Building a Bridge Between Rare Disease Patients and the Technologies that Could Help Them

In recent years, whole genome sequencing has made it easier to diagnose rare genetic diseases while scientific advances have put individualized treatments within reach. Yet, the regulatory processes, typically designed for large-scale drug production, are lagging behind. This, combined with limited funding and a lack of awareness, makes it painfully difficult for people with rare diseases to access the life-saving therapies they so desperately need. Julia Vitarello is hoping to change this.

Mila’s story

Ten years ago, Julia had very little knowledge of genetic diseases, she also had no idea how quickly this would have to change. Her daughter Mila was a typical child for the first few years of her life. Growing up in Colorado, she was skiing by the age of two, was very bright, and was always the center of attention.

However, at around four years, old Mila’s parents noticed that she was becoming clumsy, her feet had started turning in, and she was also getting stuck on her words and beginning to have vision problems. What followed was more than two years of appointments with doctors and specialists who said she would grow out it.

Eventually, with Mila’s condition declining rapidly and nowhere else to go, Julia took Mila to the emergency room at Children’s Hospital Colorado. MRI scans showed mild cerebral and cerebellar atrophy and 24-hour electroencephalography revealed subclinical generalized seizures. Laboratory tests for mitochondrial or metabolic diseases all came back negative until a skin biopsy showed abnormal lysosomal inclusions in a swirling fingerprint pattern that is typical of Batten disease.

Genetic testing then identified a known pathogenic mutation for Batten disease in the CLN7 gene, confirming the diagnosis. “There were twenty-five known cases in the world at the time,” says Julia. “I went from being scared to really scared and then also relieved that there was an answer. It felt like if there was an answer, I could do something about it—a little naive at the time. Then I was levelled once I started learning what Batten disease was and that no kid had ever lived.”

Receiving the diagnosis was only half the story though. Batten disease is an autosomal recessive neurologic condition that needs two mutations to manifest but only one had been found. Julia knew that she had to find the second mutation. “I was very, very driven to figure out what the other mutation was, so I could fully test my son because I was afraid of testing and only getting half of an answer. Every single day I looked at him I thought I was going to lose both of my children,” she says.

Finding the second mutation required whole genome sequencing (WGS), which was not readily available at the time. One laboratory at Harvard had a 5-month wait and a cost of $25,000. Julia was therefore looking for ways to speed up the process. In January 2017, she put a post on her Facebook page asking for help, which was shared to a physician mom’s group and ultimately found its way to Timothy Yu, MD, PhD, a neurologist in the Boston Children’s Hospital Division of Genetics and Genomics. His lab had extensive experience using WGS and a particular interest in looking for mutations that cause neurologic diseases.

Within 24 hours, Yu contacted Julia and said that he would sequence Mila’s blood. After weeks of searching, his team eventually found a small section of genetic code, known as a retrotransposon, inserted at intron 6 of the CLN7 gene in both Mila’s and Julia’s DNA. Mila’s brother had neither mutation and was not at risk of developing the disease.

When Yu shared this information with Julia, he also had a proposition. He knew that the retrotransposon caused a problem with gene splicing, the process that removes non-coding introns from the DNA before it is translated into proteins from mRNA. This meant that Mila’s body was unable to make functional CLN7 proteins.

Yu thought that he could design a personalized drug called an exon-skipping antisense oligonucleotide (ASO) that would fix the aberrant splicing and restore CLN7 expression. ASOs are short segments of artificial genetic code that are complementary to the RNA. They can work by either modulating splicing to restore normal protein production or by silencing mRNA and decreasing protein overproduction.

Around the time of Mila’s diagnosis, the U.S. Food and Drug Administration (FDA) approved an ASO drug called nusinersen (Spinraza) for spinal muscular atrophy (SMA), a rare disease in which the motor neurons waste away, causing muscles to weaken. It works by changing the splicing pattern of the SMN2 gene so that it can stand in for a mutated SMN1 gene. Nusinersen was a success story for people with SMA, being administered to over 10,000 children so far, and Yu reasoned that he could use the same splice modulating approach to treat Mila.

In the spring of 2017, Yu and team began designing and testing exon-skipping ASOs for Mila’s cells. They found that one candidate, which they named milasen, trebled the ratio of normal to mutant splicing and restored lysosome function. It consisted of twenty-two nucleotides and had the same backbone and sugar chemistry modifications as nusinersen.

By December 2017, manufacturing had been established and Boston Children’s Hospital applied to the FDA to test milasen as a Single-Patient Compassionate-Use Investigational New Drug without first showing its efficacy in animal models of Batten disease as these did not exist for Mila’s mutation.

Meanwhile, Julia set up the not-for-profit Mila’s Miracle Foundation and had been working relentlessly to raise money to help find a treatment for Mila, whose condition was getting worse. “She said her last words to me, she lost her vision completely, she started choking on her food, she was starting to not laugh and smile as much, and she started to have visual seizures that got longer and more intense,” Julia recalls.

When the FDA granted official permission for milasen to be used as an investigational medicine in January 2018, it set a new precedent. The agency had previously allowed existing drugs to be repurposed for seriously ill patients with no other options, but the compassionate use pathway had never been used to test a brand-new drug created for a single patient. Mila received the first of nine escalating, biweekly doses of milasen, given under general anesthesia at the end of January. These continued through June 2018. In August 2018, she received her first maintenance treatment, given every two to three months.

In the first year of treatment, Julia saw improvements in Mila. The frequency and length of her seizures greatly reduced, often to none or just one brief seizure per day, she was eating by mouth again, her legs were stronger, and she was laughing and smiling more. Importantly, she did not experience any treatment-related serious adverse events. Mila’s condition was relatively stable in the second year of treatment, but in the third year she slowly began to decline. Mila passed away in February 2021, at age ten.

“We started the treatment to try to stop her disease and that was the goal of it,” says Julia. “Initially it did just that, but over time, it was clear that too many dominoes had already fallen by the time she began treatment.”

Julia wakes up every day to face life without her daughter by her side, a sadness she doesn’t know how any parent can bear. But she says she feels a huge sense of opportunity and responsibility to turn Mila’s story into an entirely new treatment pathway for individualized medicines. “I feel like I owe it to the millions of children and families who will follow Mila to do whatever I can to keep the momentum going for individualized medicines. This potentially mainstream approach to treating genetic conditions could really help solve the massive global health crisis of rare disease.”

A global problem

There are over 10,000 rare genetic diseases with a known molecular basis, affecting more than 30 million people in the U.S. alone. Yet, approved treatments are available for only around 5% of them. The rarity of the conditions means that it is often not economically viable for drug companies to develop treatments.

Julia finds this incredibly unethical as she rightly points out that science is no longer the barrier to producing treatments for many rare disease patients. Rather, “every aspect of finding patients to designing the medicines to getting them approved and then reimbursed is going to have to drastically change,” she remarks.

She uses a bridge analogy to describe the scale of the problem, with millions of children with rare diseases on one side of the Grand Canyon and an increasing number of technologies able to treat them on the other side. There are two bridges to reach the treatments, the first is a large highway that can accommodate many people, but you can only cross it on busses reserved for large groups of patients with the same commercially viable disease. The second is a small rickety bridge built by highly motivated parents capable of raising millions of dollars and lucky enough to find a similarly motivated physician. Most children with rare diseases are unable to cross either bridge.

“When you know that just Mila’s approach [ASOs] could help tens of thousands of dying children alone, and soon gene editing and RNA therapeutics will offer hope to exponentially more, the urgency and demand to build an entirely new bridge for individualized medicines becomes a moral imperative,” says Julia.

Meetings in 2022 between Julia and Dan O’Connor, PhD, deputy director of the MHRA’s Innovation Accelerator at the time, Parker Moss, chief commercial and partnerships Officer at Genomics England, and Matthew Wood, PhD, director of the Oxford-Harrington Rare Disease Centre in the U.K., helped lead to the creation of what could be the first of these much-needed bridges in the form of the Rare Therapies Launch Pad.

Rare Therapies Launch Pad

The Rare Therapies Launch Pad was officially announced by the U.K. Government in November 2023 as a pilot program that that will develop a pathway for children with rare conditions to access individualized therapies.

The first project will explore the use of ASOs to treat children with ultra-rare and life-threatening neurologic conditions. It is being developed by a consortium that includes Genomics England, the MHRA, Oxford-Harrington Rare Disease Centre, EveryONE Medicines, Mila’s Miracle Foundation, the Association of the British Pharmaceutical Industry (ABPI), and the Yu Lab at Boston Children’s Hospital.

The group will work to identify a sustainable and scalable approach to delivering individualized therapies via a risk proportionate regulatory pathway. This pathway will cover diagnosis, the design, development, and rapid manufacturing of these therapies, and treatment. The project also aims to generate evidence to help establish potential reimbursement for individualized therapies beyond the pilot.

The emphasis on proportionate is important. Rather than an attempt to cut corners, it is an acknowledgement that some of the current steps needed for regulatory approval for larger populations could be removed or substituted as they are not fit for purpose for the individualized medicine approach. It is not possible to rely on large numbers of patients to run clinical trials for evidence generation. Instead, regulators will need to utilize other tools and consider data extrapolation and iterative learning. The pilot will determine how this can be done without putting patients at undue risk. For example, requirements for multiple animal studies could be removed from the process, but the Rare Therapies Launch Pad will need to establish what is done instead and what aspects of the current pathway must be preserved, notes Wood.

He says: “The fact that ASOs have already been used in thousands of patients tells us that there’s actually a huge body of safety information that already exists.” Adding that “calibrating the risk that patients and families are willing to accept is also part of the equation.”

The pilot is expected to run for three years, with the first year focused on the concept and administrative side of what needs to be done. The second year should see the first patients undergoing treatment, explains O’Connor, who is now Director of Regulatory Policy & Early Access at ABPI. He stresses however, the importance of managing expectations: “It is a pilot, and unfortunately, it’s not going to offer every medicine for every patient at the current time. But the hope is that during the pilot, we will really be able to have this paradigm shift in terms of thinking about the regulatory and access pathway for these types of medicines. Then clearly, that’s a benefit to a much larger group of future patients.”

He adds that more pharmaceutical companies will be able to get involved as the pilot evolves, but first we must understand where the expertise and the scalability of industry fits within the pathway. “We understand where industry fits in the current model of drug development, but this is a completely new way of thinking about developing medicines.”

The U.K. is an ideal place to start such an ambitious project. National infrastructure such as Genomics England, the U.K. Biobank, and the Nucleic Acid Therapy Accelerator are already in place. The NHS makes it easy to find and recruit patients for trials, and the regulatory independence gained by the MHRA following Brexit means that it can make its own decisions, taking a strong stance towards supporting innovative technology and science.

O’Connor says the Rare Therapies Launch Pad “really offers a great opportunity to strip down the essentials of the regulatory system. We’ve got the technology, we can find the patients, how do we now create a pathway to ensure that these patients have access to really potentially transformative and life-saving medicines? I can’t think of anything better to work on than creating something new that could offer patients with these really, truly high unmet medical needs an opportunity to have a therapy that they otherwise wouldn’t have access to.”

The project could ultimately offer a blueprint for gaining large-scale access to individual medicines.

Other pathways

In the meantime, many other organizations, such as the International Rare Diseases Research Consortium, the N=1 Collaborative, and the Western Australian LaunchR network, are seeking their own pathways.

EveryONE Medicines, a company co-founded by Julia and contributor to the Rare Therapies Launch Pad, is working to show that developing individualized precision therapeutics is commercially viable. The company is developing a platform-based approach to developing ASOs that will streamline the process, reduce time and costs, and make access equitable.

Irina Antonijevic, MD, PhD, chief medical officer at EveryONE Medicines, says that “so far, nobody has tried to change the regulatory requirements for developing individualized ASOs and that’s what we want to do. The regulatory discussions we have had clearly indicate that regulators understand that there has to be a change in how they approve these drugs because obviously there is no clinical trial and time is of the essence. We also work on reimbursement from insurers so that it’s not on the parents or the academic institutions to pay. Then if a drug is developed by us, accepted by regulators, and reimbursed, it creates a sustainable business where the reimbursement feeds back into the platform and so on.”

In 2019, The EveryLife Foundation for Rare Diseases estimated that the total economic burden of 379 rare diseases with a prevalence of 15.5 million people was $966 billion. Expanding access to treatments for these conditions could potentially lower this burden.

Taking a different approach is n-Lorem Foundation, a not-for-profit organization set up by Stanley Crooke, MD, PhD in 2020 to treat patients with “nano-rare” conditions (typically defined as conditions affecting less than 30 people), for free, for life.

Crooke has a long history in the field, being one of its earliest pioneers. In 1989, he founded Ionis, which is responsible for the discovery and early clinical development of nusinersen among others. Rather than settling for a quiet retirement, he was compelled to help families of children with diseases that were too rare to pursue at Ionis.

“It dawned on me that, in principle, the technology that we had invented was efficient enough that I could make a drug for their children and treat them and give it away for free,” says Crooke. “These families are being destroyed and we have the means in many cases to alleviate that misery and save them.”

To do so, he conducted discussions with the FDA, which authored guidance for the development of ASOs for severely debilitating or life-threatening diseases, that were published in 2021. These guidelines only apply to ASO medicines for a single patient and are not meant to provide a pathway for commercial approval.

As of March 2024, n-Lorem has had more than 260 applications to treatment, of which more than 120 have been accepted into the organization’s pathway. Nine patients have been treated. All that are evaluable are showing clinically meaningful benefits without drug-related adverse events, others are too early in treatment. Their data will be published when available, Crooke reports.

Despite all these efforts, Julia believes that not much has changed since Mila’s diagnosis eight years ago. “There are hundreds of different groups, all working in silos, academics, parents, companies, redoing the same process repeatedly with their data and learnings stuck in drawers and behind closed doors. There’s not much sharing and little willingness to drastically change the process in order to ensure access to treatments at scale. To me, measuring progress is pretty straight forward. It’s simply whether exponentially more children like Mila have been treated with this individualized approach to medicine, and the answer is no. We can do this, we are simply choosing not to and that is unethical. We have a moral imperative to build a new bridge to access treatments” she says.

Yet she is beginning to feel excited that there are more eyes on individualized medicines and some of the critical people, including regulators, are willing to sit at the table and begin building this bridge, which is in no small part due to the work she has done and continues to do.

“Mila’s story feels like the tip of the spear for making big change in how sick and dying people access treatments well beyond Mila, beyond Batten disease, beyond ASOs,” says Julia. “If I were to disappear, there’s a great relief knowing that individualized medicines are here and my daughter’s life is giving a future to millions of others like her.”

Read more:

1. answers.childrenshospital.org/milasen-batten-disease
2. Kim J, Hu C, Moufawad El Achkar C, et al. Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease. New Engl J Med 2019; 381:1644-1652.
3. Synofzik M, van Roon-Mom W, Marckmann G, et al. Preparing n-of-1 Antisense Oligonucleotide Treatments for Rare Neurological Diseases in Europe: Genetic, Regulatory, and Ethical Perspectives. Nucleic Acid Therapeutics 2022; 32: 83–94
4. globalgenes.org/rare-disease-facts
5. www.genomicsengland.co.uk/news/pilot-launched-to-support-children-with-rare-conditions-to-access-personalised-therapies
6. everylifefoundation.org/wp-content/uploads/2021/02/The_National_Economic_Burden_of_Rare_Disease_Study_Summary_Report_February_2021.pdf
7. www.nlorem.org/media/publications/fda-guidance

Laura Cowen is a freelance medical journalist who has been covering healthcare news for over 10 years. Her main specialties are oncology and diabetes, but she has written about subjects ranging from cardiology to ophthalmology and is particularly interested in infectious diseases and public health.