Gene therapy’s time seems to have come

Once considered too risky, now offering hope to patients long without it

By Carolyn Y. Johnson | Source: The Boston Globe

Two boys born with a fatally flawed gene that leaves them defenseless against common infections have returned to their homes in Argentina and Chile after receiving an experimental gene therapy at Boston Children’s Hospital.

Untreated, babies with their “bubble boy” disease would die in infancy, but in 2010 and 2012, doctors inserted good copies of the gene into their bone marrow cells, restoring the boys’ immune systems. Both are now well into toddlerhood.


Kirsti Pigney is participating in a trial for gene therapy to treat blindness. She can’t tell whether the therapy is working, but said her vision hasn’t worsened.

Meanwhile, Kirsti Pigney, a 76-year-old from Taunton who woke up one day unable to see, is participating in a safety trial of a gene therapy being tested by Cambridge-based Genzyme for a form of blindness. She recently had a virus, modified to carry a therapeutic gene, injected into one of her eyes.

Years after it was hyped, then vilified after the death of a teenager, then mostly forgotten by the general public, gene therapy has rebounded, and hospitals, companies, and investors in the Boston area have jumpedon the bandwagon. Patients are enrolling in a growing number of clinical trials here, and in some cases showing dramatic improvement. The technique, in which doctors “infect” patients’ cells with viruses engineered to carry useful genes, has matured and evolved.

It is a future few could have predicted a decade ago. Once trumpeted as a possible panacea for diseases ranging from sickle cell anemia to cystic fibrosis, gene therapy faced serious questions after the high-profile death of an Arizona teenager in a clinical trial in 1999. The case seized national attention, led to inquiries into failures of regulatory oversight, and scared away many investors. But some researchers continued to work to overcome the safety and technical hurdles.

“When I first went to UMass, several prominent scientists said, ‘What do you mean, gene therapy? They tried that and it didn’t work,’ ” said Dr. Terence Flotte, the dean of UMass Medical School, who has been working in the field since the late 1980s.

Over the years, scientists have improved the safety of the viruses used to insert good copies of genes into cells. Cautiously, they began to test the technique in people again. In 2008, two groups of researchers reported restoring some vision in people with a rare retinal disease. The next year, eight out of 10 children with bubble boy disease were cured in a European trial.

Scientists reported in 2010 that a French man with a genetic blood disorder no longer needed monthly transfusions after being treated by a gene therapy made by Cambridge-based Bluebird Bio.

Pigney and her husband Keith thoroughly researched the procedure when her doctor mentioned the Genzyme trial. Instead of replacing a defective gene, the treatment inserts a gene directing eye cells to produce a protein that inhibits the abnormal growth of blood vessels — the reason for her vision loss.

Undaunted by gene therapy’s checkered history, the couple was intrigued by recent promising results. Pigney had always enjoyed sewing and crocheting, and now can do those things only if her husband threads the needle. She can’t write or drive a car or read small print.

“I tend to be a little bit optimistic, and I dreamed about my eyesight coming back. I never felt afraid of the injection,” Pigney said. “They’ve given me so many now. I’m like a pincushion.”

She can’t tell whether the therapy is working, but said her vision hasn’t gotten worse. At this point, the trial is testing only the safety and dosage.

With a handful of experimental trials open or in the works at local hospitals, gene therapy seems to have found its footing.

Dr. David Williams, director of translational research at Boston Children’s Hospital, said he plans this summer to bring together key players from area hospitals to share the expertise Children’s has gained from launching trials. The trials include one for a rare, genetic immune system disease called Wiskott-Aldrich syndrome and another scheduled to begin this summer for the neurodegenerative disease adrenoleukodystrophy, best known from the role it played in the movie “Lorenzo’s Oil.”

UMass Medical School has several active trials for patients with a genetic flaw that leads to lung and liver disease; the most advanced trial one has treated eight patients. They have also treated two patients, including Pigney, with age-related macular degeneration. At scientific meetings, Flotte, the UMass dean, said he’s begun to notice something he hadn’t seen before: lots of interest from the business community — including drug companies and investors — eyeing a hot field.

Bluebird Bio went public earlier this month, raising $101 million. The first gene therapy, Glybera, made by the Dutch company uniQure, was approved in Europe last year, for a rare disease that causes fat to build up in the bloodstream. A spokesman for the company said it had requested a meeting with the US Food and Drug Administration to get clarity on the approval process.

As the technology has matured, the understanding of its possible uses has also expanded as scientists have learned more about basic biological mechanisms. UMass Medical School biologist Craig Mello’s co-discovery of a way to turn off genes won him a share of a Nobel Prize in 2006 — and it introduced the possibility that gene therapy could be used not just to introduce good copies of genes, but to shut down malfunctioning ones.

Dr. Robert Brown, a professor of neurology at UMass who studies ALS, said that the ability to do more than just add good genes has ignited broader interest in the technique.

“Many of these diseases have a need for silencing” a gene, Brown said. “In Huntington’s, some forms of Parkinson’s, and most forms of familial ALS, the real challenge is not loss of [gene] function, but how to respond” to mutated genes that are producing proteins that harm the body.

Animal testing in primates or other large animals set to begin this year are beginning to change the discussion about the potential for using gene therapy in those neurodegenerative diseases.

“I’ve been doing this for many years starting in the early 1980s, and we’re now at a point where we’re talking about when we would treat the patient,” said Dr. Neil Aronin, a professor of medicine and cell biology at UMass who has long studied Huntington’s. “We didn’t even have that discussion before.”


A Little Girl With Giant Axons, a Deranged Cytoskeleton, and Someday Gene Therapy

Hannah, age 7. (Dr. Wendy    Josephs)

Source: Plos Blogs

By Ricki Lewis, PhD

When you hear hoof beats, think horses, not zebras.” So goes the mantra of first-year medical students. If a common disease is a horse and a rare disease a zebra, then giant axonal neuropathy (GAN), with only 50 or so recognized cases worldwide, is surely a unicorn.

Five years ago this week, 9-year-old Hannah Sames of Rexford, New York, who lives near me, received a diagnosis of GAN, a disease much like amyotrophic lateral sclerosis. And this month, thanks in part to the herculean fundraising efforts of Hannah’s Hope Fund (HHF), the cover and lead article of the Journal of Clinical Investigation reveal most of the story behind the devastating inherited disease, with repercussions that will reach far beyond the tiny GAN community.

If all goes well at the next Recombinant DNA Advisory Committee meeting at the NIH, a phase 1 clinical trial may be underway before year’s end to evaluate gene therapy for GAN. “A fire started burning deep in my core exactly 5 years ago when Hannah was diagnosed. We will not rest until we have a successful treatment for our kids. They are rare, but they are no longer neglected,” says Lori Sames, Hannah’s mom and executive director of HHF.

On March 5, 2004, when Lori and her husband Matt first glimpsed their newborn daughter’s kinky reddish fuzz, they were both delighted and puzzled. Madison, five, and Reagan, two, have stick-straight hair, as do Lori and Matt. When the birthing goop dried, Hannah’s cap of tight curls sprang to life.

For many months, the little girl seemed okay. She smiled, sat, crawled and hauled herself upright on schedule. But her footsteps were halting, hesitant. Hannah slowly grew clumsy, the strength ebbing from her legs. Lori made the usual rounds of specialists assuring her all was well, but already, filaments of protein were distending the long axons of the motor neurons running down Hannah’s legs, blocking messages to her muscles.

By Hannah’s third birthday, Lori and Matt suspected something was seriously wrong. Both of Hannah’s arches now bowed, and she tottered. More doctors gave false reassurances, hardly hiding their diagnosis of Lori as a helicopter mom. Then Lori’s sister showed cell phone video of Hannah walking to a physical therapist friend, who thought Hannah’s gait was like that of a child with muscular dystrophy. Six months of neurological tests followed, all results normal.

Lori Sames, Executive Director, Hannah’s Hope Fund

Lori Sames, Executive Director, Hannah’s Hope Fund

That’s what happens with a disease so rare that few physicians have seen it, or even heard of it. They can’t recognize a unicorn, don’t know what to test for. But finally an astute pediatric neurologist gave Matt and Lori an answer, and it didn’t come from an exome sequence or a sophisticated scan. “He took out a huge textbook and showed us a photo of a skinny little boy with kinky hair, a high forehead, and braces that went just below the knee – he looked exactly like Hannah. And he had GAN,” Lori recalls. Three days of tests at a children’s hospital in New York City confirmed the diagnosis.

Meeting with a genetic counselor was devastating. Lori recites what they learned: “Matt and I are each carriers of GAN, and we passed the disease to Hannah. Each of our two other daughters has a two in three chance of being a carrier. GAN is a rare ‘orphan genetic disorder’ for which there is no cure, no treatment, no clinical trial and no ongoing research.”

“So you are telling us this is a death sentence?” Lori recalls asking the genetic counselor.


The disease would progress slowly, the counselor said. Hannah’s legs would continue to weaken. By first grade she’d likely need a walker in addition to her ankle supports, and soon after, a wheelchair. She might lose her sight and hearing, and eventually be bedridden.

hhfMatt and Lori walked around like zombies for a few days. And then they founded Hannah’s Hope Fund. Their basement became a war room where they used their business backgrounds to assemble the first ever research conference for GAN. As Lori taught herself molecular biology, she became convinced that gene therapy was a logical approach, but at the same time recognized the value of learning anything about GAN. They were lucky to find Jude Samulski, director of the Gene Therapy Center at the University of North Carolina at Chapel Hill, and he recommended a young investigator, Steven Gray, to lead the team. It’ll be the first gene therapy delivered to the spinal cord. A clinical trial is incredibly expensive, and HHF’s fundraising efforts are amazing – they’ve earned $1 million in just the past 8 months. They’re just one of many not-for-profits in the rare disease community who have taken the helm of funding research.

Reproduced with permission from the American Society for Clinical Investigation; J. Clin. Invest. 2013; 123(5)

Reproduced with permission from the American Society for Clinical Investigation; J. Clin. Invest. 2013; 123(5)

In parallel to the gene therapy efforts, HHF supports research into the nature of the cellular glitch behind GAN, in the labs of Robert Goldman and Puneet Opal at Northwestern University, Jean-Pierre Julien at Université Laval in Quebec, Pascale Bomont at the INSERM neurological institute in Montpelier, France, and others. The group reports on a remarkable set of experiments in May’s JCI that probe the out-of-control parts of the cell’s inner skeleton, the intermediate filaments (IFs).

GAN is the perfect disease to investigate IFs because it’s caused by a single gene and has a large, measurable effect. Other conditions may affect IFs secondarily, or reflect input from several genes or environmental exposures.

At fault in GAN is a protein called gigaxonin that normally interacts with the IFs. Most kids with GAN have abnormal forms of the protein; Hannah is highly unusual in that she lacks it entirely.

A cell’s inner scaffolding has three types of girders: microtubules made of the protein tubulin, microfilaments made of actin, and the intermediate filaments made of several other types of proteins. The recipes for IFs vary with cell type: keratins in hair, neurofilaments in neurons, and vimentin in fibroblasts, the connective tissue cells that make up much of our bodies. But all IFs share a basic dumbbell shape, with a head, a tail, and a long helix in the middle. The dumbbells align and aggregate into filaments.

(Dept. of Energy)

(Dept. of Energy)


Being a nerd, when I hear “T and A” I think “tubulin and actin.” And when I hear “UPS” I don’t think of brown delivery trucks spewing package-clutching people – I think of the ubiquitin-proteasome system. The UPS is how cells round up their garbage and get rid of it.

Ubiquitin is a molecule that tags other molecules bound for destruction, like marking rotten produce at a supermarket or the tire of a parked car exceeding the time limit. Other proteins help escort the debris to proteasomes, which resemble spools that tear apart what’s dumped into them, spewing out pieces that are then further degraded.

Gigaxonin – what Hannah’s cells lack – is technically an “E3 ubiquitin ligase adaptor,” based on its DNA sequence. In Hannah’s motor neurons, hair follicles, and probably other places, the utter absence of gigaxonin means the IFs aren’t broken down and recycled. They remain extended and build up, slowly, which is why Hannah was okay for the first two years. I don’t mean this in a bad way, but Hannah is, genetically speaking, like a knockout mouse because she has two deletions of a major part of her gigaxonin genes.

Green IFS enmesh orange mitochondria in these mouse fibroblasts. (Linda Parysek + Trudy Aebig)

Green IFs enmesh orange mitochondria in these mouse fibroblasts. (Linda Parysek + Trudy Aebig)

Dr. Goldman and his group looked at fibroblasts from knockout mice and from three patients (called “GAN cells”; not including Hannah’s), tracking the interaction between vimentin and gigaxonin. Their discoveries confirm and extend what’s known about the disease:
• GAN affects IFs, leaving microtubules and microfilaments alone.

• GAN cells don’t overproduce intermediate filaments – the mRNA level for vimentin is normal. Rather, the filaments aren’t broken down on schedule, like garbage collectors going on strike.

• GAN cells are strikingly abnormal. Like a creeping wad of chewed gum, the glommed filaments pervade the cytoplasm, cling to the nucleus in clumps, and capture mitochondria, rendering these energy-extracting organelles swollen and misshapen. The cell’s organelles drown, swept up and suspended in the gunk of a deranged cytoskeleton.

Gigaxonin grabs onto vimentin by the helix part of the barbell. But the researchers were surprised to find that ubiquitin doesn’t enter the picture – gigaxonin must route the IFs to the proteasomes by some alternate pathway. However it happens, the researchers hypothesize, gigaxonin normally dismantles the long IFs into pieces that enzymes further chew up – like splintering a pile of logs into twigs.

GAN’s correctible! At least in a dish. Giving gigaxonin to GAN cells lowered IF levels within 72 hours, which is what gene therapy would ideally do. But kids aren’t collections of cells. If gene therapy goes off target, what could happen? If it works too well, will cells without IFs survive?

The research results may suggest new (or perhaps old) drug targets for GAN. Meanwhile, the slow crawl towards clinical trials continues.

(Dr. Wendy Josephs)

(Dr. Wendy Josephs)

In a disturbing twist, Hannah will not be among the first to receive the experimental gene therapy, because she doesn’t make gigaxonin. So if genes placed in her spinal cord enable her motor neurons to make gigaxonin, her body will see a protein it’s never encountered before — a red flag to the immune system. And so before Hannah can join the clinical trial that has not yet begun, she must have treatments to accustom her immune system to gigaxonin. That means suppressing T cells or a stem cell transplant from one of her sisters.

This week at the American Society of Gene and Cell Therapy annual meeting in Salt Lake City, researchers are brainstorming ways to modulate the immune system to accept a protein introduced with gene therapy, with Hannah the case study. “How can they safely treat her? What is the best way to suppress her immunity? And how will they determine when it’s safe to wean her?” Lori asks. She’s there, of course.

Casey Davies Ketcham lost her battle with GAN in March.

Casey Davies Ketcham lost her battle with GAN in March.

Casey’s legacy is also that what researchers learn about GAN will likely help many others. “IF aggregates form in several types of neurological disorders in addition to GAN—such as ALS and Parkinson’s disease,” says Dr. Goldman. Add to that variants of spinal muscular atrophy and Charcot-Marie-Tooth diseaseAlexander diseaseLewy body dementia, and Alzheimer’s disease. ”Our results suggest new pathways for disease intervention. Finding a chemical component that can clear the aggregations and restore the normal distribution of intermediate filaments could one day lead to a therapeutic agent for many neurological disorders,” says lead author Saleemulla Mahammad, a postdoctoral researcher at Northwestern.

I hope the days when rare diseases were considered “orphans,” and ignored, are finally gone, as more and more families form not-for-profit organizations that push research far beyond what was once possible. What we learn about the unicorns and zebras can often help the horses too.

(Hannah’s story is told in chapters 10 and 11 of my book The Forever Fix: Gene Therapy And The Boy Who Saved It.

About Ricki Lewis, PhD

Ricki Lewis is a science writer with a PhD in genetics. The author of several textbooks and thousands of articles in scientific, medical, and consumer publications, Ricki’s first narrative nonfiction book, “The Forever Fix: Gene Therapy and the Boy Who Saved It,” was published by St. Martin’s Press in March 2012. In addition to writing, Ricki provides genetic counseling for parents-to-be at CareNet Medical Group in Schenectady, NY and teaches “Genethics” an online course for master’s degree students at the Alden March Bioethics Institute of Albany Medical Center.

Rare disease tweet chat: how can rare diseases gain more media attention?

Imageby Rebecca Aris


Rebecca Aris highlights the recent tweet chat on the topic of rare diseases hosted by pharmaphorum.

On Friday 1st February this year, pharmaphorum hosted a tweet chat on the topic of rare diseases. Many rare disease patients came together through this social media channel to discuss topics in this space. This article details some of the responses and themes that arose.

How has social media affected rare disease patients?

The first question we asked participants was how social media has affected rare disease patients. Here are some of the responses we had to this question:-

  • Information via social media is power for rare disease patients.
  • Social media has provided an amazing opportunity for rare disease patients to find each other and share support.
  • Social media allows patients the opportunity to engage with companies who are developing drugs for rare diseases.
  • In Wilson Disease group, someone newly diagnosed from the UK posted a question and got replies from people in five countries in approximately 36 hours.
  • Social media has given people with cystic fibrosis the tools to put real pressure on public healthcare systems to fund new drug.

So it seems that social media offers information, a platform to connect, support and access to global communication – instantly.

Rare disease patients and clinical trials

We asked our tweet chat participants how they found clinical trials and how they calculated the risk of participating. Here are their answers:-

Patients are clearly quite clued up when it comes to resources in this area. They naturally still express concern over the fact there is often no alternative treatment option, and they want to be as informed as possible.

How can we raise awareness of rare diseases?

Rare diseases need more media attention! This was a message that echoed throughout the chat. Rare diseases need more media press so the public can see that this is a common problem that needs to be addressed. Some popular responses to this question from the tweet chat are below:-

  • One tweet, one post at a time.
  • Sharing the simple fact that collectively rare diseases are not rare. One in ten Americans lives with a rare disease.
  • Need high profile media attention.
  • Increased interaction between all relevant stakeholders from patients to regulators.

So how can we gain media attention in this area? The question remains and given the fact that collectively rare diseases are common it’s clearly time that this area received more attention.

How can we reduce isolation of rare disease patients?

When interviewing rare disease patients a common topic that arises is the feeling of isolation that rare disease patients experience. When questioned on how we could reduce this feeling of isolation our tweet chat participants came up with the following suggestions:-

  • So many wonderful online options like @inspire @patientslikeme @wegohealth and groups like @RareConnect and @bensfriends can also help
  • Check out #pcori.
  • Social media, especially Facebook groups can reduce isolation of rare disease patients.

Online rare disease communities, it seems, really do make a difference in offering support and reducing isolation.

If you could tell pharma one thing – what would it be?

Many patients express an interest in wanting to be able to communicate more openly with pharma. We asked our tweet chat participants if they could tell pharma one thing what would it be. Some of the responses were as follows:-

  • Newly diagnosed rare disease patients want pharma to extend to support groups and offer an explanation of the drug development process.
  • Rare disease patients need safe, effective treatments and they want to work together with pharma.
  • We want a cure, but we’ll take a treatment.

A common theme was that they wanted to work more closely with pharma and wanted more education on how pharma works and, specifically, the drug development process.

As a rare disease patient, what gives you hope for the future?

We closed the tweet chat by asking what it is that gives rare disease patients hope for the future. Here is what they said…

  • Other inspiring rare disease patients / families.
  • More funds being allocated for research into rare disease treatments.
  • Incredible gene therapy advances.
  • More venues to communicate.
  • Industry interest, young generation of academic researchers.

It seems that rare disease patients are hopeful that therapeutic advances, increased communication with pharma and increased funds in this area are contributing toward the treatments and cures of the future.

We’d like to thank those who participated in the chat for sharing their thoughts with us and engaging in this lively debate.

You can view the whole conversation on Appeering here or on Storify here.

Rare Diseases: 5 Recent Reasons to Cheer

By Ricki Lewis

On Sunday morning, July 21, I faced a room of people from families with Leber congenital amaurosis (LCA), an inherited blindness caused by mutations in any of at least 18 genes. It was the final session of the Foundation for Retinal Research’s bi-annual LCA family conference, and I was there to discuss the history of gene therapy. But I zapped through that quickly, because the future is much more intriguing.

Leber's Congenital Amaurosis - Gavin

Exome sequencing identified the rare mutation that causes Gavin Stevens’ hereditary blindness (Leber congenital amaurosis, or LCA). (Jennifer Stevens)

The excitement pervading the room that day was palpable, following a day of scientific updates, and not only because those with young children were soon to visit Sesame World and the sights of Philadelphia.

Jennifer and Troy Stevens exemplified that hope. Two years earlier, at this conference, they’d learned that researchers had been unable to identify a mutation behind their toddler Gavin’s blindnessNow they know the name of their gene:NMNAT1. I’ll return to their story.

The star of the 2010 conference had been 10-year-old Corey Haas and an energetic young sheepdog, both cured of LCA with gene therapy. This weekend, the stars were the new programs and technologies that would allow other families to join Corey’s – and not just those with blindness.

The rare disease community in the US collectively belies its name: at least 30 million people suffer from 7,000+ diseases, many so rare that they hover beneath the radar of big pharma. But maybe not for long, thanks to the following recent reasons to cheer:


On July 20, the European Medicines Agency (EMA) announced impending first approval of a gene therapy in the western world.

It’s for lipoprotein lipase deficiency (LPLD). The enzyme normally breaks down tiny triglyceride-packed globules called chylomicrons, and its absence causes episodes of very painful pancreatitis that can be fatal. LPLD is an ultra-rare disease, striking 1-2 people per million. And the only treatment is a diet so low in fat that most patients can’t stick to it.

The gene therapy, Glybera, consists of adeno-associated virus type 1 delivering an overactive variant of the LPL gene, injected into a leg muscle during a single day. But not many people have had it.

wilson - leber's congeintal amaurosis

James Wilson, MD, PhD, developed the vector, AAV1, used in the lipoprotein lipase deficiency gene therapy. (University of Pennsylvania).

The research team, led by Daniel Gaudet, MD, PhD, a professor of medicine at the University of Montreal, with colleagues from Amsterdam Molecular Therapeutics (recently replaced by privately-held UniQure), reported a two-year follow-up of 14 adult patients receiving 100 billion to 1 trillion viruses. And it seems to have worked, depending upon how one assesses success.

“The triglycerides dropped, but after 60 days they trended back up. The primary endpoint had failed, but the secondary endpoint was recurring episodes of pancreatitis – and they found a statistically significant, or close to it, decrease,” explained James Wilson, MD, PhD, editor-in-chief of Human Gene Therapy and professor of pathology and laboratory medicine at the University of Pennsylvania, who developed the vector. Tracking a few more patients, work not yet published, may have led the EMA’s Committee for Medicinal Products for Human Use to finally recommend approval, after three rejections.

Tomas Salmonson, MD, acting chair of the committee, points to the new data as well as restricting use to the sickest patients in pushing the gene therapy forward. “Our established ways of assessing the benefits and risks of Glybera were challenged by the extreme rarity of the condition and also by uncertainties associated with data provided.”

For the additional study, the researchers looked at what was happening in the chylomicrons in the blood, and found that triglyceride level can fluctuate, contrary to assumptions of steady change. And that means something is happening that might explain the decrease in the painful episodes – a very real measurement. Summed up Jean Bennett, MD, PhD, leader of one of the LCA2 clinical trials at Penn, “It’s a huge vote of confidence for the entire field of gene transfer.”

Dr. Wilson agrees. The repercussions won’t be at the FDA, where scientists make decisions based on data, he said, but on the willingness of big pharma to invest in gene therapy. Despite recent successes – LCA2, hemophilia, adrenoleukodystrophy — the pharmaceutical industry has been hesitant to fund gene therapy because it has lacked an approval. “So-called regulatory uncertainty has been the biggest problem, and if there’s no precedent, they can continue to say no. Biopharma is not interested in the ultra orphans. But I have a feeling we’ll be seeing some activity,” he added.


By August 14, researchers can submit pre-applications to the National Center for Advancing Translational Sciences (NCATS) Discovering New Therapeutic Uses for Existing Molecules program. The idea is simple yet brilliant: match compounds that are languishing on company shelves to diseases with newly-discovered mechanisms. Such candidate drugs have passed initial safety tests but were dropped for business reasons, such as a tiny market, or because they didn’t treat what they were intended to.

corey and hannah - LCA2

Corey Haas and Hannah Sames are ambassadors for the rare disease community, here signing their photos in “The Forever Fix: Gene Therapy and the Boy Who Saved It.” Corey has LCA2, successfully treated with gene therapy, and Hannah, awaiting hers, is one of 54 people in the world who has giant axonal neuropathy. (Sandy Andersen)

Since the announcement in June, eight industry leaders have signed on, offering an initial 58 compounds to find new therapeutic homes. And the need is compelling: of the 4,500+ diseases with recently-revealed mechanisms, only about 250 have treatments. “If researchers funded through this effort can demonstrate new uses for the compounds, they could significantly reduce the amount of time it takes to get a treatment to patients in need,” said Kathy L. Hudson, PhD, NCATS acting deputy director.

Everyone wins.


On July 9, President Obama signed into law the FDA Safety and Innovation Act, which updates the 1983 Orphan Drug Act. The new law provides $6 billion over the next 5 years to assist the agency in evaluating new drugs and medical devices. The Act will speed access to new treatments and development of especially promising ones, and the Humanitarian Use Devices program will target those that treat rare diseases, giving priority to diseases of children. “Treatments are desperately needed because most are serious, many are life-threatening, and about two-thirds of the patients are children,” said Peter L. Saltonstall, president and CEO of the National Organization for Rare Disorders (NORD), which was critical in developing both acts.

The Act may be a lifesaver for people such as 8-year-old Hannah Sames, one of 54 people in the world known to have giant axonal neuropathy. The gene therapy trial that she will take part in is nearing phase 1, but the sponsoring not-for-profit, Hannah’s Hope Fund, is about to run out of money.


When the Supreme Court upheld the Affordable Care Act on June 28, I scrolled through the relieved statements from various rare disease organizations. Thanks to the ACA, children like Hannah Sames and Gavin Stevens will not be penalized for their pre-existing conditions, nor face annual or lifetime insurance caps.


Exome sequencing can identify mutations when single-gene tests don’t. The strategy sequences the protein-encoding part of the human genome in individuals, usually young children, whose syndrome has evaded recognition, searching for mutations passed silently from parents, with functions that could explain the symptoms. Once that’s known, researchers can develop new treatments, or repurpose existing ones.

New exome-derived discoveries are being reported nearly weekly, some appearing in the media before the technical papers are published. A recent news release about a 4-year-old named Maya with a neurological disease, for example, made its way into many news reports and blogs, with a touching story and accolades. Yet none named the gene or its precise function – the part I’m most interested in.

In contrast to the incomplete Maya story, when John Chiang, PhD, director of the Molecular Diagnostics Laboratory at the Casey Eye Institute in Portland, Oregon told me he’d discovered Gavin Stevens’ mutation among nearly 2,500 gene variants in the blind boy’s exome, he asked that I not report it. That was 8 months ago – the mutation is unveiled in a quartet of papers in the current Nature Genetics, after something of a turf war among four research groups.

Gavin’s parents had heard about Dr. Chiang at the Foundation for Retinal Research meeting two years ago, where Jennifer had called him, distraught, after learning that single-gene tests couldn’t explain their son’s blindness. Dr. Chiang, who described his skill as “I do the dirty work, I find the mutations,” had helped several families after existing tests had fruitlessly, but expensively, probed the most common parts of only the most common genes. Dr. Chiang had first developed larger gene testing panels, and when those still didn’t identify some families’ mutations, quietly sent their DNA off to the Beijing Genome Institute for whole exome sequencing.

Now that exome sequencing is commercially available in the U.S., Dr. Chiang cautions that it still doesn’t help all families, and that costs can greatly exceed the oft-mentioned $1,000 pricetag when considering analysis. “I would only recommend it as the last resort when all known genes are ruled out,” he advised.


Karen Poulakos, Leber congenital amaurosis patient smiling

Karen Poulakos has Leber congenital amaurosis, and does quite well in her world of shadows. Gene therapy may return the vision that she remembers from her childhood. (Ricki Lewis)

On Saturday at the retinal research conference last weekend, I watched Jennifer and Troy beam as Eric Pierce, MD, PhD, director of the Ocular Genomics Institute in Boston and co-author of one of the Nature Genetics papers, talked about their mutation. Discovery of the gene, which affects cellular energy (NAD synthesis), is a starting point for gene therapy, and this particular candidate is a great target. “The gene is small, and encodes an enzyme,” said Dr. Pierce.

The next day, as my talk about the history of gene therapy wound down, I took stock of my audience. Two young women with canes sat in the front row. A few rows back sat Karen Poulakos, also with a cane, whom I’d chatted with earlier.

Karen has Corey’s disease, LCA2, but, at age 63, had been deemed too old for the gene therapy clinical trial two years ago. But things had changed, she’d learned at the meeting, and she just might be eligible for the phase 3 trial coming up. Karen has lived a full life in her world of shadows, barely remembering when she could see better, and she’s now contemplating what it might be like to see again.

As I collected my things, I marveled at the hope radiating from the faces in the room, sighted as well as not. And I thought that this is science at its very best. This is what it is all about, the molecules, the mice, the deciphering of nature’s mechanisms: helping people.

Ricki LewisAbout the Author: Ricki Lewis received her PhD in genetics from Indiana University. Her ninth book, The Forever Fix: Gene Therapy and the Boy Who Saved It, narrative nonfiction, was just published by St. Martin’s Press. Most of her other books are college life science textbooks, including “Human Genetics: Concepts and Applications,” (10th edition, 2012) from McGraw-Hill Higher Education. Routledge Press published “Human Genetics: The Basics” in 2010. Ricki has published thousands of magazine articles, from Discover to Playgirl, but mostly in The Scientist. She is a genetic counselor at CareNet Medical Group in Schenectady, NY and teaches “Genethics” online for the Alden March Bioethics Institute of Albany Medical College. Ricki is a hospice volunteer and a frequent public speaker (Macmillan Speaker’s Bureau). Ricki’s blog Genetic Linkage is at and she tweets at @rickilewis. Follow on Twitter @rickilewis.
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