RARE Daily

A Next-Generation RNA Therapy Targets Telomere Disorders

March 2, 2023

Telomere biology disorders are a set of rare genetic diseases caused by a shortening of the protective DNA that appears at the ends of chromosomes. Between 80 and 90 percent of people with these conditions will suffer from bone marrow failure by age 30, the leading cause of mortality for people with these disorders. The only available treatment today is transplantation of donor human stem cells. Elixirgen is developing what it calls self-replicating RNA therapies to treat telomere biology disorders and other conditions. We spoke to Akihiro Ko, CEO Elixirgen Therapeutics, about telomere biology disorders, the company’s self-replicating RNA therapies, and the advantages this new therapeutic approach offers over more traditional mRNA therapies.

Daniel Levine: Aki, thanks for joining us.

Akihiro Ko: My pleasure. Very nice to speak with you.

Daniel Levine: We’re going to talk about Elixirgen, it’s next generation RNA technology, and its efforts to develop a treatment for telomere biology disorders. Perhaps we can start with the limitations of existing cell and gene therapies. What would you say those are?

Akihiro Ko: Thank you, Danny. Yes, the field of cell and gene therapies is extremely wide, of course. So, I think as a growing and expanding field, there are many places that can still be addressed, and many different solutions for many different existing problems. And so, the potential for cell and gene therapies for these new treatments for suffering patients is extremely high. This is something that I’m very positive about. And to give some examples, concrete examples of some current limitations would be potential trade-offs that you see with the different vectors that are being used for delivery, for trade-offs regarding logistics when you’re using your own cells or donor cells for autologous or allogeneic cell therapies, for example, which genes are being targeted and which targets are being addressed. All of these, I think, have room for improvement. For example, for autologous gene therapies they’re often shipped to a separate location for manufacturing. And so there are some shipping and logistics issues that have historically existed. So now, with the field expanding towards more allogeneic allograft therapies, there’s a different set of trade-offs.

Daniel Levine: Elixirgen has developed what it calls self-replicating RNA or c-srRNA technology to address these challenges. What is c-srRNA, or let me try that again. What is c-srRNA and how does it work?

Akihiro Ko: c-srRNA stands for controllable self-replicating RNA, c-srRNA, and self-replicating RNA has been known for decades at this point, and it’s known for potentially stronger and longer expression than traditional mRNA. And as with everything, there are some nuances to this, of course. Now c-srRNA, why is it controllable self-replicating RNA? It’s a unique type of self-replicating RNA based on the Venezuelan equine encephalitis virus, a single stranded positive sense RNA genome virus. And it is controllable in that it is temperature controllable. So, the expression is optimized and on at 32-35 degrees Celsius, and it’s inactivated at 37 degrees Celsius and above. And we use these features to turn protein expression on and off, ex vivo and in vivo. And there are many strengths and ways to use this, but to pick one for illustrative purposes, we would be using this ex vivo to tune and control protein expression to make it transient expression, is one way to do so. We do this by lowering the temperature of the cell incubation to produce protein, and then raise it to inactivate that expression. And c-srRNA has additional viral proteins as well, particularly RNA-dependent RNA polymerase, which is also turned off with this mechanism. So, by the time the cells go back into the patient’s body in this scenario it’s already turned off. Thus, it is both a safety feature, and it’s also an efficacy feature that makes c-srRNA unique.

Daniel Levine: The company has also developed stem cell therapy platform technology. What’s the significance of this technology?

Akihiro Ko: Yes. The stem cell therapy platform is referred to as ZSCAN4 therapy. ZSCAN4 is a very special gene whose functions were discovered by our scientific co-founder, Dr. Minoru Ko, at the National Institute on Aging at the NIH. And it was originally discovered when he was researching embryonic stem cells. And it’s a specific gene that’s rarely but highly expressed at time points that are critical for the genome during human development, particularly for stem cells. And at these time points ZSCAN4 stabilizes the genome, it corrects karyotype, it can repair DNA damage, renew aging stem cells, and extend their telomeres. So, these sound like some very highly applicable features for major implications in therapy for many kinds of diseases. And we’re focusing on the telomere extension aspect for a proof of concept for this. So, this stem cell therapy platform, ZSCAN4 therapy, is using the functions of ZSCAN4 and controlling the expression with c-srRNA.

Daniel Levine: Well, let’s talk about telomere biology disorders. What are these?

Akihiro Ko: Telomere biology disorders are characterized by short telomeres and accelerated shortening, resulting in cell loss or different kinds of dysfunctions. And the most severe phenotype is called dyskeratosis congenita and in some cases, mutations in genes involved in telomere maintenance have been found as the reason for this.

Daniel Levine: And how do these conditions manifest themselves and progress?

Akihiro Ko: Telomere biology disorders are a very complex type of condition. And short telomeres themselves can manifest in many different ways and in many potential cells in the body. But I would like to highlight in particular, the hematopoietic stem cells found in the bone marrow. So hematopoietic stem cells or HSCs, when they are suffering and affected by short telomeres, can lead to blood cell deficiencies. You start to lose the ability to produce new blood cells and for telomere biology disorders with the short telomeres, there’s also a cancer risk. This is also something that is potentially worse in children. And in one example, 80 percent of patients had bone marrow failure by 30 years old, which is a critical condition.

Daniel Levine: How are patients with the disorder generally diagnosed?

Akihiro Ko: There are some physical manifestations that are classic, but it’s also not always guaranteed that those are there as well. And the major clinical feature that is noticeable, and we’re focusing on, is the bone marrow failure. And there are also genetic testing that is involved with diagnosis.

Daniel Levine: How are patients generally treated once diagnosed with the condition, or what’s the prognosis for someone who has it?

Akihiro Ko: There are supportive therapies with side effects, but the only cure is hematopoietic stem cell transplant from a donor. However, the procedure comes with some very serious side effects, both upfront and later on. And one example is when something called pre-conditioning is done, which is to effectively destroy the existing bone marrow stem cells to make room for the donor’s hematopoietic stem cells. Some reduced conditioning methods are being tested, but this preconditioning for patients with fragile cells can be potentially quite damaging. There’s also some immunosuppression that must be done post-transplant, and I think all of that, in conclusion, means that safer or gentler therapy is needed and desired.

Daniel Levine: EXG34217, this is your lead candidate. This is an autologous cell therapy. How does it work?

Akihiro Ko: I think you know, Danny, you understand this of course, but for potentially the listeners, this is autologous, meaning your own cells as opposed to a donor’s, of course. And in a nutshell, we collect a portion of the patient’s hematopoietic stem cells from their blood, treat them with ZSCAN4, and then give them back to the patient. And the whole process is 28 hours inpatient, roughly. So, I think a relatively short process. And maybe to give that some detail, if we go further in depth, we’re expressing ZSCAN4 in a transient manner, which is how it works in nature to extend the patient hematopoietic stem cells as telomeres. And since this is a short telomere disease, this is addressing the root cause of the issues for these patients. ZSCAN4 is inactivated using temperature control and then returned to the patient. Some safety features are also involved in this. There’s no pre-conditioning. The vector has no genome integration. And then the temperature control safety switch inactivates the vector within days. There’s also no post-transplant immunosuppression. So, this is what we believe is safety focused and safety first, and designed for patient safety, which is how we originally sought to apply this therapy. And this all takes place onsite locally at the clinic. So, it’s performed on a tabletop cell processing machine called the CliniMACS Prodigy by Miltenyi. And the cell incubation and culture takes place in a functionally closed tubing system and no open air culture is used. The system’s also automated and that can reduce potential human error and increase ease of use.

Daniel Levine: That’s interesting. Most people think of autologous therapies as being very costly and time complex and difficult to scale. How does having this type of bedside approach change what it might mean in terms of costs and speed of delivering these therapies?

Akihiro Ko: That is a great question. And so, how we’re currently using this and how we ourselves are seeing this is in a clinical trial, so there’s some extra steps, of course, but the dream is to make this a point-of-care autologous therapy using ZSCAN4 and controllable self-replicating RNA. And there are some manufacturing and scaling considerations for this.

Daniel Levine: And once the cells are prepared, how are they delivered to the patient?

Akihiro Ko: Since this is done locally and in the clinic, the cells are simply infused back to the patient after the procedure is performed on site. And the process is streamlined for the technical people that are actually doing this due to the automation from the cell processing equipment, and also the function of ZSCAN4 itself. So, it is performed in an entirely functionally closed tubing system. There’s no open air cell culture and there are no shipping logistics that are involved with this. And so, it’s a much simpler procedure. And furthermore, for c-srRNA specifically, the biosafety level requirement is lower since it’s simply RNA. It’s not like a viral vector such as an adeno-associated virus or lentivirus. And this ultimately leads to what we believe to be a scalable cell therapy. And one direction that we are looking into right now is developing micro GMP suites that would help facilitate cell therapy administration. We recently signed a memorandum of understanding with Hitachi Global Life Solutions to go further into this direction. And we think that developing this could lead to improvements in logistics, reduced timelines for cell therapies, and better scaling, which would ultimately lead to cost savings, better patient outcomes, and accessibility.

Daniel Levine: What’s known about the safety and efficacy of the therapy from studies that have been done to date.

Akihiro Ko: So, this study is still ongoing, but our principal investigator presented a case study at ASH last year showing a good safety up to nine months and two things, two facts that could be considered the first ever for these patients. So, the first is that the hematopoietic stem cells returning to the patient had 1.24 fold increase in telomere length after treatment with ZSCAN4. So, we learned that ZSCAN4 did indeed extend telomeres for this patient’s HSCs going back to them. And then second thing that is potentially first ever for these patients and these cells—the second is, this is preliminary, but telomere flow-FISH suggests potential emergence of a cell population with longer telomeres in the peripheral blood. So, this would mean that the treated HSCs with longer telomeres potentially created blood cells that also had longer telomeres, which is, again, addressing the heart of the problem for telomere biology disorders. So, with these two promising data points, we are cautiously optimistic.

Daniel Levine: What’s the development path forward?

Akihiro Ko: Going on for this, we are looking to continue this trial for these patients, of course, and then also continue to expand to additional diseases that can also be helped with ZSCAN4 of which there are many.

Daniel Levine: The shortening of telomeres is associated with aging. Elixirgen is also developing therapies for age-related diseases. Is it understood the role the shortening of telomeres play in aging, or is this just an observed effect?

Akihiro Ko: Let’s talk about the general perception for this that telomeres and aging have a long history and lots of publications and discussion, and there’s a correlation certainly to telomere length and aging. And as we age the cells’ telomeres do get shorter as a fact. And we can kind of look at some interesting examples such as in centenarians, where some reports that people who live longer have been shown to have longer telomeres than their peers. So, there are some hints for this and this is a huge field, so I can’t even begin to get into this. But there is a correlation.

Daniel Levine: Ultimately, how broad a potential do you see self-replicating RNA having to treat other diseases?

Akihiro Ko: For self-replicating RNA, and in our case, our controllable self-replicating RNA. So, controllable self-replicating RNA, you could compare it to the potential of messenger RNA, which people have been excited about the potential of messenger RNA towards all sorts of indications. And you can consider that c-srRNA can be applied to those as well, being a next generation RNA platform with the control and safety features.

Daniel Levine: Akihiro Ko, CEO of Elixirgen Therapeutics. Aki, thanks so much for your time today.

Akihiro Ko: Thank you, Danny.

This transcript has been edited for clarity and readability.


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