STEMATA Interview with The To Cure A Rose Foundation on CRISPR and Gene Therapies
Mar 24, 2023 | Video Transcript by Sophia Mai
Transcript:
Sophia: Hello! My name is Sophia Mai, and welcome to a STEMATA interview with Casey from the To Cure A Rose Foundation. To begin, can you briefly introduce yourself, your organization, and your goals?
Casey McPherson: Sure. My name is Casey McPherson and I am the founder of the To Cure A Rose Foundation. We build genetic treatments for children with ultra-rare neurological diseases.
Sophia: Thank you! To begin, can you briefly explain the function of the HNRNPH2 (Heterogeneous nuclear ribonucleoprotein H2) gene and some of the signs or indications that a child is developing a disorder related to this gene?
Casey: Absolutely. It’s a family of genes that’s responsible for our development. My daughter has it which is how I got into this in the first place and it has a set of about four different variants within the mutation. It is an allele-specific mutation so you're going to see it on one allele, so you'll have one healthy H2 gene and a mutant H2 gene and it’s often misdiagnosed or undiagnosed as an autism diagnosis or a CP(Cerebral palsy) diagnosis. And because it’s not on any of the panels in the states so you need to run a whole exome or genome sequence. Clinically the phenotype might look like a drastic developmental delay not being able to speak or losing your words, balance issues, CBI(Covert Brain Infarcts) issues, and sometimes seizure-ish issues. There’s a small malformation of the face so the eyes are a little bit further apart. Some of the children have problems with their feet. The boys are usually catatonic or wheelchair-bound, but for some of the girls, can be as wide as they can hold sentences and they are severely underdeveloped to catatonic and in a wheelchair and anything in between.
Sophia: Thank you. If possible, can you discuss any breakthroughs the foundation has made or has been able to fund since its establishment?
Casey: Yeah. So the problem with ultra-rare diseases is they’re not commercializable, and so we have technologies that can fix many of these diseases, we just don’t have the systems, and the pipelines, and the funding to do it. So when I started the foundation, I wanted to find a treatment for my daughter but use that path as a way to create a platform so that the next child with an ultra-rare genetic disease has a path. So what we did is we developed a cell line and a mouse model, the first in the world for Rose’s particular variant. Those are your toolbox and those assets will tell you a lot more about the disease. And you can work on understanding that disease in a dish, you can look at the phenotype in an animal, and you can use those animals and those cell lines to test drugs on. And the next step is we design in silico some potential RNA therapeutic designs utilizing the antisense oligonucleotide technology which is basically for those of you like me who aren’t scientists it’s a bandaid to convince your body to make the right protein or to not make a protein or to make more of a protein. And so in this case, what we’ve done is we’ve designed ASOs (Antisense Oligonucleotides). We started with a thousand different designs in order to knock down the expression of HNRNPH2 because what we saw in animals was if you did that it would elevate the expression of HNRNPH1 which is a gene that is 95% similar to HNRNPH2, and in mice when you do that it rescues phenotype. They have abilities that they didn’t have otherwise with this mutation. So we’ve designed those we’ve shortlisted them down to about 20 different designs and we are in the middle right now to shortlist our favorite five and they’re working in Rose’s cells. So we’re seeing those expression changes and our hope is that we can take those five into the Rosie mice that we made which are just mice with Rose’s particular mutation CRISPRed into the mouse and we want to see if we can rescue phenotype in those “diseased” models in which case then we will be able to file an IND (Investigational New Drug Application) and take it to the FDA (Food and Drug Administration).
Sophia: How do scientists identify the specific mutated genes responsible for HNRNPH2 and similar diseases?
Casey: The way that we identify these genes currently is by doing a whole genome or a whole exome sequence. So if a family is seeing symptoms in a child like they are not meeting their developmental milestones or strange symptoms that a doctor is not able to diagnose then at this point you can do an entire genome sequence relatively affordably even though insurance doesn’t cover it. So something I suggest anybody should do on all of their children and even yourself is to do a whole genome sequence to find out what mutations you have, what variants you have, it just gives you more information about your health but that’s how you find the mutations.
Sophia: Can you explain why HNRNPH2 and similar diseases are so rare and difficult to cure despite our current advancements in gene therapies?
Casey: The primary reason is money. Our current model is that our pharma companies are usually venture capital-backed and when you look at drugs they are built around intellectual properties. They are products and so in order to make money you need a drug that affects a lot of people. This is how the business model of drug development is, and the more people you can affect with this drug the more money this company will make. What we’re seeing with genetic diseases, which most of them are rare genetic diseases and many are ultrarare, is that if they fall at under about a thousand diagnosed patients and even more than that, they don’t make as much money. So that’s one problem, the other problem is that FDA regulatory requirements work on these large disease indications they don’t work on these smaller disease indications. To give you an example, when I file an IND (Investigational New Drug Application for Rose’s drug, which means I have requested the FDA to approve a new drug, they are going to require a talk study which is typically done in animals. That talk study that they require me to do for a drug just for Rose is around a million dollars. It’s the same cost that it would be for a disease with ten thousand kiddos. And there’s a bunch of other things like that in the FDA, manufacturing is another one. In order for me to manufacture this drug in a GMP-like (Good Manufacturing Processes) environment, so that it’s safe for humans, I have to use a facility that manufactures tons and tons of drug content. And so I use a beer example, it’s like hiring a Budweiser plant to make you a homebrew. So you can imagine the cost of that. We have the technology to cure these diseases but we don’t have the systems in place to do it in the affordable way which we totally could.
Sophia: What do you find most rewarding about working towards finding a cure for HNRNPH2?
Casey: I guess two things, one is I want to save my daughter. She lost her ability to speak. She can’t play with any kids. I would love to see her maybe play again. I’d love to see her maybe find a skill that she loves to do. I’d love to hear her say dad again, but she never will unless we create a genetic treatment for her. So that’s one very rewarding thing is it gives me hope for my daughter. The other is that this is the space if we can cure one child, we can cure a million meaning that if we’re creating platforms and systems through the work we’re doing for Rose it means I’m going to make it easier for the next Rose that’s born with her disease and the next Rose that’s born with a completely different disease that’s amenable to one of these technologies. For me, if I think about dying on my deathbed what did I leave this planet knowing the work that we’re doing now is going to save literally, my belief is millions of children's lives in the future then I feel like I’m doing something worth it.
Sophia: How did you discover that music was a way to connect with your daughter, and what was your initial reaction?
Casey: So I was a professional musician before I did any of this and I had a couple of hits and a video on VH1 and toured the world and did all that but I gave all that up to pursue this for Rose. And when I would sit down with her, especially in the evening right after bathtime, and play for her, her eyes would stop darting she would start focusing on me she would start smiling and giggling. We can’t talk to each other she doesn’t communicate as a neurotypical person does and so when I play we become connected. As a dad, that’s huge. When you have a special needs child that can’t connect with you or an autistic kid that can’t connect to you, you feel very alone and you know that child feels very alone at least that’s a pretty good guess so it’s a moment that neither of us feels alone and now my performances are for her. She’s my fan club of one and I’m her fan club of one.
Sophia: Finally, what advice do you have for families that have a child or family member experiencing this?
Casey: I would say that knowledge is power. If your child is autistic or shows some strange symptoms that are getting blanket diagnoses, they are not biological diagnoses, where they’re running a test and saying this is your problem, then I can’t stress this enough to go get a genome sequence. It cost me ten thousand dollars at the time now you can do it for as little as a few hundred bucks. Insurance usually doesn’t cover that yet but I suggest getting that and then talking to people like me and others. I run a lab now for children with rare genetic diseases, so families can actually begin to build these treatments for their kids without having to beg an academic institution or hope that a pharma company is going to do it so the time is now to find out and to start working on a treatment.
Sophia: That's all I have for you today. Thank you so much for your time and responses! It was great being able to talk to you about this rare disease, and I hope people found value in this interview.
Casey: Me too. Thank you for having me.
Sophia: Thank you again, and I hope you have a great rest of your day!
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