

The gene therapists had thought they were using tame viruses; clearly they weren’t. The solution was two-fold. First, look to nature for viruses that were less likely to provoke catastrophic immune responses. Instead of the inflammatory adenovirus, they recruited its mild-mannered partner, adeno-associated virus (AAV). Second, they engaged in some serious tinkering to minimise the likelihood of these viruses triggering cancer and to equip them with homing devices for specific organs. Some researchers used manual forms of genetic engineering, while others, such as David Schaffer at the University of California, Berkeley, co-opted nature to carry out some directed evolution (similar to the approach that won a Nobel prize last year). The ultimate result: a fleet of safer precision-engineered nanobots able to target an organ of choice and offload their cargo of DNA. It is this new fleet that is powering the resurgence of gene therapy.

The first generation of gene therapies deploy a functional new gene copy in the virus payload. But waiting in the wings is a process by which viral payloads carry an editing crew to fix what is wrong with the gene, in a manner analogous to a word processor’s “Find and Replace” function. CRISPR is a famous example, but there are other editing crews with equally snazzy, obscure titles such as “zinc fingers”. This editing treatment is ideal for diseases where the problem is not that there is a lack of a functional gene but that the gene is producing a toxic product, the case in Huntington’s disease. The editing approaches are just now entering clinical trials.

For now, replacement gene therapies are way ahead. In 2012, the first such therapy was approved in the European Union for the disorder lipoprotein lipase deficiency. In August 2017, the US FDA licensed its first gene therapy, for a leukaemia treatment. There are more than 700 gene therapy trials under way.

By any measure, the gene therapy revolution has arrived.


In 2011, Megan Donnell had never heard of gene therapy. Little wonder, she was a very busy woman. A manager for an IT consultancy, she had 40 staff reporting to her and was also the proud mother of two-year-old Isla and newborn Jude.

It was a routine health check for six-week-old Jude that cast a cloud over this sunny picture. The nurse queried Isla’s language development. Most two-year-olds are putting words together into sentences. Isla wasn’t. She’d hit all her earlier developmental milestones, so until then Donnell hadn’t been concerned. Over the following months, more troubling signs surfaced. Isla had trouble properly gripping a pencil, and even after 12 months Donnell and her husband, Allan, were getting nowhere with her toilet training. Yet paediatricians reassured them, pointing to the tremendous variation in the rate at which toddlers hit their milestones. Isla’s language delay could also be put down to blocked hearing tubes; she needed grommets. Still, one paediatrician did acknowledge Donnell’s concerns: “Mothers are right 99.9 per cent of the time.”

By the time Isla was nearly four and enrolled in the community preschool, the director took Donnell aside and asked if she was worried about her child. Donnell recalls it as a moment of relief. “Yes, I’m worried and no one will listen to me.” Comprehensive testing by child psychologists revealed that Isla showed a global developmental delay. She would need intensive cognitive therapy. She was also referred to a pathology lab for blood and urine tests.

Her body fluids showed high levels of a sugary molecule called heparan sulphate. An excess of sugary molecules may not sound all that sinister but this sugar plays a crucial role. It forms a scaffold between cells that keeps proteins in place, rather like motifs on a tapestry. However, this tapestry needs to be continually unpicked and the components broken down and excreted. In Isla’s case, they weren’t. The build-up of the sugar was slowly poisoning her brain cells.

The single simple reason for the malady was that neither of her two copies of chromosome 17 carried a functional gene for the enzyme that breaks down the heparan sulphate. Isla’s fuzzy symptoms had crystallised into a hard diagnosis: Sanfilippo syndrome, named after Sylvester Sanfilippo, the paediatrician who nailed the cause of the disease in 1963.

There was worse to come. As unaffected carriers, Megan and Allan Donnell each carried one bad and one good copy of the gene. At odds of one in four, Isla had unfortunately drawn the genetic short straw from each parent. Was Jude also so unlucky? Now aged two, he was above average in his intellectual capabilities. Yet in her heart Donnell already knew the answer. “There’s a look,” she tells me. Along with big bellies and protruding belly buttons because the sugary molecules enlarge their organs, “they’ve got big heads, coarse hair and eyebrows and often big lips. Then there’s the shape of their eyes. It’s not unattractive.”

In July 2013 the couple’s worst fear was confirmed. Jude had also inherited both copies of the faulty gene. “We went into a fog,” Donnell recalls.

It was Angeline Veeneman – a former business colleague and friend – who led her out of it.

Veeneman, a mother of twin toddlers, leapt into action as soon as she heard of the diagnosis. Scouring the internet, she discovered trials had attempted to administer the missing enzyme to children. They had not been all that effective. The difficulty was delivering the bulky enzyme to the brain. The blood vessels that supply it have impregnable walls – forming what is known as the “blood–brain barrier”. The new excitement, she discovered, lay in gene therapy. Some viruses are adept at breaching the blood–brain barrier.

Donnell guesses her friend’s efforts saved her about six months. “We took our kids to the zoo and she laid it all out for me.” Donnell discovered three companies that were planning to conduct clinical trials for Sanfilippo in various parts of the world but not in Australia. Three months after Jude’s diagnosis, she resigned from her job, and on September 17, 2013 she established the Sanfilippo Children’s Foundation (SCF).


At first Donnell bemoaned her uselessness: why hadn’t she studied medicine? But little by little, it dawned on her that her business management skills could be put to good work. “I could harness the talents of all these brilliant doctors!”

She was a fast learner and her charisma played its part. A year after registering the foundation, she had raised a million dollars.

Her chief scientific adviser was John Hopwood at the South Australian Health and Medical Research Institute (SAHMRI). As a young biochemist in Chicago in the 1970s, he’d been introduced to a family afflicted by a disease similar to Sanfilippo. With such a clear cause, the route to treating these diseases appeared maddeningly simple: clear away the sugars. But as Hopwood emphasises many times, “it was not simple”. These diseases became his life’s work: first to develop tests to diagnose them, then to treat them.

It was Hopwood’s lab at SAHMRI that diagnosed both Isla and Jude. Later, when Donnell invited him to be the first chair of her foundation’s scientific advisory board, he couldn’t refuse. “I was impressed with her great energy and determination to conduct trials in Australia,” says Hopwood. “She’s clever at what she does.”

Hopwood is positive about the prospects of gene therapy. For one thing, unlike enzyme replacement therapy that must be carried out on an ongoing basis, gene therapy offers the promise of a single treatment – because the cells of the body acquire their own instructions to make the enzyme. The bugbear, however, remains getting the DNA across the blood–brain barrier.

Three companies were trying different approaches. Lysogene, based in a suburb of Paris, had been founded by a French woman who could be Donnell’s doppelganger: a striking, 40-something, business-savvy mother of a child with Sanfilippo. This trial planned to do numerous injections directly into the brain by boring holes in the skull. Esteve, a company based in Spain, planned to reach the brain via injections into the cerebrospinal fluid. Finally, Abeona, in Ohio, was planning injections into the blood stream. The type of engineered virus it used, called AAV9, was the same one that had delivered the “biblical” results for infants with SMA. This virus appeared to be able to break through the blood–brain barrier.

Not only did Abeona’s science look promising but it was also an opportune moment to plant a stake in the company. It had recently spun out of research at Nationwide Children’s Hospital in Ohio and was hungry for capital.

Donnell and her board insisted their investment should carry some strings. Crucially, Australia would be one of the centres, along with Ohio and Spain, for the trial. SCF would own shares in the company and the payments would be made against milestones.

The hard-nosed approach paid off. Only two milestone payments were made before Abeona merged with the NASDAQ-listed company PlasmaTech Biopharmaceuticals, which changed its trading name to Abeona. The stock market approved. Overnight, SCF’s equity multiplied six-fold, turning a $450,000 investment into $2.7 million. They cashed in three quarters of it.

“Isn’t that amazing? So we can spend that on lots of other projects,” says Donnell, breaking into a radiant smile.


May 2016 saw the first patients with Sanfilippo treated in an early-stage trial in the US. The first Australian patients, to be treated at the Women’s and Children’s Hospital in Adelaide, were scheduled for 2017.

To qualify, Isla and Jude had to pass some cognitive and physical tests. And crucially, their immune systems had to be clear of antibodies for the particular strain of the virus: AAV9. If not, within moments of injection into the bloodstream, the virus would be destroyed by antibodies, taking with it any chance of a therapeutic response.

Donnell knew that antibodies were the wildcard. Some parents hoping to be in the trial had gone to extraordinary lengths to avoid exposing their child to the virus. But isolation was not an option for her, especially with the foundation to run. Besides, she was told that the risk of testing positive for virus antibodies was a low 5 per cent.

Since then, other studies report that up to 30 per cent of children are screening positive for the virus.

Donnell cannot say whether Isla or Jude was accepted for the Abeona trial. She does reveal that one of them tested positive to the antibodies, leaving that child ineligible, and for the one and only time in our two-hour interview, Donnell breaks down. “I get emotional, sorry …”

But for the 11 children who have so far been treated, the company reports clear benefits without major side effects. Up to a year after treatment, the levels of the heparan sulphate sugar were slashed by more than half in their urine, and importantly in the cerebrospinal fluid that bathes the brain. Their livers, normally swollen by the sugars, have also shrunk in size, and for some subjects their intellectual performance appears to have stabilised or improved.

The trials Donnell and others are funding will provide answers that are crucial to long-term therapeutic success. For instance, what is the best way to evade the immune system and most effectively deliver the virus to the brain? Meanwhile, there is another urgent question that needs answering: With a ridiculously small market, is gene therapy actually economically sustainable?

For one big pharma, the answer was no.


In 2016 a gene therapy for treating bubble boy syndrome was approved for use in the European Union. The drug giant GlaxoSmithKline was selling the one-shot treatment under the brand name Strimvelis. But with 26 patients across the US and Europe, even a price tag of US$665,000 didn’t make sense for GSK. In April 2018, it sold off Strimvelis and the other gene therapies in its pipeline.

The previous year, another frontrunner for gene therapy fell away. This was Glybera, a treatment for lipoprotein lipase deficiency, a one-in-a-million-person genetic disease where people end up with creamy blood because their triglyceride fats can’t be broken down. It causes debilitating stomach pain and pancreatitis. A single treatment appeared to be effective. Glybera, offered by the Dutch company uniQure, held the distinction of being the first gene therapy to gain EU approval in 2012. At a cost of €1.1 million per treatment, at that time it also held the distinction of being the world’s costliest medicine. As of 2016, only a single patient in Germany had persuaded their health insurer – DAK, one of Germany’s largest – to pay for a treatment. In 2017, uniQure announced they were dropping the product.

But the fate of these two drugs seems to have been a small dip in what is otherwise a rising tide. Strimvelis has not been left stranded. GSK sold Strimvelis and its other gene therapy products to a London-based start-up called Orchard Therapeutics, with GSK acquiring 20 per cent of Orchard’s shares.

Orchard’s focus is entirely on rare genetic diseases. It has eight products in the pipeline, two of which are a treatment for Sanfilippo.

And while uniQure may have jettisoned Glybera, its pipeline also carries gene therapy treatments for haemophilia and Huntington’s disease.

And at least one big pharma is showing interest in a rare disease. In May 2018, Novartis forked out US$8.7 billion to acquire AveXis, the US company that stunned the world with its successful gene treatment for infants with SMA.

“This frothing at the mouth shows that gene therapy has arrived,” says John Rasko, who heads the Gene and Stem Cell Therapy Program at the University of Sydney. In April 2018, his team was part of a gene therapy trial by the company Bluebird Bio that “cured” several patients of beta thalassemia, one of the most common inherited genetic diseases.

Nevertheless, the question remains: How do these companies plan to make money? The research costs are huge, the regulatory hurdles high and the numbers of patients small – hardly the bottom line that brings joy to investors. Yet in 2018, overall US$9.7 billion of capital poured into gene therapy, a 64 per cent increase on the previous year.

The strategy for these companies appears to be to use rare diseases to catapult them into the gene therapy space. For instance, when a treatment is the first to be able to cure a rare disease, it is eligible in the US for “orphan drug status” or “breakthrough therapy designation”, free passes that fast-track and shepherd drugs through ponderous and snarled regulatory systems.

It’s also the case that for rare genetic diseases the costs of developing a drug are relatively cheap. The basic research has already been done, with the underlying cause of the disease known and the curative gene in hand. And because these diseases are so severe, clinical trials can demonstrate clear results with smaller numbers of patients: tens rather than the thousands needed for a common disease. So the costs of a clinical trial can be far lower.

This gives small start-ups like AveXis the possibility of entering the market. And hopefully being bought out for billions.

By purchasing AveXis and its SMA therapy, Novartis also bought the team that had expertise in the finicky art of manufacturing and testing the genetically engineered viruses; patents for said viruses; and experience in how to navigate the regulatory process.

As Ian Alexander puts it, “companies see these products as loss leaders”.

The strategy then is to follow with gene therapies for more common disease.

Indeed the Novartis gene therapy menu includes a treatment called “CAR T-cells” for a form of leukaemia (ALL) that strikes about 3000 patients each year in the US. Licensed by the FDA in August 2017, the treatment resulted in complete remission in 40–60 per cent of patients whose leukaemia resisted all prior treatment. Four months later, the FDA licensed Luxturna, offered by Spark Therapeutics, which reverses blindness in greater than 50 per cent of patients who have inherited a progressive retinal disease.

One might wonder why companies haven’t targeted the more common rare diseases, such as cystic fibrosis or muscular dystrophy. It turns out both diseases have presented a greater challenge for gene therapy than initially thought. In the case of cystic fibrosis, where the faulty gene causes the secretion of excessively thick mucus, that mucus also blocks the genetically engineered virus from reaching the cells lining the airways. So far patients in trials carried out by the UK Cystic Fibrosis Gene Therapy Consortium have shown limited improvement. In the case of Duchenne muscular dystrophy, a fatal muscle-wasting disease that affects males, the gene itself is so large it does not fit inside the viral payload. Last October, US-based Sarepta Therapeutics tested a “micro” version of the gene on four boys and found some improvement.

While some gene therapies are clearly working better than others, a staggering 724 of them are currently making their way through regulatory pipelines around the world. “We’re at the inflection point of the Gartner curve,”, says Berkeley’s David Schaffer. He is referring to a graphic representation of the trajectory of new technologies paraphrased by the aphorism “We tend to overestimate the effect of a technology in the short run and underestimate the effect in the long run.”

But it’s not just medical technology that is inflecting. With million-dollar price tags, how can patients, governments, insurers and society at large sustain such costs?

Schaffer suggests it may be time to move on from the “subscription model” of medicines. Just as buying a house outright can end up costing less than life-long rent payments, so too, when all the costs are added up, gene therapy will turn out to be the better deal.

He points to the gene therapy for haemophilia that is soon to be launched by uniQure. (Schaffer sits on its board.) He estimates the cost of current treatments, which inject the missing clotting factors, are US$250,000 per year. Over a 70-year lifetime that’s $17.5 million, not counting periodic hospitalisation costs. The one-off payment is clearly the better deal, as long as it is indeed a one-off.

Recognising that it may be too soon to say whether the current treatments will indeed be enduring, “a lot of companies are willing to accept ‘pay for performance’”, says Janet Lynch of the Alliance for Regenerative Medicine.

For instance, Spark Therapeutics is offering some insurers rebates based on how effective Luxturna is in the months and years after treatment.


While these new health economics evolve, Megan Donnell is considering whether the next goal for her foundation should be to raise funds to enable children to access treatments. Her focus remains fixed on the big picture – it’s her way of coping.

“Most people understand that this is a terminal illness. But actually the hardest thing isn’t how it’s going to end; it’s what we’ve lost of life in the meantime.” Though she describes her kids as happy – “they live in the moment, they love life” – it has come at the expense of her personal life.

In the middle of last year, the strain broke up her marriage. “I didn’t want to become a statistic in that way, but it’s kind of unavoidable in the end.”

She and Allan now take turns moving out into a nearby granny flat and staying in the family home to care for their hyperactive children, who can never be left unsupervised lest they harm themselves, who will run off in a carpark unless firmly held on to, and who often have sleepless nights requiring the parent on duty to stay vigilant. Ironically the marriage breakdown has made it easier for them to access government support through the National Disability Insurance Scheme. Four times a week, they are entitled to a carer who will bathe and supervise Isla and Jude while Megan or Allan cooks dinner. “Cooking is very dangerous,” she says.

The help is allowing her to relax more, enjoy her kids and be in the moment. “It’s the same challenge for any mum, but a bit amplified,” she suggests.

As is often the case with Donnell, that would seem to be an understatement of the relentless challenges she faces every day, in a life that stretches out with little sign of them ever abating.

Isla is growing increasingly anxious, mostly around school attendance. She no longer fits in socially with her peers at the mainstream school. She can also be physically aggressive. Donnell is trying to assuage her anxiety, in part by changing schools.

“Isla is at middle age for a Sanfilippo child,” says Donnell. According to the normal trajectory of the disease, from here on she would soon stop walking, talking and eating. “I’d be looking at pushing her around in a wheelchair and feeding tubes.” But Isla and Jude have always been at the high end of the spectrum for Sanfilippo children, says Donnell. “I may be looking at caring for 20-year-olds, who have all the same challenges.”

I ask Donnell: What sustains her?

“The greatest tragedy of my life was Sanfilippo. It’s also the biggest opportunity of my life to do something, and having purpose is what keeps me focused and driven and going … What else could I do?”

Elizabeth Finkel

Melbourne-based Elizabeth Finkel is an erstwhile biochemist who switched to telling the stories of other scientists. She is the former editor of Cosmos magazine.  

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