It’s Monday. It’s still Rare Disease Day.

Today is Monday. One day after Rare Disease Day, and we are still thinking about the 400 million people affected by rare diseases - the children, adults, their families, and those who may have only been recently diagnosed. We know that many of you feel that the healthcare system as a whole has failed you. Less than 5% of rare diseases have approved treatments[1]. We also know that many of you are working hard to change that statistic. Every Monday - whether or not it’s the day after Rare Disease Day - marks the start of another week and a chance to tackle these challenges, broadening our perspectives on the hurdles we face every step of the way.

On Rare Disease Day in particular, the borders that define the thousands of rare diseases dissolve. We take this opportunity to look beyond the diagnosis that makes us think of our community as only a handful of patients. We can continue to recognize that collectively, being diagnosed with a rare disease is not rare at all. Rare Disease Day or not, if we continue to look across rare disease communities, we might find synergies to discover and develop therapeutics in places we did not know existed. 

The borders that define the thousands of rare diseases dissolve.

A Few Big Challenges Over 7,000 Small

If you haven’t read my story, in 2015 I was diagnosed with neurofibromatosis type 2, or NF2, a rare disorder in which tumors grow from the cells surrounding neurological nerves that control my hearing, balance, and movement. A genetic mutation affecting these types of cells predisposes them to form the tumors. Through a series of connections, some luck, and a lot of determination from the NF2 research community, we identified and repurposed an mTOR inhibitor drug that has stabilized my brain tumor now for over a year. Although I had already lost my hearing on the left side, this drug has helped me save my hearing on the right, at least for the last 365 days, and for the foreseeable future.

This class of drugs [mTOR inhibitors] are currently approved for a number of indications, such as kidney and liver transplant rejection, and for women with breast cancer[2]. To my own surprise, since I started taking the drug, I have met several patients with other rare diseases that have been using the same drug, such as David Fajgenbaum who has Castleman disease, a rare disease that affects the lymph nodes. He has written about his experience with the drug in his book Chasing My Cure. Success stories in drug repurposing are showing that the solutions for one problem are often found through success in other diseases. I believe this is the future of rare diseases, and we are going to see many examples of applications across rare diseases beyond drug repurposing[3].

Untapped Potential to Learn From Each Other

Examples like this have made me a big believer in the power of new ways to look at rare diseases. For example, I have NF2 but I also have “Schwannoma tumors”. I benefit from an mTOR inhibitor. I have a stop-codon mutation affecting tissues in the central nervous system. What if there’s a technology that can help with the stop-codon mutations in these tissue types, and who else might benefit from it? I have met and connected with people with whom I share one or more of the above classifications, and these connections make me realize the opportunities for all of us. 

Together, we are looking beyond the limits of diagnosis and creating a platform driven approach that bridges the gaps between isolated rare diseases and will help us to identify the fastest path to potential treatments.

At Rarebase, we’ve been working with a diverse group of patient foundations, families, clinicians, scientific researchers, pharmaceutical companies, and biotech partners to increase the odds of these synergies to emerge. Together, we are looking beyond the limits of diagnosis and creating a platform driven approach that bridges the gaps between isolated rare diseases and will help us to identify the fastest path to potential treatments. What works for one, could work for many.

From n-of-34 to n-of-thousands

Amber Freed, the founder of SLC6A1 Connect, learned that her son was one in 34 children with a rare neurological disorder caused by a mutation on his SLC6A1 gene. At the time of diagnosis, Amber was told it was incurable. But when she started to dig deeper, she learned that it just hadn't been researched. By looking into genomic databases at Harvard and MIT and the NIH, she discovered that the prevalence of reported SLC6A1 genetic variants was one in 38,000[4]. Although not everyone with a variant has the disorder, the disorder is very likely underdiagnosed. She learned that SLC6A1 is the tenth largest cause of autism, the sixth largest cause of epilepsy, and that it plays a major role in schizophrenia. “Because the SLC6A1 gene also is associated with autism and schizophrenia, [the drug makers] believe the market for this type of gene therapy could be bigger than just patients like Maxwell”[5], Amber says. 

A Community of Communities

Dr. Terry Jo Bichell entered the rare disease community after her son was diagnosed with Angelman Syndrome. Determined to find a cure, she enrolled in graduate school to get her PhD in neuroscience and later worked as a scientist for the Angelman community. Over time, she recognized that the fastest path to treatments would need to involve bringing together the knowledge and learnings of many groups focused on rare neurological disorders. In early 2020, she started COMBINEDBrain, a nonprofit consortium that has since grown to over 13 patient foundations. For Terry Jo and her team, the idea is that many rare genetic neurological disorders will share similar biomarkers and outcome measures, so they shouldn’t have to reinvent the wheel in the drug development process. While each of the members are still focused on their individual disease area programs, COMBINEDBrain has created an opportunity for its members to share learnings and collaborate on therapeutic R&D more effectively. 

A Platform Approach To Developing n-of-1 Treatments

The last few years have brought major advances in the development of antisense therapies (antisense oligonucleotides or ASOs). ASOs are short strands of modified DNA designed to bind with RNA and halt the process of creating a protein that causes a gene abnormality. They are highly targeted and can be developed relatively quickly and inexpensively. With the approval of Nusinersen for Spinal Muscular Atrophy in 2016 and the development of the first n-of-1 ASO, they have more recently been used as a platform to develop treatments for single patients across many different disorders. The opportunity for technologies like these, sometimes pioneered in a single patient, is to discover the cases in which they work and therefore become a platform to treat many.

Breaking Down Barriers to Rare Disease

For millions of people, it’s Rare Disease Day every day of the week. We come together to find a way to treat rare diseases as a few big problems rather than thousands of small ones. The reality is, it is still the early days for rare disease. We’re likely going to see huge technological advances in the next few decades. There are many examples out there of people trying to build synergies and cross connections. However, as we all know there’s more to be done. If we want to make a leap forward, we need the therapeutic technology as well as the infrastructure to be able to implement it. As a community, we can keep improving the infrastructure by building more networks and equip them with the appropriate research tools and data. 

When our team works with patient communities and families on therapeutic discovery and development, we are always looking for opportunities across rare diseases. What type of mutation does someone have? What organ system is involved? Which targetable pathways may be involved? Anything we learn from one disorder, or the infrastructure we build for another disorder, can easily be applied to any others. In order to capture these ideas and learnings from other cases, we don’t limit ourselves to one “rare disease” label. The future of rare disease is finding and taking advantage of new correlations and crossovers that will ultimately create a path forward for everyone.


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