Rare Diseases: 5 Recent Reasons to Cheer

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.

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 blindness. Now 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:

#1: GENE THERAPY PENDING APPROVAL

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.

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.

#2: FINDING HOMES FOR STALLED DRUGS

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 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.

#3: SPEEDING FDA APPROVAL

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.

#4: EASING INSURANCE ACCESS

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.

#5: IDENTIFYING DISEASE GENES

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.

CODA

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.

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