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Straightening the Winding Road for Rare Disease Odysseys

An interview with Ethan Perlstein, CEO of Perlara

Straightening the Winding Road for Rare Disease Odysseys

There are over 6,000 rare human diseases that affect virtually every population in the world, and the majority of these have genetic origins. We sat down with Ethan Perlstein, Ph.D., CEO of Perlara, a scientific discovery public benefit corporation, to learn more about their unique approach to discovering personalized treatments for rare conditions.

What is Perlara and what is its mission?

Perlara is a global patient portal and drug discovery platform for families affected by rare disease. Not only is there a large, unmet need in the rare disease space, but also it’s a perfect place to embark on a new way of doing science and business. With rare conditions, there’s a high level of personal involvement from affected families combined with the ability to unravel the genomic, cellular, and physiological basis of complicated conditions. We’re a public benefit corporation and we want to really follow through by partnering directly with patients and do drug discovery beginning with the individual family.

Perlara’s approach is to create complete, personalized disease models of rare conditions and then use these to screen potential therapeutics. How does this work?

Rare conditions are complex and have many symptoms, but are often caused by changes in a single gene. We start by making models in simpler animals like worms or fruit flies, with the goal to create “avatars” for every gene change that exists in actual patients. The mutation-matched models exhibit cellular and physiological defects in common with the patient, and are used to screen potential precision drug candidates. We first partner with patient advocacy groups and then partner in pharmaceutical companies to advance these candidates to the clinic. It’s our hope one day to look at the patient registry in real time and clone genetic changes into models and then have them at the ready, closing the gap between the diagnostic and drug discovery odysseys.

The first conditions you are focusing on are Niemann-Pick C (NPC), a metabolic disease, and N-glycanase 1 deficiency (NGLY1), responsible for a host of developmental delay issues. How and why did you choose these conditions?

We started with NPC because a lot of research has gone into that disease, and there’s a strong advocacy community. NGLY1 was a different story that I think is coming to typify rare disease in the internet age. Families that would otherwise have no contact can now connect with other families affected by the same disease because of social media. NGLY1 fit the mold of working with families that are completing their diagnostic odyssey and realizing they have a whole other odyssey ahead of them. There are other important differences: while NPC is rare, NGLY1 is known in fewer than 100 patients. So if Perlara’s platform was going to truly work for rare conditions, it had to also work for the ultra-rare cases.

Which advances in genomics would move Perlara’s vision forward in meaningful ways?

The magic wand of genomics that I would want to have first is to make genomic reporting a standard, data-friendly procedure. For rare cases where you’re figuring out the genetic changes for the first time, you have to eliminate a lot that ends up not being responsible. It would also be useful if there was an automatic pipeline for assessing gene changes in animal models, which is not trivial-- so that once you get a sequencing report, you’ve got disease models at the ready to start finding leads for therapies.

Where do you want to see Perlara’s progress a year from now?

We would like to show that we’ve gone from building models to finding new lead compounds for two separate diseases. For NPC, we want to see a therapeutic candidate heading somewhere towards the clinic and, for NGLY1, we want to have repeated the model/screening process so we’re confident that our approach is reproducible. Including NPC and NGLY1, we have six disease programs in the Perlara pipeline and a year from now, we expect that number to double.

In the future, we want to develop capacity to perform genetic screens with our animal models to identify new mutants and targets that will complement rare disease discovery efforts especially as human genome sequencing becomes more prevalent.

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