Frequently Asked Questions

Program Overview

  • rareSHIFT is Unravel Biosciences' drug discovery platform for rare disease patients. It analyzes each patient's RNA profile (collected via a simple nasal swab) using a validated computational model (BioNAV) to rank existing molecules — drugs and supplements — by how likely they are to shift the patient's biology toward a healthier state, usually their first degree healthy relative as a control. The platform rests on the idea that molecular similarities in disease pathology and treatment response can be found across different rare disorders, regardless of clinical diagnosis or genetic root cause, so that therapeutic development can benefit more than one orphan disorder at a time. Top candidates are reviewed with families and clinicians and can be validated further in vivo if needed. 

    Considerations: This is for research use and not intended as a treatment recommendation. Typical timeline for personalized results is about 8–12 weeks but rush options are available. Results are agnostic to genetic diagnosis, comborbidities, or lack of diagnosis. 

  • A Therapeutic Response Group is Unravel's concept for clustering patients — using its AI algorithms and RNA signatures — by predicted treatment response rather than by root cause or diagnosis, since two patients with the same diagnosis don't always respond to the same drug. Unravel emphasizes RNA as the source of patient data because, unlike DNA (which is largely fixed), RNA gives a dynamic, ongoing picture of a patient's condition, reflecting environment, sleep, diet, medications, activity, and even the microbiome, and continues to inform understanding of a disorder as it progresses or is treated. We can use RNA to understand the disease state and monitor patient changes over time, changing due to natural disease progression or in response to treatment. 

  • Unravel's platform uses a network biology approach, analyzing entire systems and pathways together rather than single genes. While gene expression varies greatly from tissue to tissue, we have found that mechanisms for restoring the network are relatively conserved across the body. This allows BioNAV™ to infer, from one tissue source, how to potentially address a genetic perturbation reflected elsewhere in the body. Nasal tissue is not strictly required — Unravel can work with other tissue samples — but nasal swab collection is what falls under Unravel's existing IRB protocol; any other tissue collection would need to be arranged independently or through a custom research protocol. Nasal swabs are also used because the preservation solution we use inactivates pathogens to simplify international shipping, reaching patients worldwide. 

  • A list of genes Unravel has worked with is available on our rareSHIFT™ website at https://www.rareshift.org/. There are no prerequisites to participate in a rareSHIFT™ study. Unravel's personalized-medicine approach is built around individual patients, and the only required input is transcriptomic data. We can work with any diagnosis (or undiagnosed patient) and any variant. 

  • Unravel used patient RNA data to identify a new therapeutic mechanism for Rett Syndrome (using an existing prescription drug) within about a year; in mouse models this candidate outperformed the only approved drug, and it is in multiple clinical trials. Unravel has repeated this approach for other neurodevelopmental and neurodegenerative disorders. Multiple patients have used their generated data and drug-hit lists with their own clinical teams to evaluate off-label options, with some reporting promising results. One lead prediction for a neurodegenerative disorder, generated and validated in under a year, has been nominated for that foundation's first clinical study. Unravel also reports its platform has led to 25 N=1 clinical success studies and has developed/discovered several molecules (e.g., RVL002, RVL027, RVL069) targeting mitochondrial metabolism and remyelination. 

Participation & Eligibility

  • Patients of any age >6 months can participate, given the nasal swab sampling method is non-invasive and appropriate for infants and children. However, we recommend considering resampling multiple times in very young patients (<2 years), given the extensive developmental changes undergone in the first few years of life. 

  • Participation gives access to Unravel's drug discovery platform, a personalized analysis and report, and potential drug-repurposing candidates. This provides patients with many options in their therapeutic odyssey. The results can drive further research or potentially inform clinical action while also contributing RNAseq data to a shared, collaborative database aimed at accelerating rare-disease drug discovery across many disorders at once. Each personalized study's report is shared back with participants. Finding shared therapeutic responses across unrelated disorders creates opportunities for multiple foundations to pool (“syndicate”) resources for drug development Unravel syndicates drug programs so that each patient can access cutting edge drug development no matter how rare or complex their condition. 

  • Yes. rareSHIFT collects specimens collected where possible under valid, IRB-overseen human-subjects protocols that permit sharing de-identified data for research while strictly protecting participant privacy and confidentiality. Patient identifiers, including genetic sequence data and Protected Health Information (PHI), are removed by Unravel or its clinical research institutional partners per IRB guidelines before any data sharing or publication. Unravel does not use your clinical data to train its AI/ML models, so your data are not incorporated into the underlying BioNAV™ platform and always stay separate. 

Samples & Study Design

  • Nasal swabs, self-collected at home at multiple timepoints across 48 hours, from the patient and one healthy first-degree relative serving as control. Kits include instructions and pre-paid return shipping. Unravel also works with patients with episodic symptoms to collect samples over appropriate time periods to inform on the patient’s biological state and use the patient as their own control. Further customization is available. 

    Considerations: Controls should be symptomatically healthy; swabs should be collected during stable health (no acute illness or recent medication changes). 

  • Yes — Unravel can analyze external RNAseq datasets to shorten timelines and reduce sequencing costs and can incorporate existing clinical metadata to improve interpretation. 

    Considerations: Subject to confirming data format/quality/quantity first. 

  • If no such relative is available, please notify the Unravel team and we can assist with identifying another suitable family member and/or matching suitable control(s) from our database. 

  • This depends on the specific study design and the questions it's meant to answer. As one example, a patient could be sampled at baseline and also act as their own comparison sample for a flare-up period. Unravel recommends discussing specific questions and annotation needs directly with our research team. 

  • A personalized study focuses in depth on one patient plus their specific control, for individualized guidance. This involves sampling 8 samples over two days for each person. Personalized studies for one patient apply to that patient and, due to their personalized nature, cannot be necessarily extrapolated to any other patients, even with identical diagnoses or mutations. A population study collects a single sample from many patients (recruited by the partner, since Unravel itself does not recruit patients) to identify therapeutic subgroups and population-level priorities. Population studies offer greater perspective of a whole disorder at a lower cost per patient but are less directly actionable for any one individual’s unique state. Multiple personalized studies can be combined to provide both a personalized set of result for each patient while also generating population-level insights. 

    Considerations: Unravel has seen patients with the exact same genetic variant predicted to respond to therapeutics in opposite ways (and vice versa), so a more diverse patient population is generally recommended if the aim is to understand how all patients may respond to treatments. Ultimately, study structure should be shaped around the foundation's specific goal’s and we recommend speaking with our scientific team. 

  • Unravel will replace the swabs free of charge. 

  • This is detailed in the consent forms. Participants are free to leave the study at any time. Any data or specimens already collected and processed before withdrawal remain part of the study records. 

  • Kits are shipped worldwide using validated preservation reagents that stabilize RNA at room temperature for many weeks. Some countries require additional import steps or local distributor partners, which Unravel manages case-by-case. At this time, Unravel is unable to work with patients located in mainland China or Russia. Ongoing global events can impact shipping times. 

Results, Timeline & Deliverables

  • Typically, about 8–12 weeks from receipt of samples to a final report for a personalized study. Population studies take longer because of the larger number of samples. 

    Considerations: Subject response times, international shipping, sequencing vendor scheduling, and any expedited options can affect timing. 

  • Yes — Unravel can analyze external RNAseq datasets to shorten timelines and reduce sequData shared back for research use includes RNAseq gene counts data, differential-expression summaries, pathway/network outputs, a ranked drug-candidate list with confidence scores, negative-control comparisons, and a written methods summary — with the exception of raw sequence-level (identifying) data, which requires an additional consent form to release. An example personalized report and an example spreadsheet of raw BioNAV data are available on request. Results are intended to be usable by academic researchers, computational biologists, and treating clinicians alike; Unravel guarantees a results-review meeting (often more than one) to help all involved parties interpret the findings. As a rare disease partner, Unravel routinely supports publication of research results, in peer-reviewed publications, conferences, and other venues. A standard Data Use Agreement is used to share data broadly with researchers to support their work. 

    Considerations: Results are for non-commercial research use and are not diagnostic or treatment recommendations. encing costs and can incorporate existing clinical metadata to improve interpretation. 

    Considerations: Subject to confirming data format/quality/quantity first.

  • Candidates are ranked by confidence (see the report's “Percentile rank” column). Unravel discloses internal reasoning behind the overall candidate drugs and is developing a dashboard to show which pathways are impacted (up- or down-regulated) by each candidate molecule in each patient. 

  • Unravel's database includes 40,000+ molecules.While most of these are for research use only,~3,000 are FDA-approved and ~7,000 are nutraceuticals or supplements with potential human use. The report's “drug annotations” tab lets you search which candidates are FDA-approved and which are known to cross the blood-brain barrier. Blood brain barrier penetrability is annotated where available based on published databases, which are subject to the limits and assumptions of the experimental processes used by third parties. 

  • Predictions come from a large perturbation database and a validated pipeline; clinicians and families have reported meaningful clinical responses in multiple cases, and in-vivo models have validated many top predictions. Unravel filters candidates for factors like safety during report generation and uses its SquishyWare (tadpole-based) platform to help validate top candidates for safety and efficacy. Underlying data is also shared back so partners can independently test candidates in existing models. 

    Considerations: Not every candidate works for every patient — results are individualized, and while promising, success is variable. No drug is inherently “safe” in isolation; dose materially affects the risk/benefit picture. Determining appropriateness for a specific patient, including any off-label use, is ultimately the responsibility of that patient's treating clinician. 

  • Visit this page for more information.  

  • Yes — As one possible next step, Unravel offers an optional rapid in vivo validation step using its SquishyWare tadpole-based platform (or partners with mouse/iPSC labs) to test top candidates for efficacy and toxicity. Tadpoles offer a fast vertebrate model system with meaningful immune and CNS parallels to humans. If an animal model does not exist for your specific disorder, Unravel may be able to build one for you. Studies require 4-8 weeks to build an initial model and approximately 4 months for characterization and drug screening. The specific design (e.g., generic knockdown vs. haploinsufficiency vs. variant-specific modeling, or separate designs for truncating/loss-of-function vs. missense variants) is worked out with Unravel's scientific team based on the specific disorder; foundation partners may also use their own model systems to use alongside or instead of tadpoles. 

    Considerations: In vivo validation is optional and adds cost and time (months) but can meaningfully increase clinician confidence for higher-risk candidates. No model is a perfect mimic of a patient — even matched phenotypes don't guarantee matched drug response — so models are best used as a downselection/screening tool. 

  • Reports contain many drug candidates to select from, giving far more than one option. Unravel offers resampling and re-analysis (shorter time and lower-cost than the original study) to monitor a patient's molecular response over time and help guide next choices; families can work through the ranked candidate list with ongoing clinical oversight and the Unravel team available as needed for consultation. 

  • Should patients pursue changes in their treatment under the guidance of a clinical team, whether for Unravel-generated predictions or from any other sources, Unravel provides molecular-level before/after comparisons to enable deep insights into the underlying therapeutic effects. The Unravel clinical research team is available to consult on potential clinical metrics to track outcomes. Families and clinicians have paired this with objective outcome measures such as standardized clinical scales, videos, therapist notes, actigraphy, or seizure logs. 

    Considerations: Establishing baseline clinical measures and an agreed monitoring plan with the treating clinician up front supports more rigorous tracking of changes that can more quickly confirm how well any treatment decisions are working 

  • Unravel partners with families to brief treating clinicians on study results, provides physician-friendly versions of reports, and can offer peer-to-peer calls or introductions to telemedicine providers and other clinicians experienced with off-label implementation. 

  • Results can guide clinician-led off-label use or be used to help design observational studies and clinical trials. The program is not FDA-approved and insurance coverage is not likely, though some corporate programs have funded these studies. Additional validation (e.g., observational data, preclinical testing, or IRB procedures) may be required. Unravel collaborates with foundations to design and conduct clinical trials. 

    Considerations: A typical pathway looks like: single patient observational study → expanded population observational study → clinical trial. Clinic partnerships can help build the needed evidence base. 

Data, Privacy & Intellectual Property

  • Under our standard partnership model, which is designed to allow foundations to benefit from research results while being mindful of limited budgets, pricing for studies is drastically reduced in exchange for Unravel retaining commercial rights and ownership of results. Partners have access to all of the data for any non-commercial use, such as further scientific or clinical research. This supports Unravel's goal of defragmenting rare-disease and identifying shared therapeutic mechanisms across disorders while supporting foundations’ individual research goals. Unravel works case-by-case with groups pursuing their own commercial development. 

    *A separate, industry-based partnership model agreement is available where the partner owns all data and results. Contact Unravel’s team for pricing. 

  • Unravel provides a standard research Data Use Agreement (DUA) so that data can be shared for non-commercial use with third parties. Unravel does not intend to offer data access on a commercial basis (e.g., for sale or licensing for AI model training), but may research the data further for commercially relevant applications. Under the DPA, Unravel owns the data/results and retains the right to share results with third parties, reflecting Unravel's broader strategy of enabling syndication of drug development and pooled progress across disorders/collaborators. An alternative industry-type agreement (similar to a CRO arrangement) is available in which the partner owns all data and results; because the data isn't integrated into Unravel's models, it can be removed after study completion and handoff. We welcome foundations or individual partners interested in leading commercial development of the results and work with them to develop a licensing agreement. 

    Considerations: The alternative CRO-like agreement is priced at industry rates (about 2x standard pricing), since it doesn't give Unravel or other parties any long-term benefit like syndication or data sharing. Most foundations to date have chosen the standard DPA approach; a small number have used this alternative. 

  • No. BioNAV™ and BioX™ are used to generate therapeutic-response predictions and understand mechanism of action, but patient/control data is not used to train these models — the models are models of health and are pretrained on other datasets. This is part of what allows Unravel to make personalized predictions from just a few samples and means a given patient's data can be added or removed without changing the underlying model. 

  • All Protected Health Information (PHI) — the information necessary for initial communication and shipping — is stored on a HIPAA-compliant platform, and all data are maintained under IRB-approved conditions. Patient identifiers, including genetic sequence data and PHI, are removed by Unravel before any data sharing or publication unless specific additional consent is provided by each subject. 

  • The partner who is responsible for the master Discovery Project Agreement (DPA) and each Statement of Work (SOW) retains rights to the data/results for non-commercial research use, while Unravel retains commercial rights — this is outlined in Unravel's DPA. Unravel has an IRB in place for its clinical research studies and can connect partners with its clinical operations team for pediatric-consent-specific questions. 

Cost & Payment

  • The standard personalized-study fee covers sample kits, sequencing, computational analysis, a detailed report, and a results consult; pricing for nonprofits is designed to cover Unravel’s costs, which offers a significant discount over industry rates. A single personalized study/patient-control pair is $15,500; a 15% bulk discount applies at 5 or more studies conducted together, bringing the price to $13,175 per patient — this bundled option includes both individual personalized reports and a population report comparing all studies. 

  • (1) Group of personalized studies: $15,500 per patient-control pair (4 or fewer participants), or $13,175 per patient with a 15% discount at 5+ studies conducted at once (includes personalized reports plus a population report). (2) A 20-patient population study: $75,000, plus $2,100 per additional patient-control pair beyond 20. (3) A 10-patient population study is also offered but is recommended only when a population is so limited that reducing to 10 patients is necessary, given the reduced statistical confidence at that smaller scale — expanding the population (e.g., to include related disorder subtypes) is generally suggested first. 

  • Recruitment criteria are determined by the partner (foundation/family), not Unravel. The requirement tied to the discount itself is that all studies in the group must be contracted and conducted together, in unison. 

  • Only the personalized-study results in a personalized report. A population study does not generate enough per-individual data to enable the statistical analysis required to produce a report specific to any one patient, and Unravel recommends against treating an individual's data from a population study the way you would a dedicated personalized study, due to reduced statistical confidence from relying on a single sample. The value of a population study lies at the population level. 

  • Pricing is in US dollars and includes all taxes and fees charged by Unravel; however, any additional fees Unravel itself incurs in unique situations (for example, a bank fee for credit card payments) are passed through to the partner. Accepted payment methods are domestic ACH transfer, wire transfer, and credit card (credit card payments carry an additional 2.8% processing fee). 

  • Yes — Unravel works with foundations, fiscal sponsors, and family fundraising efforts. Bundled studies (5+ personalized studies conducted together) often qualify for a discount, and foundations can sponsor population studies. Additional opportunities may be possible, including by partnering on innovative programs. Unravel also collaborates with many researchers directly to obtain grant funding for studies. 

    Considerations: Practical fundraising routes include foundation sponsorships, fiscal-sponsorship arrangements, and grants. 

  • Unravel contracts with foundations/families through a master service agreement  (Discovery Project Agreement) and specific Statements of Work including RNAseq data generation, in silico drug screening, and potentially animal-model development/screening.  

Commercial Pathways & Advanced Development

  • Interest in licensing results for commercial development can be discussed upon the delivery of the results. Unravel is open to co-development, when it is a good strategic fit, and to other partnership models for commercial development. Unravel acknowledges we can't realistically pursue every commercial finding and, at that point, would engage with a strategic partner, including a foundation. Unravel already partners with foundations and families on both discovery and development. A key advantage to drug development with Unravel is the ability for Unravel to bring diverse foundations and individuals together to syndicate development of a drug, making it far less expensive for each group.