Megan Donnell set up the Sanfilippo Children's Foundation when her children Jude and Isla were diagnosed with Sanfilippo syndrome.

Isla Donnell was two and a half years old when her mother, Megan, first became concerned about her development. When other children her age began to speak in full sentences, Isla could string only a few words together. Paediatricians in the family's home city of Sydney, Australia, assured them that Isla's development was within the normal range, but by the age of four, her mental and physical development was clearly behind. Tests confirmed their suspicions: Isla had a rare genetic condition called Sanfilippo syndrome. Also known as mucopolysaccharidosis type III (MPS III), Sanfilippo is one of the 50 or so known lysosomal storage disorders (LSDs).

As the Donnell family struggled to take in this diagnosis, Isla's little brother Jude — by then a chatty two-year-old — was tested too. Four weeks after Isla's diagnosis, Megan and her husband discovered that Jude had the condition as well.

Sanfilippo syndrome affects 1 in around 70,000 children, and few make it to adulthood. There is currently no treatment, although ten research programmes have a therapy that is in or about to enter early stage clinical trials. “The message we were given was that research is happening, but a treatment is a long way away,” says Megan, a former management consultant. “I began to look at what research was being done, and discovered there was quite a bit.” But only two of the programmes were run by established pharmaceutical firms; the rest were within academia or small spin-out companies that struggle to finance human trials.

So Megan — like many parents before her — stepped in to help. In 2013, she set up the Sanfilippo Children's Foundation. Today, the charity is helping to fund one promising therapy through the first phase of clinical trials, and is considering which other programmes to support.

Foundations formed by parents and researchers are powerful advocates for the development of treatments for rare diseases. As well as helping to bridge the funding gap, many of these foundations are calling for an overhaul of the regulations that incentivize pharmaceutical companies to bring drugs to market, arguing that the current system is not working.

“For rare diseases, there is an enormous amount of bureaucracy to get a therapy trialled and approved. I'm sure all of that could be streamlined,” says John Hopwood, an LSD researcher from the South Australian Health and Medical Research Institute in Adelaide. “The reality is that not doing anything means these patients are going to die.”

Parent power

Part of  Nature Outlook: Lysosomal storage disorders

Emil Kakkis knows first-hand how important financial support from a family foundation can be. In the early 1990s, Kakkis was a medical-genetics researcher at Harbor-UCLA Medical Center in Torrance, California. He was working on an LSD called Hurler syndrome (MPS I). He had synthesized some of the enzyme that was missing in people with the condition and showed that it treated the disease in animal models. “My feeling was, my job was done,” says Kakkis. “I'm going to hand it off to some company to develop the product.”

But no company was interested. Kakkis went to Genzyme, which in 1992 had gained approval from the US Food and Drug Administration (FDA) for the first enzyme-replacement therapy for an LSD, Gaucher's disease. But whereas Gaucher's affects up to 1 in 50,000 people, Hurler affects only 1 in 100,000. “Genzyme said, 'This is kind of small',” Kakkis recalls. He then tried speciality pharmaceutical company Orphan Medical, whose mission was to develop 'orphan' drugs for rare diseases. “And they said no. My product was too small even for an orphan-drug company.

Fortunately, his research caught the attention of the Ryan Foundation, which was set up in Carrollton, Texas, by the parents of six-year-old Ryan Dant, three years after his diagnosis with Hurler syndrome. The foundation's support enabled Kakkis to produce pharmaceutical-grade enzyme for clinical trials. In 1997, newly formed Californian biotech company BioMarin stepped in to take it on.

Ryan was one of the first children enrolled in the trial the following year. Five years later, in April 2003, the FDA approved the therapy. “Ryan has been on the treatment for 18 years, and he's doing well, finishing college,” Kakkis says. “The story opened the door to treatments for other rare diseases.” But as Megan Donnell observed ten years later, that work is still going on, and foundations such as hers still need to provide support.

Homes for orphans

The US Orphan Drug Act was passed in 1983 to encourage companies to develop drugs to treat rare diseases by offering perks such as tax incentives and fee waivers. But so far only seven LSDs have an FDA-approved treatment. An analysis led by paediatrician Markus Ries at Heidelberg University Hospital in Germany showed that LSDs that mainly affect the body are now quite well treated — Gaucher's disease has five approved treatments, for example. But most LSDs have a neurological component, and there are no approved treatments for these conditions (see page S154). “LSD treatments are biased to enzyme-replacement therapies,” says Ries. “The trouble is, the enzyme molecule is so big that if you infuse it into the blood, it doesn't cross the blood–brain barrier.

Gene therapy (see page S158) or other future treatments might be able to get over this physiological barrier. But the bigger problem, advocates say, is the regulatory barrier. Typical drug trials use clinical endpoints. “You compare your drug to the natural history of the disease, to show a difference,” Ries says. For Hurler syndrome, for example, the endpoint was based on the distance a patient could walk in six minutes after therapy, compared with the distance they would be expected to reach without it.

But for many LSDs, their rarity means that the natural progression of the disease is not well known. Such complications are amplified when measuring the effect of a drug on cognitive development, Ries adds. Speech progression, for example, varies according to language. And there are few established, standardized protocols for testing neurological drugs. The lack of good endpoints is holding up drug development, he says.

These problems frustrated Kakkis so much that in 2009 he left BioMarin to found the EveryLife Foundation for Rare Diseases, and launched the Cure The Process campaign. One of the key issues on which the foundation is lobbying is the need for greater flexibility from the FDA in its approach to rare-disease clinical trials. The Cure the Process campaign urged the FDA to clarify its guidelines on the use of biological markers to make it easier to start such trials.

Rather than use clinical endpoints, a biomarker-based trial would measure changes in the body. Therapies for Gaucher's disease have previously used a physiological marker as an endpoint: a reduction in the volume of the swollen liver and spleen, says Kakkis. But the best example is HIV. “In HIV there is a really simple biomarker, the viral load,” he says. By measuring the amount of virus in the blood, HIV researchers could conduct small, rapid drug trials to discover effective drugs and drug combinations. “The reason AIDS got solved is because the approval pathway allowed a biomarker endpoint,” he says.

For neurological LSDs, Kakkis would like to use similar biomarkers that measure the amount of particular molecules in the patient's urine or blood. Many rare diseases have distinct biochemical markers, directly related to disease progression, that might be used in this way. But since 1992 the FDA has agreed only two new biomarker endpoints of any type, he says. “Nobody can break through with a new endpoint because the requirements are impossible,” Kakkis says. The FDA needs to formulate clear scientific criteria for assessing new biomarkers, he adds.

But there has been some progress, says Kakkis. The FDA Safety and Innovation Act of 2012 stipulated that the FDA should consider novel endpoints, “especially in instances where the low prevalence of a disease renders the existence or collection of other types of data unlikely or impractical”. And in August 2015, the FDA released draft guidelines for industry on the development of orphan drugs, including an initial discussion on biomarkers. “The ball is moving,” says Kakkis, although he wishes it would move a bit faster.

Finding funding

Megan Donnell knows that her foundation's work will not end with the first approved therapy for Sanfilippo syndrome. “Advocacy will be critical when we have a treatment we need funding for from the government,” she says (see 'Counting the cost'). But right now, getting a therapy through clinical trials remains her focus.

With advice from Hopwood, Megan has decided to fund a gene-therapy trial at the Nationwide Children's Hospital in Columbus, Ohio. Thanks in part to this seed funding, the research has led to the creation of a spin-off company, Abeona Therapeutics, which will commercialize the therapy. Abeona has just started its first clinical trial.

Isla and Jude Donnell are now seven and five years old. “The disease is progressing in them,” says Megan, “but they are doing quite well, all things considered.” She hopes that they will be eligible to join Abeona's trial later in the year.

The progress in finding treatments for rare diseases continues to rely on foundations such as Megan's. “There is a community of kids that needs treatment, and we are close to having something for them,” Megan says. “A little bit of focus on research in this area is going to make a big difference to a generation of patients.”