Project Baby Lion

TNPO2 Foundation

Despite dramatic clinical benefits and economic scalability, frontline clinicians are unfamiliar and uncomfortable with the use of Whole Genome Sequencing (WGS). This diagnostic tool leverages the progress in both the genomic revolution, as well as the digital revolution, to diagnose the lowest incident cases in rare diseases.  Judicious use of sequencing can end the diagnostic odyssey, which frustrates and exhausts patients and caregivers of rare disease patients.  Most of these patients are pediatric, and most of these patients frequent specialists and hospitals, with severe yet confusing symptoms.

What do families do when they eventually receive a precision diagnosis?  For the vast majority, there are no treatment options and the story ends with palliative care.  A few enterprising families attempt to develop treatments by banding with other families, forming foundations, attracting industry partners, etc.  

The journey after a precision genetic diagnosis is not yet well defined.  Families such as mine are left wondering what, if anything they can do.  Clinicians have little familiarity with diseases with ultra-low incidence rates, and even less in the way of published literature.  Professional ethics and regulations leave them no flexibility to advise families on where to go for help.  

Each family must re-invent the wheel, re-discovering what those who came before took great pains to learn.  These parents and caregivers are the least resourced and begin the journey with the least expertise; yet they are the most well-meaning and most motivated of all stakeholders in the rare disease space.  While parents get up to speed, valuable time is slipping by; genetic diseases onset quickly and cause damage to young, oftentimes days old patients.

For well studied inclusion-exclusion criteria, ultra-rapid Whole Genome Sequencing (urWGS, or rWGS) has a high diagnostic yield (40%) in NICU patients.  Furthermore, because rapid correct diagnoses lead to avoided procedures, this test has a highly positive economic ROI; we save more in healthcare resources than the cost of the tests themselves.  This has been demonstrated in by many studies, beginning with Project Baby Bear.  

The healthcare infrastructure (insurance coverage, standard of care practice) hasn't fully caught on and the vast majority of infants and patients with diagnosable ultra-rare diseases continue to slip through the cracks. Our program seeks to remedy this by spearheading the implementation of rWGS in our local community, then statewide.  

Ending the diagnostic odyssey at scale leads us directly into the second goal of Project Baby Lion.  

Project Baby Lion will help all families who are willing to undertake the "therapeutic odyssey", in whatever way we can; by connecting families with well run scientific patient groups, by establishing partnerships with best-in-class therapeutics partners; from drug-repurposing organizations to precision genetic medicine developers.  

By accelerating the process and enabling patients and their families to sit in the drivers seat and take a proactive approach in one of the most challenging situations a family can be thrown in.

We will also begin "wet-lab" work, as soon as a positive diagnosis is reached.  The initial steps of the drug discovery and development process are time and cost efficient.  Initiating patient cell line development and data collection within days of birth can bring forward by months, the initiation of treatment; leading to the potential to intervene within (or even before) the critical window of opportunity.

We believe that every ultra-rare disease patient is rescuable, and that they can be rescued in a sustainable way.  We begin with NICU patients to give ourselves the most time, which is the most expensive resource.

Infants admitted to the NICU with suspected genetic rare disease.

- We will diagnose approximate 40% who satisfy our inclusion/exclusion criteria.  Current standard of care diagnoses approximate 25%; the difference is constituted by NICU patients who go on to have the longest and most difficult diagnostic odysseys, because they have the rarest diseases that are generally missed by standard-of-care testing

- For positively diagnosed patients: 

- - We will immediately begin development of the most relevant cell lines, so that any academic or industry partner can begin work immediately.

- - We will immediately connect patients with drug-repurposing partners who have an excellent clinical track record (Matthew Might lab, Every Cure).

- We will preemptively iron out bureaucratic hurdles and make sure all stakeholders understand the outcomes at stake for each child.

- For those without a positive diagnosis, we confer with leading experts and centers (Bellen Lab, UDN, Genomics UK, etc.) to improve the dataset and "start the ball rolling"; to help both the patient in question, as well as the broader undiagnosed community.

We have built the end to end process for our own child; diagnosis to precision therapeutic development and clinical trial.

We successfully diagnosed one child at 4mo of age, and successfully dosed him with a genetic precision medicine (an antisense oligo) at 20mo of age.  He is now approaching 32mo of age, and we have been seeing positive effects from the trial.  

The incidence rate of the disease our child suffered from is 1 per 3 billion.  Due to the low incidence rate, there was very little in the way of basic science foundations.  We thus had to develop almost all the preclinical toolkit from scratch.  

Thus we believe we can tackle almost any rare disease which surfaces from the diagnostic process, even if we had to start again from scratch.

We are now taking everything we've learned from our own diagnostic and therapeutic odysseys, and improving upon it for others.

We are developing the link between diagnosis and disease-modifying therapeutics.  

We are the first to attempt to connect diagnosis with therapeutics.  We believe building this link will be the key to realizing the vision of "bench-to-bedside" precision medicine.

We are attempting the most vertically integrated process for rare disease patients; with genetically ill infants as the target patient population, because they have the most to gain, being at the very beginning of the journey of life.

The "usual" patient advocacy journey consists of 1. gather a community 2. fundraise and seed academic papers 3. attract for-profit partners such as biotech and VC 4. develop a pipeline asset and push it into the clinic.  Our program will partner with every stakeholder in the process above; as well as running an end-to-end drug development process where no other options exist.

Our end goal is to build the infrastructure (both material and process) to develop and deliver personalized medical care.  We believe that infants are the correct patient population to begin with since they have an opportunity at entire lifetime of economic contributions, as well as an entire lifetime of disability benefit entitlements at stake.  All depending on how their disease progression impacts their lives and how independently they can function.

1.  The Amgen prize would help us fund more iPSC lines for positively diagnosed infants.  The Amgen prize would also help us slightly expand our sequencing pilot, increasing the probability that a diagnosed patient could receive a promising repurposing hit.

2. The Amgen prize would also provide our project with more visibility.  It would give us a platform to advocate for widespread adoption of rapid Whole Genome Sequencing in the NICU, to educate clinicians, healthcare administrators, and insurance executives about the benefits of this tool.  It improves patient outcomes, physician satisfaction, and lowers healthcare expenditures all at the same time.

3. The Amgen Prize would help us build partnerships for our "post-diagnosis" odyssey process.  Partnerships are essential to finding the most appropriate innovative treatment for each ultra-rare patient, and awareness is the missing piece.  With more awareness for our project, we could connect our patients with the academic labs and industry partners who may have assets or programs in pipelines which can be licensed on a compassionate use basis, which may ultimately save the life of a newborn infant.

We are partnered with the Rady Institute of Genomics (affiliated with UCSD and Rady Children's Hospital), and Stony Brook Children's Hospital.

Rady is a world class leader in genomic medicine, and the pioneer of rapid Whole Genome Sequencing. 

Stony Brook is the flagship university of the SUNY system, and where our child received much of his treatment before his diagnosis.  We are expanding access to world class genomic medicine, from diagnosis to therapeutics, outside of the standard academic medical centers.  

Our team lead is a member of the community we are serving; a parent who lives in the community that the local hospital serves, and who has become deeply familiar with the patient/caregiver's journey.

Our primary impact goal within five years is the systematic adoption of the use of rapid Whole Genome Sequencing for NICU patients with satisfying specific inclusion-exclusion criteria, in New York State.  These patients have a diagnostic yield of approximately 40%.  

Within the next 3-4 months, we expect to begin an finish a pilot NICU sequencing project that establishes a partnership between Stony Brook Children's Hospital (New York partner) and Rady Children's Hospital (sequencing partner).  The Stony Brook NICU serves over 1000 patients annually; of these, approximately 600 satisfy the inclusion-exclusion criteria

Within the next year, we hope to put rWGS in widespread use at Stony Brook, and begin pilot programs in other Long Island hospitals, as well as SUNY hospitals statewide.  

During subsequent 4 years, we hope to make rWGS standard of care, addressing the attendant systemic and bureaucratic hurdles (reimbursement and clinician uptake).  Our tracking of the economic ROI based on our pilot (which essentially repeats previous replicated studies) will empower our (and others') advocacy efforts for reimbursement policy changes at NY Medicaid, NY BCBS, and other insurers and employers.  We will also work on systematically educating the frontline prescribing physicians, and most intensivists are still new to the clinical practice of genetics in the ICU setting.

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Our secondary, though more important, impact goal is to study the economic ROI of the change in clinical management post diagnosis.  While the Project Baby Bear (Manatee, Dear, etc.) study series compared the clinical and economic ROI for changes in care management, this was all under the practice of "standard of care".  Our goal is to introduce and study the systematic sustainability of more of "bench-to-bedside" types of precision care. 

Starting with the least innovative and escalating to the most innovative as needed

1. FDA approved disease modifying therapies; this is available for less than 5% of rare and ultra rare diseases.

2. Evaluating and recommending clinical trials where possible.

3. Attempting compassionate use applications where possible and feasible, facilitating the introductions and necessary conversations with relevant patient groups sand biopharma industry organizations.

4. Running bio-informatics drug-repurposing searches, escalating to in-vitro screening when advisable.

5. Accelerating pipeline assets, not yet in the clinic (as in Jacifusen, a.k.a. ION-363, an lifesaving drug by IONIS Pharmceuticals).

6. Running de-novo drug campaigns; but using cutting edge technology to meaningfully drive the orders of magnitude reductions in cost in the process.  This is the most resource intensive, however we believe our partners have viable pathways to achieving these cost reductions.

1. We expect our solution to have a significant impact on shortening the diagnostic odyssey (2-4yrs), because we search for those patients who are currently the most difficult to diagnose, and for whom the current standard of care process is almost designed to miss.  

2. We expect to explore (and publish everything we learn) about how to systematically map the post-diagnostic odyssey.  We have a comprehensive plan and by tracking both clinical and economic (in the sense of healthcare resources used) outcomes, we expect that the rapid application of low-resource efforts (such as linking patients with relevant clinical trials, and bioinformatics drug repurposing) may also have positive sustainability margins.

3. With the positive sustainability margins from the diagnostic odyssey and the low-resource super-standard-of-care approaches (clinical trials and repurposing) in hand, we plan to invest these resources in the rapid development of precision therapeutics.  This we have already done once, and know where to gain the most time, and save the most in mistake effort, and we believe we can address the most difficult problem: developing precision therapeutics rapidly, and sustainably.

1 full time staff

3 part time staff

5 contractors/individuals at partners

2.5 years for first patient

.5 years for subsequent patients

Diversity: We appreciate and leverage the many differences of the rare disease community, and we involve and reflect the various communities we serve through partnership and open innovation.  Our in house staff is majority women, and half people of color.

We design our policies, practices, and resources with the goal of providing patients of all backgrounds an equal opportunity for a science driven approach to rare disease treatment.  Our recruitment efforts emphasize the prioritization of equity for patients, that NICU patients are new to the world and should be treated equally in the eyes of the healthcare system.  We recruit our staff with the same meritocracy in mind, and with the aim of serving a diverse and inclusive patient population.

We strive to create an environment in which everyone feels valued and respected. The TNPO2 Foundation supports patients, scientists, clinicians, and industry members who use patient-centered technologies to collaborate on the incredibly difficult challenge posed by ultra-rare diseases. We prioritize the patients with the greatest unmet need; with the least resources; the resulting infrastructure for precision medicine will be applicable to everyone. 

Our key beneficiaries (outside of patients and families) are insurance companies (and the state) who simultaneously save costs by avoiding unnecessary medical procedures, yet elevate the medical care of their insured patients.

Our primary goal is accelerating the widespread adoption of a proven technology, and tracking the performance of the technology at scale.  

Insurance providers need this because it is elevating the diagnostic healthcare they pay for (true-positive diagnoses; in lieu of false positives and false negatives) while reducing their costs (healthcare expenditure incurred by prolonged diagnostic odysseys).

Our secondary goal serves the patient community, and by extension the healthcare system and the biomedical research industry.  We are building the roadmap for families who have no options, linking them to the most appropriate and well regarded partners (often led by patients and caregivers who have undergone the journey, i.e. Drs. Matthew Might, David Fagjenbaum).  We will fill in the gaps that take newly diagnosed patients the most time, and we will find the opportunities that are most scientifically sound, always prioritizing the risk-benefit profile of the patients.  The healthcare system as is often puts risk-management for everyone, except the patient, first.  Our partners have both the credibility and the courage to stand up for others who now face the same challenges that they made meaningful progress against.

Our plan for financial viability for expanding rWGS is reimbursement for the test.  Our work is primarily advocacy and education; we may charge a consulting fee for our work.

Our plan for financial viability for the second goal of mapping the post-diagnostic odyssey follows the footsteps of Project Baby Bear; i.e. track clinical outcomes and demonstrate both clinical improvement on both individual as well as statistical levels for the different interventions (i.e. drug repurposing), while also tracking the economic healthcare resource expenditures.  Our hypothesis is that the improved clinical outcomes for the cases for which drug repurposing works will lead to lower healthcare expenditure, enough to offset bioinformatics resources spent on sorting and interpreting the data to identify appropriate patients and repurposed drugs.  While repurposing works for a small proportion of the patient population, it can still have dramatic effects, and the AI/ML aided literature review is significantly less capital intensive than wetlab work.  We will gather funding from the state and public sources to resource these studies.  If hour economic hypothesis is validated, we will negotiate with insurance to provide this service for subsequent patients.

Business model for de novo precision therapeutics is more similar to the traditional drug development pathway, however we have several innovative alterations.  In particular, the rapidity of the intervention is often critical for rescuing the neurodevelopmental course.  Here the economic savings result from a lifetime of dependence and care that the state (NY in particular has very generous disability benefits) is liable to provide.  The opportunity to change this outcome is an immense social benefit to the family, and a welcome respite for the state budget as well.