Today's n-lorem podcast airs in an exciting moment. We're about to initiate treatment of four new patients with experimental ASOs. And before the end of the year, we expect that number to grow to as many as eight patients to do this in a few months is is truly a great achievement. The work required to support initiating treatment with an experimental ASO is enormously complex. And an IND document for an n-lorem. Patient is more than 1000 patients. And next year, we expect the number
of new INDs. And of course that means new patients treated to grow quite substantially. As we look to a longer term future we've put in put the infrastructure in place to treat 1000s of patients. While the discovery and development of an optimal personalized ASO is extremely challenging, and we bring decades of experience and AI informed automation to that process. The challenges do not end there. We then have to
manufacture the ASO and assure that it is pure. Finally, ASO must be put into vials under sterile conditions so that it can be administered to our patients. That is where our partner Argonaut comes in. Argonaut performs the highly regulated process called sterile fills. We are fortunate to have such a strong partner and appreciate Argonauts in kind contributions that reduce the cost of this step meaningfully. We're also pleased to welcome Argonaut as a sponsor of the
n-lorem podcast series. Many of our partners and other organizations are now becoming sponsors. We welcome sponsors. If interested in sponsoring our webcast, please contact us at podcast@nlorem.org Hello, and welcome to the n-lorem podcast series, a series that focuses exclusively on patients now referred to as having nano rare mutations. I'm Stan Crooke, and I'm the
founder, chairman and CEO of n-lorem. If it sounds impossible to you that any drug discovery technology could discover and develop a new medicine for a specific patient in 12 to 15 months, then provide that medicine for free to for life. You can imagine my reaction more than four years ago, when I first realized that it might be possible for the technology that was created under my leadership to do exactly that. And it certainly is possible. And we've already proven that can be done.
And we've treated now 14 patients by doing that, given that I've already provided a basic framework to understand how drugs work, and come to be and discuss the basics of ASO
technology. In this podcast, I will focus on a more detailed step by step explanation of how we actually make the impossible possible that in n-lorem, if you've listened to any of our podcasts or any of my presentation, you've heard me argue that the only organization that is fully capable of discovering the best personalized ASO for a single patient efficiently and expeditiously is in n-lorem. I would imagine that you've wondered why I take that
position. Of course, the reason is, we inherit and benefit from more than three decades of pioneering effort to create ASO technology. The first step in creating an optimal ASO for a patient is to identify the best sites in the target RNA that needs to be altered. And for that particular patient. Since RNAs are many 1000s of nucleotides long, we evaluate a ASOs designed to bind to hundreds to 1000s of sites. And we call that process ASO site screening. So let's begin there.
The first question is, why do we have to screen hundreds of to 1000s of sites in RNA to find an optimal site to bind the ASO? Well, there are several very good reasons. RNAs are very large. And they have very complex three dimensional structures. The ideal site for an ASO to bind to a target RNA is an area in that RNA that is basically unstructured RNAs are so complex that it's not possible to predict the structure of RNAs
and cells. The problem is even greater because RNAs don't exist as RNAs himself. They have many proteins associated with them and that are bound. And they form structures called ribo nucleo proteins or rnps. Therefore, we screen not the RNA, but the target RNA in a very complex three dimensional structure comprised of RNA and proteins that we call RNP. In fact, the same RNA can have different structures at different times and be bound by different proteins. So screening is
essential. Now, over the last three decades, we've screened many millions of ASOs have a wide range of chemistries and designs. We screened those a ASOs in scores of cell lines, including human derived cell lines. And then those efforts have been followed up in 1000s studies in various animal
species. And of course in 10s of 1000s of patients. All those data have been integrated into enormous databases coupled to machine learning, and that then has created an ever more sophisticated algorithm that helps us rapidly design the right sorts of a ASOs and avoid problem types of have a ASOs further. So screening is highly automated. So we can screen hunters to 1000s of sites in an RNA very rapidly, very
inexpensively. And we have proven over and over again, that the more sites screened, the better the performance of the so therefore, this uniquely capable approach that is accessible at in n-lorem is critical to enhancing the potential for
success in treating nanorare patients. But if we had only screened ASOs and not invested broadly and consistently and understanding the molecular mechanisms that explain the observations that we make during screening and in treatment, it is unlikely that RNA targeted drug discovery technology would
exist today. And certainly, it would not be capable of discovering and developing and providing personalized experimental ASOs to patients with natur rare diseases for free for life, to leverage to advance the technology and steadily improve the performance of a ASOs derives from the seamless integration of Asa medicinal chemistry with ever deeper understanding of molecular mechanisms, by which ASOs producer effects coupled to massively parallel screening and
AI analytics with all that has been learned and animals and unmanned over these decades. This cycle of innovation results in consistent feedback from which we learn consistently. And that process has been in play for more than three decades, and is ever more productive. And that is how we come to be where we are and how we come to be able to do what we're doing. To understand the final element that makes it possible to meet
the needs of many patients with Nano rare diseases. One must understand that within a chemical class, all the ASOs of that chemical class are very similar. And they behave very similarly because they only differ in their genetic zip code, or sequence. Consequently, we can predict the behavior of an ASO that we just discovered, based on the behaviors of hundreds of ASOs of the same chemical class that preceded it.
This means that before we even begin developing a personalized so for a patient, we have a very good idea of the right dose to use the right route of administration, and how often to administer the So finally, because we've constructed databases that summarize all the safety observation from all controlled clinical trials of each of the chemical classes that we use it and more, we can predict the possible side effects to watch for. Given that the safety data bases have been
published. treating physicians and patients or parents can inform themselves as well. And the FDA has access to these databases as needed as desired. Also, this then means that we can be confident that we're exposing and n-lorem patients only to prove risks, and that we can keep our patients and parents and regulators fully informed the choice we have made and to focus solely on RNA targets in
liver and kidney after systemic dosing subcutaneously. The eye after direct injection in the eye, the CNS after injection of the ASO into spinal fluid, and the long after aerosolized administration assures that low doses will be needed and that we really understand what we're doing, further enhancing the potential of for benefit and reducing risk for our patients.
Now, what happens when an application is submitted? Well, what actually happens then is the application is submitted and prior to the application being submitted, a great deal of work has taken place. The patient has been identified as potentially having a nano rare mutation and referred to a tertiary care center to be genetically and phenotypically characterized.
This work identifies the mutation characterizes the type of mutation, for example, is an unknown mutation or a gain of toxic function, or splicing, mutation, etc. And the function of the gene product is defined. The other major effort is to define the phenotype and identify the principal manifestations of the mutation that make the patient sick.
Numerous tertiary care centers have submitted applications. And on some occasions at n-lorem, we have to do additional work, including added genomic sequencing characterization of the mutation. And sometimes we need to do added studies to understand fully what the function of the gene is. As we gain and personalized medicine senators gain experience, I'm very optimistic that the process will become more efficient. And so we have less catch up work to do once we have an application.
Now, all that precedes the application coming at us, then the first step in processing the application is of course, to ensure the patient identity is protected, then we must do a search of the literature to learn more about the gene, the prevalence of the mutation, and the nature of the mutation and the ASO strategy to employ. Once we have all of that necessary information put together, we prepare a detailed presentation with a recommendation to be presented to our access to
treatment committee. Remember that the access to treatment committee is comprised of, of a broad range of experts in various diseases, genetics, bioethics, as well as clinical trials. And of course, Aniston's technology. And so we lean on
that group to help us in these complex decisions. If the committee and the executive committee of n-lorem agree, then the patient can be treated if that patient can potentially be helped with an ASO this process that assures that we know what we're treating, why we're treating it, and that it will be a value to the patient if we succeed, I think is vital. And this process is, I think, unique
to n-lorem. Now, we next then work with the investigators to define treatment goals, and clinical measures to be used and then we ask that the investigator and patient or parent perform a detailed natural history study during the year or year and a half that it takes to discover and develop the so for that patient. That then allows us to compare on treatment to what was happening to the patient immediately before treatment
begins. The screening process that I've discussed, is then initiated once we have clearly gotten an agreement that the patient should be treated out of the process of screening we typically have multiple candidate ASOC that undergo further testing in cells and animals. When those studies are completed, we assemble all the data and select the best looking
ASO to manufacture. The special FDA guidance for it of one patient's allows us to perform a single three month toxicology study in rodents, if the results of that study are satisfactory. Then the ASO is transferred to our partner Argonaut, and the ASO is deposited in sterile vials that we use to treat the patient. During this process, then we file the necessary documents with the FDA to permit initiation of experimental
treatment. And of course, those documents were also involved with the tertiary care center that it will be treating the patient. Of course, from the patient's perspective, the first dose of an experimental as as the beginning. But getting there requires a great deal of work and could not be done, well, without all of the knowledge and experience that we've gained
over these three plus decades. During treatment, our task is to evaluate the performance of the ASO and assure that all of the stakeholders learn as much from the treatment of this patient as we can. I think we owe that to every one of these patients and the opportunities to learn are just extraordinary. As you can imagine, then to complete all this complex experimental scientific work in 12 to 15 months is extremely challenging. If we encounter any problem, such as the ASO we select having
issues in the toxicology study, delays can happen. On occasion, we may even be unable to identify a personalized ASO that we feel satisfactory for a patient. For these reasons, we cannot promise that we will be successful, or that we will achieve our goal to treat the patient within 15 months or so.
So, what we can do, and can promise is that we will do everything possible to meet the needs of our patients, we will do everything possible to meet the needs of every single one of our patients, and that is the only promise that we can make. And n-Lorem is a nonprofit committed to discovering and providing personalized experimental treatments for free for life to patients with genetic diseases that affect one to 30 patients
worldwide, referred to by a n-Lorem as nano rare. Many of these patients progress and die without ever achieving a diagnosis. This is where n-lorem comes in. They do the impossible by providing hope and for those that they can help free lifetime treatment. For more information about n-lorem or today's episode, visit nlorem.org. Any questions can be sent into podcast at and n-lorem dot org search and n-lorem on Twitter, Instagram, YouTube, LinkedIn and Facebook to connect with us.
Please rate and review the podcast on Apple, Spotify, or wherever you listen. This truly helps us climb the charts and allows others to find the show. This podcast is hosted by Dr. Stan Crooke, our videographer is John Magnusson of Mighty One productions. Our producers are John Magnuson and Kira Dineen of DNA today. Thank you for listening