Reaching Beyond the Limits of Enzyme Replacement Therapies with Gene Therapies

December 30, 2022

Though enzyme replacement therapies have proven a viable strategy for treating lysosomal storage disorders, one problem is that these medicines face challenges reaching all of the cells throughout the body that are affected by these conditions, particularly in the brain. Avrobio is developing one-and-done gene therapies to treat cystinosis and other lysosomal storage disorders to overcome the limits of ERTs and possibly halt or reverse diseases. We spoke to Geoff MacKay, president and CEO of Avrobio, about cystinosis, the company’s gene therapy platform, and how it’s leveraging its technology to develop therapies across a range of rare diseases.



Daniel Levine: Geoff, thanks for joining us.

Geoff MacKay: Oh, my pleasure—happy to.

Daniel Levine: We’re going to talk about cystinosis, Avrobio, and its efforts to develop a gene therapy to treat the condition. For listeners not familiar with cystinosis, can you explain what it is?

Geoff MacKay: Sure thing. Well, to begin with, it’s caused by mutations or deletions of the CTNS gene, and that’s a gene that encodes for cystinosin. So it’s a lysosomal disorder. You know, many, many listeners would know lysosomal disorders, but often it makes you think of an enzyme deficiency. In this case, cystinosin is a transporter protein. This is a protein that’s needed to transport cystine out of the lysosome. Absent this functioning protein, it translates into a quite serious progressive, in fact, life-threatening disease that causes multi-organ damage. We’ll get into it in a little bit, but just broadly, it leads to very serious acute kidney disease, which progresses at a pretty rapid rate to end-stage kidney disease. And one of the main issues with cystinosis is caused by an accumulation of cystine in the lysosomes. And what this leads to is a formation of cystine crystals. So, these are toxic crystals that build up across multiple tissues and organs in the body at different points in different degrees throughout the patient’s life. Untreated, a patient with cystinosis will die at quite an early age. I think life expectancy is into the thirties. It’s believed to impact thousands of patients worldwide. And if you limit the discussion to the U.S., Europe, and Japan, it’s estimated about 1600 patients in those three geographies.

Daniel Levine: How does the condition manifest itself and progress?

Geoff MacKay: Well, it is progressive, and as I mentioned, it’s life-threatening, and you really need to think of it as a systemic disease, meaning it impacts the entire body. And so it’s often thought of as a kidney disease, even though that’s really not true. It is a full systemic head to toe disease, but it’s thought of as a kidney disease because of the extreme early kidney damage. And it often starts with a loss of filtration in the kidney, which leads to chronic kidney disease and eventually end-stage kidney disease requiring a kidney transplant. And one of the more striking stats is that 90 percent of these kids will have a kidney transplant by the age of 20, and throughout their life, they typically will have multiple, or often have multiple kidney transplants. So, that alone gives you an idea of the severity of it. But there are other manifestations. One is visual complications, sometimes severe, and it’s caused by those same cystine crystals, but this time they accumulate in the cornea and you can actually see them in an individual with cystinosis. And what it leads to is photophobia and involuntary eyelid closure, but severe photophobia, so many individuals with cystinosis wear dark, thick sunglasses when they leave the house. And, for example, you could report pain from the light if you check your phone at night. So, you know that that’s yet another [manifestation]. So, kidney, visual, but then the list goes on and on: neuromuscular myopathy, hypotonia, tremors, swallowing, involuntary swallowing issues, and endocrine disorders beyond kidney—hypothyroidism, diabetes, infertility. So, it’s more than just those cystine crystals that accumulate, but that’s one of the key manifestations that really cascades through throughout the body.

Daniel Levine: How do patients generally get diagnosed? Is it something like the sensitivity to light that brings them to a doctor, or is it another symptom?

Geoff MacKay: Unfortunately, like a lot of rare diseases, they go through that diagnosis odyssey where they bounce from clinician to clinician and each of these clinicians, of course, would most likely have never seen a patient with cystinosis. So, often the diagnosis takes a long time. But over time, I think, generally they find themselves at a rare disease expert. And things like renal Fanconi syndrome, some of the kidney related issues, will eventually lead to a diagnosis of cystinosis.

Daniel Levine: And what treatment options exist today and what’s generally the prognosis for someone with the condition?

Geoff MacKay: Well, importantly, there is a standard of care—cysteamine, and cysteamine comes in both pill form and eyedrops. And the patients are required to take multiple, it could be 30, 40 pills a day of cysteamine and eyedrops, every few waking hours. So, it’s not ideal, but it really has been an important development for this community because what cysteamine has been shown to do is to slow down the progression of this pretty debilitating disease. So, it slows down disease progression, but it, of course, doesn’t stop disease progression, nor does it tend to reverse some of the manifestations. To say it more clearly, it won’t prevent renal decline. But one stat that was, that was referenced from a key opinion leader in cystinosis is that absent cysteamine, 90 percent of these kids would have a kidney transplant by the age of 10. On cysteamine, 90 percent of these kids would have a kidney transplant by the age of 20. So that sort of gives you an idea that it’s a very useful medicine, but certainly it doesn’t completely solve the unmet need. And we believe that there’s a lot more that can and needs to be done for this community. So, the kidney is one thing, but the crystals, as I mentioned, accumulate and they can address, or they can manifest in many different areas. Cysteamine has been shown to reduce the crystal accumulation, but not completely eliminate it across multiple parts of the body. So, as mentioned, it’s a treatment regimen that requires dozens of pills per day and carries side effects. And one of those side effects is breath and body odor and gastrointestinal symptoms. And that may seem trivial, but it translates into some compliance related issues.

Daniel Levine: Cystinosis is one of these conditions that I think people may not appreciate the daily burden of what it’s like to live with. Can you give a sense of what it’s like to live with cystinosis?

Geoff MacKay: I’ve had the opportunity to learn from members of the community about what it’s like to live with cystinosis. So, you learn by talking, but really by listening to the patient advocacy community and directly with families with cystinosis. And just to reference a few anecdotes, we know one young man who was, in fact, in our clinical trial and he spoke about how when he was on his standard of care cysteamine, he was taking up to 52 pills the majority cysteamine, but some additional medicines as well. So 52 pills a day to manage his disease. And he had intense GI issues and what that meant to him was that he was vomiting 13 times a day related not to the disease, but to the medicine. And so, you can imagine what that does to your quality of life. And this was the same gentleman that I referenced earlier who shared a story about struggling to check his phone at night due to the light sensitivity related to the accumulation of cystine crystals in his cornea. Another parent of a young child with cystinosis explained how their son, when he was six months old, started to vomit, lose weight, and failed to thrive. This is the example that I referenced earlier where very typically they bounced from doctor to doctor until they finally figured out it was cystinosis. And then at that time he was diagnosed and put on cysteamine tablets, and so, what they would describe is those days are just unpredictable. He has daily nausea, vomiting, fatigue. It’s also notable for its excessive thirst and a strict around the clock sort of medical medication schedule, whether it’s the eyedrops or whether it’s the pills that really take up a lot of, not only the young individuals themselves, but typically their parents as well, just to disrupt the schedule day and night, just to make sure that they’re compliant of their medicine. And then I mentioned a mother, but the parents, just referencing another mother, explained that the side effect of cysteamine can be medically explained as smelling like sulfur, but she says you really need to describe it as smelling like rotten eggs and that it can be so strong at times that it can fill a classroom. And so that paints a little bit better of a picture of what the impact is on a young kid and potentially the self-esteem, and as they get older, the compliance of the medicine, because it comes with these untoward effects.

Daniel Levine: Avrobio has developed a platform for manufacturing gene therapies. This is your plato platform that uses lentiviral vectors. Walk me through how this works.

Geoff MacKay: Sure. One of Avrobio’s differentiators is that when we started the company in 2015, we really wanted to solve the manufacturing bottlenecks to develop a pharmaceutical grade medicine that can be developed at scale and globally reach patients everywhere around the world. So that meant that we had to automate, roboticize, and close is sort of the technical manufacturing term, close the drug product manufacturing platform. So, we’ve invested massively over the last seven years and the culmination of that is what we call plato, which is our hematopoietic stem cell gene therapy platform, which we believe is the gold standard for this type of gene therapy, hematopoietic stem cell gene therapy. And just to explain it a little bit, the starting material for what we would call the drug product is mobilized peripheral blood, which is collected from the patient by taking their blood. We take the patient’s own blood and then we select a specific type of cell from the patient’s own blood called a CD34 positive cell. So, we can just think of that as a stem cell. We select out the patient’s own stem cells, which are transduced with our lentiviral gene therapy, and the goal there is to use the lentiviral vector to deliver the healthy functional gene that’s missing. These genetically modified stem cells are harvested, cryopreserved, and tested. And then once the healthy gene is integrated into the patient’s own stem cells outside the body, they’re then infused back into the patient. And the way that the mechanism is designed to work is once these gene modified stem cells, the patient’s own gene modified stem cells that now carry that healthy gene, are infused back into the patient, they do what they’ve been born and bred to do, the genetically modified stem cells will settle back down into the patient’s bone marrow where they will engraft into the bone marrow. And once they engraft into the bone marrow, they just follow a normal course where they will differentiate, meaning they will divide into the full blood lineage. And that’s really where the therapeutic effect comes from. These billions of now gene corrected stem cells distribute billions of blood cells through the body, head to toe. And the goal is that they will not only manufacture the active protein, but distribute the active protein into the full systemic parts of the body. That’s really the whole raison d’etre of hematopoietic stem cell gene therapy—to leverage the patient’s own hematopoietic stem cell lineage, the blood lineage, to be able to manufacture and distribute protein head to toe.

Daniel Levine: As you’ve mentioned, cystinosis affects cells throughout the body. This is one of the challenges in treating lysosomal storage disorders. What do you know about the ability of your experimental gene therapies to reach cells throughout the body and go where they’re needed?

Geoff MacKay: Well, this is really why we believe hematopoietic stem cell gene therapy is such a good match, or is so well suited to treat lysosomal disorders like, for example, cystinosis. And it comes down to the mechanism, [which] is that when the genetically modified stem cells settle back into the patient’s bone marrow, they differentiate into the blood cells and the various blood lineages. These billions of cells will continuously manufacture and distribute therapeutic protein 24/7. And not only do they manufacture and distribute protein on an ongoing basis, but they reach what we call hard to reach tissues and organs like the brain, which are critical for lysosomal disorders, pretty much all of them, but certainly including cystinosis. And so, the whole goal of hematopoietic stem cell gene therapy is to enable that true—what we call in layman’s terms head-to-toe—distribution of the corrected gene, and therefore make sure that you get that steady stream of active protein distributed through the body. So, we can do that a number of ways. I’ve mentioned the brain, but the other thing is that the hematopoietic lineage, of course, contains macrophage and tissue-resident macrophage penetrate deep into tissues and organs. And so, I’d say the really the sweet spot of hematopoietic stem cell gene therapy is when you need that full lifelong systemic distribution.

Daniel Levine: Avriobio’s developing a gene therapy to treat cystinosis. This is AVR-RD-04. How does it work?

Geoff MacKay: Yeah, we’re incredibly excited about our gene therapy for cystinosis. And there are many monogenic rare diseases where there are multiple genetic medicines, multiple gene therapy, gene editing approaches to our knowledge. This is the one and the only genetic medicine trial for cystinosis. So, you can imagine the pressure and the sense of responsibility that we feel at Avrobio to do our best to study this potential medicine as properly, as rigorously, as we can. The approach here is the same as what I just spoke of more broadly, that the investigational drug AVR-RD-04 genetically modifies the patient’s own hematopoietic stem cells outside the body to be able to express a functional version of cystinosin, which is the protein that’s deficient in people living with cystinosis. And as I said, we remove the patient’s hematopoietic stem cells, modify them in a state-of-the-art GMP manufacturing facility. And then we essentially give the patient’s own stem cells an upgrade outside the body and then reinfuse them back into the patient where they’re expected to engraft into the bone marrow. And then once this occurs, we just let these gene corrected stem cells do their job, which is to divide, propagate, and develop in all the components of the blood and immune system. And as mentioned, when I say the whole blood and immune system, this includes tissue resonant macrophage, which would distribute into deep tissue, and of course the monocytes. There are many benefits, but one of the key benefits of the monocytes is that they can cross the blood-brain barrier to enable a central nervous system effect. And that this is a differentiator because there are many different types of genetic medicine, but at least in today’s first generation of, for example, AAV gene therapy that are liver-directed, if you have a liver-directed AAV it’s unclear. And we would be pessimistic about whether it can really have a broad, central nervous system, meaning the blood-brain barrier effect. Yet in diseases such as ALD, which recently Bluebird bio got approved, and MLD from the Orchard company, this hematopoietic stem cell gene therapy has been shown to have a central nervous system effect, even to the point of receiving FDA and EMA approvals demonstrating such. So, our approach, really to say plainly, is designed to ensure billions of genetically modified cells are circulating head-to-toe, delivering a therapeutic protein everywhere that that may be needed. And so, when we narrow this down to cystinosis, the gene therapy is designed to enable patients to produce the protein that their cells need. And the goal there, why we’re doing that, is to prevent that toxic cystine buildup and those toxic cystine crystals to form in tissues throughout the body.

Daniel Levine: What’s known about AVR-RD-04 from studies that have been conducted to date?

Geoff MacKay: Well, the true champion of this field is our collaborator from UCSD, Dr. Stephanie Cherqui, and her team. She’s been just this lone champion in the field for well over a decade. She’s had tremendous support from CIRM and other funders, but she really just took it upon herself to solve this problem for the cystinosis community. She just has incredible stature in this community for what she’s advanced, and we are very honored to partner with her to take her research forward to the next stage of development supporting her. She has run a trial, a single center trial out of UCSD that is a phase 1/2 trial that is now fully enrolled and fully dosed. So, all six patients have been dosed and we at Avrobio have previously released the data on the first five patients. And I’ll talk about the top line results, but of course I need to stress that when I talk about clinical data, this is early in development and we still need confirmatory late stage trials prior to even submitting to FDA and other regulators. So, for those listening, and particularly anybody in the patient community, these are early stage results, but despite that, they’re exciting early stage results. Just top level, six adult cystinosis patients received a single infusion of our gene therapy. And just prior to receiving that single infusion of our gene therapy, they stopped all cysteamine tablets and cysteamine eyedrops. So, they stopped cysteamine a few weeks prior to study start. And what the data really reinforces is the systemic impact of the approach across multiple measures. So, we looked at things like impact of biomarkers in the blood, cystine crystal accumulation in the eye, in the skin, in the GI mucosa, neurocognitive measures, and even hair, oddly enough, just to see the full systemic reach. And one, we’re very satisfied that across the board we’re seeing this effect in this early clinical data and for the first time, we can demonstrate a few central nervous system measures from this clinical trial where there’s data that shows visual motor integration and visual perception and motor coordination measures actually positively impact, meaning reversed, in only a few patients. So, it’s too early to conclude, but what’s so exciting about that is there is natural history in this disease and there hasn’t been data generated to show that you could stabilize, let alone reverse these types of parameters—so to actually see some improvement in early days and few patients. But it’s some encouraging early data across multiple measures. And so, where we believe we are right now is that this UCSD single center study of six patients has established proof of concept in cystinosis adults. What that does is it lays the groundwork for our own Avrobio sponsored clinical trial, which we’re working very hard to get going. We have some critically important regulatory meetings just around the corner with the goal of initiating what we hope will be a registration enabling trial in 2023.

Daniel Levine: One of the unusual aspects of the gene therapy is that it restores melanin production in patients with cystinosis, and it’s possible to visibly see the effects of the gene therapy. Can you explain what’s happening and why that is?

Geoff MacKay: Yeah, we joke we may be curing the world of blondness, but it’s actually an incredibly exciting scientific point. And just to give a bit of background, people with cystinosis frequently exhibit blonde or very sort of washed out lighter colored hair and a fair complexion. And the reason for that is because of the reduced levels of melanin in their skin. And why this is that in vitro studies have demonstrated that cystinosin is located in melanosomes of melanocytes. And so, when functional cystinosin protein is absent or even reduced, melanin pigment synthesis or production is just reduced or inhibited. So, what this early quantitative data suggests is that gene therapy derives cytinosin, meaning our gene therapy may restore melanin production. And of course, this isn’t the prime goal, but it’s a byproduct of replacing defective cystinosin protein with a healthy cystinosin protein. So, 12 months after infusion, two patients exhibited progressively darkening hair color and I won’t get into all of the quantitative measures, but we suggest that this expression of cystinosin protein throughout the body leads to this melanin synthesis, or production. And just to sort of pull the lens back and the reason why we’re so enamored by this finding, because it was not expected and we had to modify the protocol to properly rigorously measure it—the reason is that it highlights the power of gene therapy. And if you just forget about melanin or cystinosis for a minute and just think of gene therapy, proteins are multifunctional and the term that’s sometimes used—moonlighting, moonlighting proteins. And the point there is that evolution made us such that proteins often have multiple functions. Some are known, some are unknown. So, the power of gene therapy is that if it replaces or delivers a healthy gene, i.e., the protein will be produced and can then perform all functions both known and unknown. And it just so happens that in cystinosis there’s this secondary or tertiary impact of the proteins related to melanin production. And because it’s the skin, it’s visual, it’s easy to measure, and you can actually see the visual features of these patients modified by addressing the cystinosin gene. So, it’s just a nice reminder that replacing genes may have effects both known and unknown, and that the mechanism is much broader than just trying to reduce the crystals that form in these cells.

Daniel Levine: What’s the development path forward?

Geoff MacKay: As I said, this UCSD trial sponsored by CIRM has delivered clinical proof of concept in adult patients. We believe that that has just been an incredible learning for us to really study what is the impact of the gene therapy and things that I haven’t mentioned, just the obvious things that we want to look at. We want to make sure that there’s durable effect. And what we can see is that going out three plus years, we’re seeing that durable effect. And one great surrogate for that durability for engraftment is vector copy number. And we’re seeing really excellent vector copy numbers across all patients in the study going out as far as three years—that groundwork that we believe we can sort of check the box and say proof of concept in adults achieved. So, the Avrobio sponsored trial that I referenced that we really want to get going in 2023 is now subject to regulatory alignment. In our very near future, we have meetings with multiple regulators—MHRA in the U.K., FDA, EMA–and Avrobio’s plan involves a two-part strategy. The first is to begin in the pre-renal, meaning the kidney transplant pediatric population and then expand it to a post-renal transplant population. And we will be measuring, because it’s a full systemic disease, we’ll be looking at measures across kidney, ocular, muscular, multiple measures across the board, all under evaluation as primary and secondary endpoints. And so, our focus is just to navigate these very near term regulatory meetings in the U.S., EU, U.K. to get the trial sites going, get the trial happening in 2023.

Daniel Levine: Avrobio’s developing gene therapies for a number of other lysosomal storage disorders. How does a gene therapy for one inform the development of, or accelerate the development of others?

Geoff MacKay: When we first founded the company, the premise was that if we could just invest inordinate resources, effort, blood, sweat, and tears to really refine our engine, which plato is our engine—our optimized gene therapy engine, then we could expand from indication A, B, C, D. And the reason that we believed that in 2015 and believe it even more in 2022 is because the difference between our different indications, whether it’s cystinosis, Gaucher disease, Hunter disease, Pompe disease, is it’s the same approach, the same plato engine. So, it’s the same CD34 hematopoietic stem cells with the same upgrade, the same four plasmid lentiviral vector system giving an upgrade to deliver the healthy gene. And the only difference between, for example, cystinosis and Gaucher disease is we switch out one disease-specific transgene. And, of course, with Gaucher disease, we’re trying to deliver glucocerebrosidase, or GCase. So, it’s just a sister lysosomal disorder. And you know, we had a very major Gaucher disease program update where we released a lot of very compelling clinical data on December 7. So, the first ever gene therapy to show effect in Gaucher disease type 3, which is a really debilitating subset of Gaucher disease, as well as just further follow up of our entire Gaucher disease type 1 patient cohort that have been dosed so far. And what we’re seeing in that disease is very similar to what we’re seeing in cystinosis, is that those patients are out two years as opposed to three years for cystinosis, but we’re seeing very solid vector copy numbers across all patients measured. And amazingly in the Gaucher disease type 3 patient, we’re seeing biochemical normalization to this young 11-year-old boy for the first time in his life. And just to paint the picture of this young individual and 11-year-old boy, he was on enzyme replacement therapy and because it wasn’t well controlled, added on to the ERT was substrate reduction therapy, so ERT and SRT as well as steroids, as well as albumin infusions, as well as a very restrictive interventional diet. And on those five interventions, he was not controlled and really spiraling in the wrong direction on multiple parameters. So that’s really why he was actually eligible for a compassionate use where he was the first person in the world to receive a gene therapy for Gaucher disease type 3. And we shared how he’s doing 15 months out. After a single infusion of gene therapy, all five of those interventions were discontinued upon infusion of the gene therapy. And out 15 months, he remains off all five. And as I mentioned, he’s biochemically normal. His albumin is trending very favorably on a background of frequent brain lesions. You’ve seen complete stabilization. So, it’s an N-of-one. Of course, we’re not trying to make claims other than how excited we are to initiate a registration trial in Gaucher disease type 3. And that was another announcement last week that we timed that update to be right after we had met with FDA and MHRA for a scientific advice meeting, and for a type C meeting from FDA. So, we believe we have the clear path to initiate a registration trial, which is also planned next year. So, Avrobio’s resources are really being applied to getting the cystinosis program moving as quickly as we can and getting this Gaucher disease program moving as quickly as we can. And to the point of the question, it’s a lot easier when you’re leveraging the same engine, the same plato platform, because there are just so many operational synergies.

Daniel Levine: Geoff McKay, CEO of Avrobio. Geoff, thanks so much for your time today.

Geoff MacKay: Well, thank you very much.

This transcript has been edited for clarity and readability.


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