![\"Science](\"http:\/\/media.springernature.com\/lw685\/springer-static\/image\/art%3A10.1038%2Fs41587-023-01724-9\/MediaObjects\/41587_2023_1724_Figa_HTML.png\")
<\/picture><\/div>\nPM Images \/ DigitalVision \/ Getty<\/p>\n<\/div>\n<\/figure>\n<\/div>\n
Last October, Susannah Rosen, an 8-year-old girl with a devastating neurodegenerative genetic disease, took her first dose of a custom-made genetic medicine. What\u2019s more, she got it at no cost, provided by the non-profit foundation n-Lorem. The drug isn\u2019t gene therapy: it doesn\u2019t change Susannah\u2019s genome or undo her mutation. It\u2019s an antisense oligonucleotide (ASO), a short sequence of modified DNA, designed to bind to a problematic mRNA transcript and stop production of the disease-causing protein.<\/p>\n
Susannah joins a small but growing group of patients who have received treatments designed just for them, called \u2018N<\/i> of 1\u2019 therapies. Personalized medicine seemed to be just around the corner for decades, but in 2018, the corner had finally been turned when a custom-designed ASO made its clinical debut at Boston Children\u2019s Hospital. Researchers there, led by Tim Yu, developed an ASO drug called milasen to treat a child \u2014 Mila \u2014 who had a one-of-a-kind genetic disorder. Incredibly, that drug was designed, manufactured and administered in less than a year1<\/a><\/sup>.<\/p>\n ASOs are only one approach to designing N<\/i>-of-1 drugs; CRISPR gene editing, an inherently customizable tool, is moving successfully into the clinic, making it another promising candidate. Clinical trials underway for genetic diseases including sickle cell anemia and congenital blindness, though these are not ultra-rare conditions, nonetheless have demonstrated that the technique can be used safely in humans. Some people are pushing to apply personalized CRISPR therapies more broadly, but regulators remain cautious. Once gene editing is performed, it can\u2019t be reversed if adverse events arise.<\/p>\n Another way that CRISPR can contribute is by creating models for drug repurposing studies. By genetically modifying yeast or other model organisms to mimic a patient\u2019s mutation, researchers can screen existing drugs to see whether any address the defect causing a single patient\u2019s disease.<\/p>\n What all these strategies have in common is the issue of cost. Without a large customer base to buy the resulting treatments, scientists working on rare diseases are struggling to build new models that enable access to life-saving treatments for all who need them.<\/p>\n ASOs aren\u2019t new; the US Food and Drug Administration (FDA) approved the first, fomivirsen, in 1998. Developed as an antiviral against cytomegalovirus retinitis in people with AIDS, fomivirsen provided a proof-of-concept for clinical ASOs. It would be 15 years before antisense drugs began to take off. Since 2013, however, no fewer than eight ASO drugs have been green-lighted for use in the United States or Europe to treat genetic diseases2<\/a><\/sup>, including Spinraza (nusinersen), the first FDA-approved therapy for spinal muscular atrophy (SMA), a motor neuron disease that, in its most severe form, causes death by age two.<\/p>\n Spinraza\u2019s development, like that of so many therapeutics, was a multi-year odyssey, beginning in 2004 and not ending until the drug won approval in 2016<\/a>. In contrast, the milasen story showed that the timeline can be accelerated. Because Mila\u2019s disease was progressive and fatal, the risks of waiting a year for animal safety studies outweighed the danger of possible adverse effects from the treatment, so Mila began treatment while the animal safety study was still in progress. Her treatment was authorized by the FDA under an expanded-access protocol, which allows a patient with a life-threatening condition to be treated with an investigational drug outside of clinical trials. However, exactly where to draw the line between letting a child suffer from a degenerative disease and trying a potentially harmful experimental treatment remains a subject of vigorous debate. In a 2019 editorial in the New England Journal of Medicine<\/i>, the same issue where the development of milasen was published, Janet Woodcock and Peter Marks at the FDA raised issues about how to proceed safely, arguing that \u201ceven in rapidly progressing, fatal illnesses, precipitating severe complications or death is not acceptable\u201d3<\/a><\/sup>.<\/p>\n Since then, the FDA has published a non-binding guidance document for investigators developing personalized ASO drugs. It lays out protocols for dose escalation schedules, regular safety assessments, and the establishment of stopping criteria in case of serious adverse events. The document explicitly does not address the level of preclinical data or drug quality requirements needed to start treating a patient, and it also excludes drugs intended for commercial marketing.<\/p>\n \u201cYou can make a really strongly ethical case that if something is safe in rats, and a patient is going to die, or is going to lose neurons, it\u2019s a better move for that patient to proceed than to wait for a monkey study, because the risk of not treating outweighs the risk of treating,\u201d says Jonathan Watts of the RNA Therapeutics Institute at the University of Massachusetts Medical School.<\/p>\n Yu points out that the ethical issues around personalized ASOs aren\u2019t unique. \u201cThrough these guidances, we are seeing concepts that are already in clinical practice and regulatory practice in fields like oncology, where patients who have failed first, second, third, fourth line therapy are often first subjects in very early stage, investigational trials of quite new agents,\u201d Yu says. \u201cPatients and their clinicians weigh their decisions to participate in these trials knowing their disease is fatal and other options have been exhausted.\u201d<\/p>\n Regulatory policies differ between the United States and Europe, points out Annemieke Aartsma-Rus, a translational geneticist at Leiden University Medical Center in the Netherlands, and this affects what types of mutations are eligible for N<\/i>-of-1 designation. \u201cThere\u2019s two things you can do with ASOs: restore a protein or reduce the production of a toxic protein,\u201d she says. An ASO that treats a disease by reducing a toxic protein could conceivably work for anyone who makes it, regardless of the specific mutation. \u201cYou can develop it for one individual, but you know it applies to others,\u201d explains Aartsma-Rus. \u201cIn the US, you are allowed to say \u2018we\u2019re going to develop this in an N<\/i>-of-1 setting\u2019, but in Europe, they would say no, it\u2019s not allowed. You either do it for everyone who\u2019s eligible, or not at all \u2014 not for one specific patient who happens to be able to fund that.\u201d<\/p>\n Milasen is an exon-skipping ASO. It is designed to bind to a mis-spliced section of the mRNA for MSFD8<\/i> that interferes with the production of a lysosomal transporter protein needed for neuronal survival in an ultra-rare form of Batten disease (a late infantile neuronal ceroid lipofuscinosis, CLN7)4<\/a><\/sup>. \u201cA cryptic splicing mutation leads to the inclusion of part of an intron in the messenger RNA, and that disrupts protein production,\u201d Aartsma-Rus explains. \u201cIf you can skip that cryptic exon, the normal transcript is back, you can restore the normal protein.\u201d A properly designed ASO can do just that: neutralize a cryptic exon, restoring the normal transcript. Thus, she says, these types of mutations are the most promising avenue for N<\/i>-of-1 therapies because cryptic splicing mutations are unique and the tailor-made ASO will work in only one patient. However, mutations occurring in introns are difficult to identify because introns contain a lot of sequence variability. It\u2019s not always obvious whether a particular variant is disrupting the transcript. \u201cPeople say [cryptic splicing mutations] are very rare, but the reality is they\u2019re probably not that rare, it\u2019s just really difficult to find them,\u201d says Aartsma-Rus.<\/p>\n Aartsma-Rus serves as chair of the Dutch Center for RNA Therapeutics, a nonprofit consortium of medical centers developing personalized RNA therapies. Identifying an appropriate mutation is just the first issue, she says (Fig. 1<\/a>). Ideally, one would want to apply it to a disease that affects the brain or the eye \u2014 someplace the ASO can be injected locally. \u201cYou can use a very low amount, and you don\u2019t have to worry about systemic exposure,\u201d she says. She adds that there must be some hope of benefit to the patient at the time of treatment. \u201cYou can do local injection in the eye, but if someone is totally blind, you can restore the protein, but they will stay blind,\u201d she says. \u201cYou\u2019re not going to return function into the cells. If the disease is too advanced, the patient won\u2019t benefit.\u201d The ultimate decision rests with the patient, she emphasizes. It\u2019s critically important that the patient and the family understand realistically what benefits they can expect and the treatment risks.<\/p>\n ASOs are under development for patients with an ultra-rare (fewer than 100 worldwide) serious, life-threatening diseases who have no therapy available, and where there is no commercial incentive to develop therapies. Source: Dutch Center for RNA Therapeutics (DCRT). ASO, antisense oligonucleotide; GMP, good manufacturing practices; IND, Investigational New Drug.<\/p>\n<\/div>\n Full size image<\/span><\/a><\/p>\n<\/figure>\n<\/div>\n<\/div>\n<\/div>\n Unlike in Europe, in the United States \u201cN<\/i> of 1\u201d can mean \u201cN<\/i> of 1 at a time.\u201d Jacifusen is an ASO designed against the FUS<\/i> gene (RNA binding protein fused in sarcoma), which, when mutated, causes an aggressive form of amyotrophic lateral sclerosis (ALS). It\u2019s named for Jaci Hermstad, who in 2019 became the first patient to receive the drug, but it wasn\u2019t designed specifically for her. The drug was already being developed by Ionis and collaborators at Columbia University and had shown efficacy in a Fus<\/i>-mutant mouse model5<\/a><\/sup> when Hermstad received her diagnosis at age 25. Her twin sister, Alex, had died of the disease when she was 17, and, terrified of losing their remaining daughter, Jaci\u2019s parents launched a campaign to get permission from the FDA for Jaci to try the drug, even though it hadn\u2019t yet been tested in humans. At the time Jaci\u2019s disease was diagnosed, the FDA had not yet released their draft guidance around the use of individualized ASOs in patients.<\/p>\n \u201cThe FDA were extremely responsive, thoughtful, reasonable partners in this,\u201d says Neil Shneider of Columbia, who developed jacifusen. \u201cTheir goal was clearly to protect my patient but at the same time recognize the desperate nature of the disease and the risks the disease presented to her.\u201d Although Shneider had limited toxicity data on jacifusen, the drug was chemically similar to two other Ionis ASOs for ALS that had already been introduced into the clinic. Jaci started treatment under an expanded-access Investigational New Drug (IND) application, and after that, more patients with FUS<\/i>-related ALS wanted to try it. \u201cThe program grew, but it was incremental, one by one,\u201d Shneider says. \u201cWe ultimately submitted 12 INDs in total for the same therapeutic.\u201d After the first few patients, the FDA set limits on the serial IND approach, urging Shneider to conduct a clinical trial. \u201cThe program might have ended, but it was saved by Ionis,\u201d he says. \u201cThey agreed to sponsor a proper clinical trial and they did it very quickly.\u201d<\/p>\n Shneider expects to publish the data on the 12 IND patients in 2023; although Jaci passed away about a year after starting the drug, \u201cshe showed encouraging signs that she was responding to the ASO,\u201d Shneider says<\/p>\n<\/div>\n<\/div>\n After milasen, Yu began hearing from families hoping that antisense drugs could help their children. Mindful of the ethical considerations involved, Yu decided to take on a devastating genetic disease, ataxia\u2013telangiectasia, creating a drug called atipeksen for a 3-year-old patient named Ipek in October 2019. Ipek is doing well 3 years into treatment, Yu says, but the results have not yet been published. In 2020, he treated two toddlers with a severe form of epilepsy with an ASO called valeriasen. Although the drug reduced the frequency of the seizures in one patient and eliminated them in the other, both children developed hydrocephalus and subsequently stopped treatment. One eventually died (of causes unrelated to the treatment); the other has seen her seizures increase in frequency since stopping treatment, and her parents are considering restarting it.<\/p>\n The unexpected adverse event underscores the importance of data sharing, which Yu emphasizes as key to advancing the field. \u201cThe moment we encountered hydrocephalus in our patients, we contacted everybody in the field we knew that worked with ASO drugs,\u201d Yu says. \u201cPeople have been studying ASOs, including extensive animal testing, for 30 years. Everyone said, \u2018No, we’ve never seen this.\u2019 So it\u2019s something that we have to work on.\u201d Although it hadn\u2019t been seen in animal studies, however, hydrocephalus had occurred previously in people treated with an ASO. In March 2021, a phase 3 trial for the drug tominersen, developed by Ionis for patients with Huntington\u2019s disease, was prematurely halted due to \u201cventricular expansion\u201d \u2014 essentially, hydrocephalus \u2014 which was observed in a dose-dependent fashion. Testing of tominersen has resumed under the auspices of Roche, which is partnering with Ionis.<\/p>\n Yu says the most likely hypothesis is that the fluid buildup is a class effect, but the mechanism responsible for it remains unclear. \u201cIt would be really nice if we could simply just get some tominersen and get some valeriasen and do the appropriate experiments to try to identify mechanistic commonalities between the two sequences,\u201d he says. \u201cThat isn\u2019t exactly how the world always works. But the sooner we can get to a point where we\u2019re doing those sorts of things in a collaborative way, the better for everybody.\u201d<\/p>\n Together with Julia Vitarello, the mother of Mila, Yu launched the N=1 Collaborative, or N1C, an organization dedicated to connecting ASO investigators around the world and providing a hub for communication and data sharing. Yu points out that, often, barriers to data sharing arise as unintended consequences of the way medical data are handled and patients\u2019 privacy is protected. \u201cOne of the critical things that I\u2019m hoping the N=1 Collaborative can do is nip some of that in the bud,\u201d Yu says, \u201cand set sharing standards that make it easy for investigators and the families they work with to volunteer for their data to be shared and aggregated in a way that informs the field.\u201d<\/p>\n Tim Yu of Boston Children\u2019s Hospital is helping to create a centralized resource to help streamline ASO development for N<\/i>-of-1 diseases. \u201cThe platform technologies are continuing to improve, and I would say right now, the therapeutic index is reasonably narrow,\u201d says Watts. \u201cWe can find sequences that are well tolerated and that save lives. But there are also definitely examples that are quite toxic of these ASOs of different sequences with the same chemistry. There are examples that are a little bit borderline \u2014 they have some beneficial effect, but it\u2019s not clear whether they\u2019re safe enough yet. I think if we could get the platform to have a therapeutic index that was ten times greater, it would be so much easier to do single-patient drugs.\u201d The way to get there, Watts says, is through collaboration and sharing of data.<\/p>\n N1C also sponsors workshops to help the field develop consensus on certain best practices, including guidelines for mutation selection, preclinical testing, safety tests, regulatory issues, and metrics to define how well a treatment is working. The organization also serves as a resource for doctors who might not have experience in genetic therapies. Last year the group published consensus guidelines6<\/a><\/sup> for designing and testing ASOs, and they are putting together an online database of control ASOs confirmed to work well in various cell types.<\/p>\n \u201cA lot of clinicians might have a patient with a rare disease and want to help, but don\u2019t have any idea how to approach the FDA. Where do you find a source of oligonucleotide for under $500,000? For a single patient?\u201d Watts says. \u201cSharing information and help, guidance and resources and protocols around all of those kinds of questions is another thing that the more clinically minded people in the collaborative do for each other.\u201d<\/p>\n One major player in ASOs has so far declined to share data in the collaborative: n-Lorem.<\/p>\n<\/div>\n<\/div>\n Stanley Crooke, founder of Ionis, recognizing that the traditional for-profit pharma company model couldn\u2019t support developing N<\/i>-of-1 ASOs, founded the n-Lorem Foundation in 2020. n-Lorem\u2019s mission is to provide experimental ASO treatments to people with genetic diseases that affect fewer than 30 patients worldwide. The foundation was launched with personal funding from Crooke and Rosanne Crooke, his wife, plus $3.4 million from Ionis and $1.75 million from Biogen. Crooke says that other companies are stepping up to contribute as well. \u201cWe\u2019ve had wonderful response,\u201d Crooke says. \u201cReally every vendor in the oligonucleotide industry is giving either free or deeply discounted work, and often cash donations as well.\u201d They\u2019ve also received donations from disease advocacy organizations.<\/p>\n Crooke also has kind words for the FDA in terms of how they\u2019ve handled the personalized therapies. \u201cBeing fast is important. Being high quality is even more important. And it\u2019s the combination of the efficiency and versatility of antisense technology with the special guidance that the FDA has issued for the treatment of nano-rare patients with ASOs that allow us to move as fast as we are,\u201d he says.<\/p>\n At the same time, he resists the idea that n-Lorem should contribute their data to the N1C efforts. Pointing out that Ionis has been \u201cperfecting\u201d ASO technology since 1989, he says it wouldn\u2019t make sense to compare their data with that of others just starting out. \u201cWe offer to collaborate with basically every investigator who approaches us,\u201d he says. \u201cOur collaborations are that we design and make the ASOs, and then we bring an optimal ASO forward, and then the investigator treats the patient.\u201d<\/p>\n Crooke expressed support for the idea of establishing databases, as long as minimum standards for preclinical testing processes and performance are defined and rigorous clinical evaluation protocols with well-defined clinical endpoints are agreed on. \u201cAs such, n-Lorem is open to contributing data to the N=1 Collaborative or other data platforms as appropriate,\u201d he says. But, because N1C pools data from different investigators all using different methods to make ASOs, Crooke says, \u201cone of the worries that I have is that this is being taken on by people who don\u2019t really understand this technology.\u201d<\/p>\n<\/div>\n<\/div>\n ASOs are not the only route to N<\/i>-of-1 therapies. CRISPR can help people with ultra-rare diseases. Rather than changing a patient\u2019s DNA, the technology enables researchers to create yeast or worm models with genetic errors that match those in the patients, thus creating a personalized resource for high-throughput screening of small-molecule drug candidates. \u201cYou don\u2019t program the medicine, like in the ASO model; you program the yeast model,\u201d explains Ethan Perlstein, CEO and founder of Perlara, a public benefit corporation (Box 1<\/a>). \u201cWhat has a faster path to the clinic than even a customized ASO? A repurposed drug that already has a safety record.\u201d<\/p>\n Perlstein says the idea behind Perlara is to \u201cproductize\u201d drug repurposing by using existing yeast, worm and fly models. The company is actually on its second iteration, having been founded originally in 2014 before shutting its doors in 2019 because of lack of funding. Yet some important unfinished business lingered. For two years, Perlara had been working with Maggie\u2019s Cure<\/a>, an LLC formed by the family of Maggie Carmichael. Maggie has a congenital disorder of glycosylation (CDG), PMM2-CDG, that affects multiple organ systems. Researchers working with Perlara were already screening yeast and worm models of Maggie\u2019s disease, looking for a drug that might be effective. The project continued after the company officially closed, and in January 2020, Maggie began a drug called epalrestat under the supervision of doctors at the Mayo Clinic in Rochester, Minnesota. The drug is not FDA-approved for any indication, but it is approved in Japan as a treatment for diabetic neuropathy. Since she began taking epalrestat, Maggie\u2019s motor skills have improved and her vocabulary has grown dramatically.<\/p>\n Around the time that Maggie was starting on epalrestat, another family was searching for answers for their son\u2019s CDG. Jake Carroll was diagnosed with Man1b1-CDG in early 2020, and his parents, Claire Fast and Matt Carroll, soon discovered how little was known about the disease. \u201cIt was quite a helpless feeling,\u201d Fast says. \u201cVery few people in the world know about this disorder.\u201d The Carrolls met the Carmichaels in a Facebook group for families affected by CDG, and that\u2019s when they learned about Perlara. In 2022, Perlstein connected the family with Clement Chow at the University of Utah. Chow works on CDGs in fruit flies, and he agreed to conduct a screen for Man1b1 drugs in flies.<\/p>\n Six-year-old Jake Carroll has an ultra-rare metabolic disorder called Man1b1-CDG. Perlara helped his parents find a researcher who could make a fruit fly model of his disease for drug screening. \u201cWe were so desperate at that point,\u201d Fast recalls. \u201cLearning about what Perlara was doing was very exciting for us, just to find somebody who knew how to navigate the research. It\u2019s really hard to know where to start.\u201d<\/p>\n Chow\u2019s fly models did not carry an exact replica of Jake\u2019s mutation, but rather a general Man1b1 knockdown made using RNA interference (RNAi). \u201cIn the future, we may want to move toward making more personalized models, using CRISPR to put in real patient mutations, but that takes so much more time,\u201d he says. \u201cWe can order up all the reagents to do this RNAi knockdown experiment right after the call with the patients, get the reagents within a week, have a few tests done in about three weeks, and then it\u2019s off to the races. If we do CRISPR, it\u2019s months before we even have a fly we can test.\u201d<\/p>\n As of January 2023, the screen has identified several drugs, and the next step will be to sit down as a team and discuss how to proceed. \u201cAbout 20% of the hits we found in our screen all fell into the same category, so that was really encouraging,\u201d Chow says. \u201cA number of them either have a pretty good history in pediatric administration or they\u2019re actually OTC [over the counter].\u201d Once a drug is selected, theoretically, Jake could begin treatment right away. Indeed, another Perlara patient named Lucy, who suffers from a different CDG, PGAP3, received her first dose 48 hours after her yeast screen was completed. In that case, the family was working with two labs in parallel: while one performed the yeast screen, the other was studying Lucy\u2019s own cultured cells, and both teams identified the same biochemical pathway. Within a week of starting her drug regimen, Lucy took her first unassisted step<\/a>.<\/p>\n The vast collection of small-molecule drugs that have already been safety-tested represents an underutilized resource that can be mined for cures. \u201cWe\u2019re banking on being able to find all these hidden gems amongst the things we\u2019ve already approved as safe,\u201d says Chow. \u201cI think that it will work for a large number of diseases. There\u2019s just so much biology hidden in these drugs. Most of them, we don\u2019t really have a good sense of the exact mechanism of action.\u201d<\/p>\n Perlstein says he has around 30 clients looking for treatments. \u201cDrug repurposing is going to go exponential soon,\u201d Perlstein predicts. \u201cWhat were these few N<\/i>-of-1s is going to become a tide of N<\/i>-of-1s. And, of course, that\u2019s what they talk about with ASOs, that\u2019s what n-Lorem is meant to accommodate, and the N=1 Collaborative. They\u2019re trying to get ahead of this tsunami. And it\u2019s coming.\u201d<\/p>\n<\/div>\n<\/div>\n One year ago, the US National Institutes of Health (NIH) launched its Ultra-rare Gene-based Therapy<\/a> (URGenT) program to accelerate the clinical development of therapies for neurological diseases7<\/a><\/sup>. \u201cIt\u2019s still under construction,\u201d says program director Chris Boshoff. \u201cAt the moment, it only consists of a preclinical component. There are two funding opportunity announcements for projects up to and including an IND filing.\u201d A clinical network is in development and projected to be up and running sometime in 2023, he says. \u201cThat will really change the dynamics of this program. We hope it will provide almost a seamless transition from preclinical to clinical, and a streamlined access process. If applicants already have an IND, they don\u2019t have to go through the same lengthy application process for funding.\u201d The clinical network database will also serve as a data sharing resource, which can help other researchers. \u201cEven if it\u2019s as small as just sharing a clinical trial protocol, or sharing assays during development, it\u2019s a start,\u201d Boshoff says.<\/p>\n No projects have been funded so far, but Boshoff says the scope of the program encompasses any gene-based or transcript-directed technology, including ASOs, gene editing, or classical AAV-based gene therapy, provided they address ultra-rare neurological diseases.<\/p>\n In a recent New York Times<\/i> editorial, Fyodor Urnov, scientific director at the Innovative Genomics Institute and professor at the University of California Berkeley, suggested that for rare diseases, public funding makes more sense than for-profit businesses, pointing to the financial struggles of two flagship gene therapy companies, bluebird bio and Editas Medicine, as evidence8<\/a><\/sup>. By contrast, he says, \u201cthe California Institute for Regenerative Medicine has consistently and vigorously supported a path to the clinic for experimental therapies including CRISPR\u201d and is the only such state-funded program to do so. At the federal level, he says, the NIH offers funding for academic researchers to develop CRISPR-based medicines. \u201cI think this is exactly the right approach,\u201d he says. \u201cThe federal government\u2019s investment in establishing the feasibility of CRISPR cures, I think, ultimately will benefit the taxpayers. Why? Because as we learn more and more about gene editing for rare disease, we will learn more and more how to safely gene edit for common disease.\u201d<\/p>\n Meanwhile, taking lessons from his prior attempt at industrial biotech, Perlstein revived Perlara in late 2021, but this time creating a leaner and stronger company. \u201cIt\u2019s decentralized biotech,\u201d he says. \u201cWe offer a fundamentally different business model, which is a virtual consultancy.\u201d Perlstein sees Perlara\u2019s role as accelerating the research to find treatments for patients who would otherwise remain under the radar of big pharma. \u201cThe whole purpose of the company now is to become the Y Combinator for rare diseases,\u201d Perlstein said. \u201cWhat Y Combinator did for overlooked founders, I\u2019m doing the same thing with overlooked families.\u201d<\/p>\n In its new format, Perlara no longer has a permanent, physical lab space or full-time employees; it has dispensed with them in favor of geographically distributed pop-up labs and \u201ccure guides\u201d who work as independent contractors with the company. \u201cIt\u2019s kind of like Uber,\u201d quips Perlstein, \u201cexcept that instead of drivers, I have cure guides.\u201d The cure guides get matched with families and form research teams to develop a personalized treatment, much as Chow\u2019s lab took on Jake Carroll\u2019s case.<\/p>\n For now, Perlstein acknowledges, families working with Perlara are largely self-financed. He calls them \u201cthe tip of the spear\u201d in the quest for rare disease treatments, which could ultimately become available to other patients. \u201cI\u2019m not trying to make something that only benefits the 1%,\u201d he said. \u201cBut I\u2019m not going to ignore the fact that they exist.\u201d Indeed, Maggie\u2019s success with epalrestat led to the launch in December 2022 of a 40-person phase 3 clinical trial<\/a>. Without the Carmichaels\u2019 efforts, epalrestat\u2019s benefits for CDGs may have remained unknown, even though the genetic and biochemical technology required to find it is accessible in most modern labs.<\/p>\n It remains to be seen whether rare disease drug discovery will be financially sustainable, whether using the Perlara model, which so far relies on funding from families; the n-Lorem model, which draws on corporate donations and advocacy organizations; or the public-funding scenario proposed by Urnov. Other for-profit ventures are springing up to try to accelerate N<\/i>-of-1 therapies; for instance, Julia Vitarello, Mila\u2019s mother, recently co-founded EveryONE Medicines with investment support from GV and Khosla.<\/p>\n \u201cThis is the time for rare diseases,\u201d says Chow. \u201cIn the next ten years, I think you\u2019ll see therapies rolling out left and right because it\u2019s just been waiting for the technology to be there.\u201d He points out that rare genetic diseases are far simpler to model in the lab than complex multifactorial conditions like heart disease or cancer. \u201cI think we have all the tools,\u201d he says. \u201cWhat\u2019s lacking is the funding.\u201d<\/p>\n<\/div>\n<\/div><\/div>\nBalancing safety with speed<\/h2>\n
![\"Science](\"http:\/\/media.springernature.com\/lw685\/springer-static\/image\/art%3A10.1038%2Fs41587-023-01724-9\/MediaObjects\/41587_2023_1724_Fig1_HTML.png\")
<\/picture><\/a><\/div>\n\n N<\/i> of 1 \u2026 and another, and another<\/h2>\n
Data sharing<\/h2>\n
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\n Credit: Michael Goderre, Boston Children\u2019s Hospital<\/span><\/p>\n<\/div>\nGiving away ASOs for free<\/h2>\n
Mining for hidden gems<\/h2>\n
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\n Credit: Carroll family<\/span><\/p>\n<\/div>\nCan rare disease drugs be profitable?<\/h2>\n