Why Does It Take So Long: A Field-guide to the Research Pipeline
Families often ask us why a promising treatment they read about seems to take years — sometimes a decade or more — to reach patients. The honest answer is that “the research” is really a chain of dozens of distinct steps, each with its own team, timeline, and checkpoint. This guide walks through that chain, step by step, so you can see where a therapy is and roughly what’s left before it.
The general model: almost every new treatment moves through three broad phases — discovery/preclinical (does this work in a dish or an animal?), clinical development (is it safe and effective in people?), and manufacturing & regulatory approval (can it be made reliably and legally sold?). Funding has to be secured continuously across all three, not just once at the start. For a rare disease like an organic acidemia, every one of these steps is harder, because there are fewer patients, fewer specialized labs, and less commercial incentive than for common diseases.
Our running example: In May 2026, the FDA cleared the Investigational New Drug (IND) application for MMA-101, an NIH-developed AAV (adeno-associated virus) gene therapy for methylmalonic acidemia caused by MMUT mutations. It’s on track to enter a first-in-human Phase I/II trial at the NIH Clinical Center. We’ll use it throughout to make each step concrete. Throughout the research milestones listed below you will find a note on the timeline of the MMA-101 gene therapy development for context.
1) Preclinical Work — typically 3–6+ years
Preclinical research is everything that happens before a drug ever touches a human being. The goal is to prove a therapeutic idea makes biological sense and that it is safe enough to justify the risk of testing it in people. The following are milestones that need to be completed to gather evidence about the biology and safety before testing a drug on a human.
Target identification & validation (1–2 years) — Researchers pinpoint the exact gene or protein driving the disease (for MMA, the MMUT gene) and confirm that fixing it actually changes disease biology. This is the foundation everything else is built on — get it wrong, and every later step is wasted.
1969 – The paper establishing an apo enzyme defect as the cause of MMA Mut0 was published (1)
1988 – The MMUT gene was cloned (2)
1990 – Mutations from methylmalonic acidemia patient liver cells were identified to be in the MMUT gene. (3)
1991 – First evidence that mutations in MMUT are the cause of methylmalonic acidemia (4).
Cell and in vitro models (overlapping, ongoing) — Patient-derived cells or engineered cell lines are used to test whether a therapy behaves as expected at the molecular level (does the corrected gene actually make functional enzyme?). These are fast, cheap, and let researchers fail early and iterate rather than moving straight to animals.
Sept 2022 – Serum samples from patients with MMA were tested for neutralizing antibodies that could prevent the AAV gene therapy from successfully transducing patient cells (5).
Animal models / proof of concept (2–3 years) — A therapy is tested in a mouse (and sometimes larger animal) model of the disease to see if it improves survival, biomarkers, or symptoms in a whole living system. This is usually the first “does this actually work” moment, and it’s what most published research updates you read about reflect.
Sept 2022 – The same publication where MMA patient patient serum samples were used, also shows evidence that the MMA gene therapy lengthens the life of MMA mut 0 mice (5).
Vector design & optimization (gene-therapy specific, 1–2 years for a program using established platforms today; historically much longer) — Engineers design and refine the viral “delivery vehicle” (here, an AAV capsid) that carries the corrected gene into liver cells, testing variants for how well they target the right tissue without triggering immune reactions. Getting the vector right is often the single biggest bottleneck in gene therapy development.
MMA-101’s own capsid work stretched across more than a decade of iteration, in part because the AAV field itself was still maturing. A program starting today can lean on vector platforms and manufacturing know-how that simply didn’t exist in the 2000s and 2010s (5,6).
IND-enabling toxicology & safety studies (1–2 years) — Formal, regulator-required studies (often in a second animal species) establish a safe starting dose and check for unexpected organ toxicity, immune reactions, or off-target effects. These must be run to strict Good Laboratory Practice (GLP) standards, and they’re what regulators actually review before allowing a human trial.
Supporting labs & assays (ongoing throughout) — A gene therapy program also needs biodistribution assays (where does the vector actually go in the body?), potency assays (how much correct protein does it produce?), and immunogenicity assays (does the body attack it?) — each developed and validated as its own mini-project before it can be trusted for decision-making.
Sept 2022 – Testing for neutralizing antibodies is an example of one of these types of tests (5).
2) Clinical Trial Design
typically 1–3 years, often overlapping with late preclinical work
Longitudinal natural history study as a control (3–5+ years of prior data collection, ideally already underway) — Because organic acidemias are so rare, there often aren’t enough patients to run a traditional placebo-controlled trial. Instead, a natural history study — tracking how the untreated disease normally progresses over years — becomes the comparison group, which is exactly what OAA’s registry work is designed to support.
2004 – Dr. Venditti began leading a longitudinal study to look at the natural history of methylmalonic acidemia.
Establishing clinical sites (6–12 months per site) — Each hospital that will run the trial needs specialized staff trained on the protocol, the right equipment (like apheresis or infusion units for gene therapy), and its own institutional approvals. For rare diseases, sites are often limited to a handful of specialized metabolic centers, which is part of why travel burden on families is so real.
IRB/ethics review & site activation (3–9 months per site) — Each site’s Institutional Review Board must independently review and approve the protocol and consent materials before enrollment can begin there. This exists to protect participants, but it does mean the same trial can open at different sites months apart.
Writing the protocol (6–18 months) — The protocol is the detailed rulebook for the trial: who qualifies, what’s measured, how often, what counts as success, and what safety rules trigger a pause. It has to satisfy scientists, the FDA, ethics boards, and families’ safety all at once, which is why it goes through many drafts.
Regulatory pre-submission meetings (several months, can run parallel to (b)) — Sponsors meet with the FDA before filing to get feedback on trial design, endpoints, and dosing strategy, so the eventual IND submission doesn’t get delayed by avoidable disagreements. For ultra-rare diseases these conversations matter enormously, since there’s rarely an established regulatory playbook to follow.
Establishing clinical sites (6–12 months per site) — Each hospital that will run the trial needs specialized staff trained on the protocol, the right equipment (like apheresis or infusion units for gene therapy), and its own institutional approvals. For rare diseases, sites are often limited to a handful of specialized metabolic centers, which is part of why travel burden on families is so real.
IRB/ethics review & site activation (3–9 months per site) — Each site’s Institutional Review Board must independently review and approve the protocol and consent materials before enrollment can begin there. This exists to protect participants, but it does mean the same trial can open at different sites months apart.
3) Manufacturing — typically 1–2 years for a gene therapy, ongoing across the whole program
For a small-molecule drug, manufacturing is comparatively straightforward. For a gene therapy, making the product is a research project of its own.
Process development & scale-up (6–12 months) — Scientists work out the recipe for growing cells and producing enough high-quality viral vector, then scale that recipe up from lab flasks to bioreactor volumes without losing potency or purity. Small changes at scale can behave completely differently than they did on the benchtop, so this step is iterative and failure-prone.
cGMP production campaign (3–6 months per batch, once the process is locked) — Vector is manufactured under Current Good Manufacturing Practice — the strict, auditable standard required for anything given to a human patient. Every raw material, piece of equipment, and process step has to be documented and controlled.
Quality control & release testing (4–8 weeks per batch) — Each batch is tested for identity, potency, purity, and sterility before it’s allowed to be used in a patient — dozens of individual assays that all have to pass. A single failed release test can mean discarding an entire batch and restarting.
Comparability & stability (ongoing) — If the manufacturing process changes at any point (which is common as a program moves from small Phase 1 batches to larger commercial-scale batches), regulators require proof that the “new” product is equivalent to the “old” one. This is a frequent, underappreciated source of delay in gene therapy programs specifically.
4) Regulatory Review & Oversight — checkpoints throughout, not one single step
IND application & clearance (FDA has 30 days to respond once filed, but preparing the application takes 6–12+ months) — This is the formal package of all preclinical, manufacturing, and trial-design data that must be cleared before any human dosing can start; MMA-101’s IND clearance in May 2026 was exactly this milestone. It doesn’t mean the drug works — only that it’s reasonable to test in people.
May 2026 – The MMA gene therapy trial was granted IND clearance in May 2026. You can read the press release here.
Orphan Drug & Rare Pediatric Disease designations (a few months to apply for, can be pursued anytime after early preclinical data exists) — These FDA designations offer incentives like extended market exclusivity, tax credits, and fee waivers, which matter enormously for diseases too small to attract typical commercial investment. Pursuing them is a strategic, non-trivial part of program planning.
Nov 2020 – The Orphan Drug designation was given to the MMA gene therapy when it was first submitted by AskBio and Selecta Biosciences (8). The designation has since been transferred to the new IND application sponsored by the NIH.
Data & Safety Monitoring Board (DSMB) oversight (ongoing for the life of the trial) — An independent panel reviews safety data at pre-set intervals throughout the trial and has the authority to pause or stop it if a concerning pattern emerges. This oversight is a major reason trials can’t simply be rushed once they’ve started.
BLA/NDA submission & approval (typically 10 months to 2+ years of FDA review, after years of trial data) — Once a trial (or trials) shows enough evidence of safety and benefit, the sponsor files for full approval, and the FDA reviews the complete dataset before allowing the therapy to be marketed. For gene therapies, this can include additional advisory committee review given the novelty of the technology.
5) Study Recruitment & Conduct — typically 1–5+ years depending on phase and disease rarity
- Patient recruitment in an ultra-rare disease (often 1–3+ years just to fill a small Phase 1/2 cohort) — When the entire eligible U.S. population might be a few hundred people, finding patients who meet strict inclusion criteria, live near (or can travel to) a trial site, and are willing to participate is genuinely difficult. This is precisely the gap OAA’s registry and community outreach exist to close.
- Time to see a measurable change (varies enormously — weeks for a biomarker, years for a hard outcome) — Some effects (like a drop in disease-related metabolites) can show up within weeks of dosing, but “harder” outcomes — fewer hospitalizations, better growth, preserved kidney function — take months to years of follow-up to demonstrate convincingly, especially in a disease that progresses slowly or unevenly. This is why some trials plan years of follow-up even after everyone is dosed.
- Phase 1/2 — safety and early efficacy (1–3 years, including follow-up) — A small group of patients receives the therapy first, with intensive monitoring to check safety and look for early signs it’s working; MMA-101’s current trial is at this stage. In gene therapy, this phase often uses a “dose-escalation” design, testing low doses before moving to higher ones, which adds time but is a critical safety guardrail.
- Phase 3 — confirmatory trial (2–4+ years, sometimes waived or modified for very rare diseases) — A larger trial (or, for ultra-rare diseases, an expanded Phase 1/2 with an FDA-agreed alternative design) is meant to confirm the benefit holds up and characterize the safety profile more broadly. For diseases as rare as the organic acidemias, regulators increasingly accept smaller, natural-history-controlled designs here rather than requiring hundreds of patients.
6) Funding — continuous, no fixed timeline, and often the true rate-limiting step
Every step above needs money, and for ultra-rare diseases, funding doesn’t arrive in one lump sum — it has to be re-won at every stage.
Early discovery funding (foundation and philanthropic grants, like OAA’s own Research Grant Program) — Because rare disease research is too early-stage and too small a market for most commercial investors, foundation and family-driven philanthropy is frequently what funds the preclinical work that later attracts bigger partners.
The Organic Acidemia Association has granted Dr. Charles Venditti research funding for preclinical studies required for future therapies.
Federal/NIH grant funding (competitive, awarded in 1–5 year cycles) — Government grants fund a large share of the basic and translational science behind rare disease therapies (MMA-101, for example, was NIH-developed), but they require competitive applications and renewal, which can create funding gaps mid-project.
Industry/venture investment (deal-dependent, no fixed timeline) — Once a therapy shows real preclinical or early clinical promise, pharmaceutical or biotech investment can accelerate manufacturing and larger trials dramatically — but attracting that investment for an ultra-rare disease population is its own uphill negotiation.
Late 2010s – AskBio and Selecta Biosciences partnered with NHGRI and carried the program through orphan drug and rare pediatric disease designations in 2020 and into GMP manufacturing, then discontinued it as corporate priorities shifted.
2023 – Rather than letting the work disappear, Selecta (later Cartesian Therapeutics) donated the manufactured drug product, key reagents, and regulatory documentation to NIH — which is what allowed NHGRI to file its own IND in April 2026 and get clearance that May.
Post-approval funding realities (begins before approval and continues after) — Even after a therapy is approved, insurers and payers negotiate coverage and pricing, which determines whether patients can actually access it. Getting a therapy invented is not the same as getting it into a patient’s hands.
Putting it all together
Add it up, and a typical modern journey from “we found the gene” to “a patient receives an approved therapy” runs roughly 10–15 years for a conventional drug — often longer for a gene therapy, given the added manufacturing complexity. None of these steps run in a neat single-file line; many overlap, loop back when something fails, or wait on funding before they can restart.
MMA-101 is a good reminder that the “typical” range assumes a field with mature tools already in place — and for a genuinely first-of-its-kind program, that’s not always true. Its real arc looks more like: early 2000s mouse model development → 2010 first successful AAV gene therapy rescue in that model → over a decade of vector redesign and optimization (including developing the AAV44.9 capsid, since off-the-shelf capsids weren’t good enough) → IND-enabling safety studies → GMP manufacturing of clinical-grade vector → IND clearance in May 2026 → the Phase I/II trial now getting underway — with years of follow-up still ahead before any conversation about approval. That’s closer to 20+ years, most of it spent building and rebuilding the underlying gene therapy toolkit almost from scratch.
The encouraging part: a lot of that toolkit now exists. Newer organic acidemia gene therapy programs — like the PCCA/PCCB and MMAB-type CblC-MMA work presented at ASGCT 2026 — can build on established AAV capsids, characterized mouse models, standardized manufacturing platforms, and an FDA that has now reviewed several similar programs. None of that guarantees a fast path, but it’s a real reason to expect future organic acidemia gene therapies to move through this same pipeline meaningfully faster than the one that came first. A related effort worth knowing about is the Bespoke Gene Therapy Consortium (BGTC), a public-private partnership between NIH, FDA, and industry and nonprofit partners that’s working to shorten the preclinical-to-IND timeline for ultra-rare gene therapies by standardizing manufacturing platforms, assays, and the regulatory playbook across a shared set of pilot diseases — propionic acidemia is one of the eight diseases in its current portfolio.
Where OAA — and you — fit in:
Our natural history registry directly shortens step 2(a) above by building the control-group data researchers need before they ask, and our Research Grant Program helps fund the earliest, hardest-to-fund step, 1(a)–(c).
But there’s a bigger concept worth naming here: participating in an observational study like our natural history registry de-risks future clinical trials.
Every family’s data helps establish what “untreated” really looks like — how the disease actually progresses, how much it varies person to person, which measurements are meaningful — so that when a sponsor is deciding whether to invest in a trial, they already have a validated comparison group and realistic expectations for what a treatment effect would look like, rather than having to build all of that from scratch (or discover mid-trial that their assumptions were wrong). That lowers the cost, time, and uncertainty of running a trial, which is exactly the kind of risk that keeps companies and funders from investing in ultra-rare diseases in the first place. Every family who joins the registry or shares their story is quite literally shortening this timeline — and making the next trial more likely to happen at all.
Have questions about where a specific study or therapy is in this process? Reach out. We’re always happy to help translate the science.
References
- Morrow G 3rd, Barness LA, Cardinale GJ, Abeles RH, Flaks JG. Congenital methylmalonic acidemia: enzymatic evidence for two forms of the disease. Proc Natl Acad Sci U S A. 1969;63(1):191–197. doi:10.1073/pnas.63.1.191
- Ledley FD, Lumetta M, Nguyen PN, Kolhouse JF, Allen RH. Molecular cloning of L-methylmalonyl-CoA mutase: gene transfer and analysis of mut cell lines. PNAS. 1988;85(10):3518–3521. doi:10.1073/pnas.85.10.3518 (PMC280243)
- Jansen R, Ledley FD. Heterozygous mutations at the mut locus in fibroblasts with mut⁰ methylmalonic acidemia identified by polymerase-chain-reaction cDNA cloning. Am J Hum Genet. 1990.
- Raff ML, Crane AM, Jansen R, Ledley FD, Rosenblatt DS. Genetic characterization of a MUT locus mutation discriminating heterogeneity in mut⁰ and mut⁻ methylmalonic aciduria by interallelic complementation. J Clin Invest. 1991;87(1):203–207. (PMC295026)
- Chandler RJ, Di Pasquale G, Sloan JL, et al. Systemic gene therapy for methylmalonic acidemia using the novel adeno-associated viral vector 44.9. Mol Ther Methods Clin Dev. 2022;27:61-72. Published 2022 Sep 6. doi:10.1016/j.omtm.2022.09.001
- Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, et al. Adenoviral-mediated correction of methylmalonyl-CoA mutase deficiency in murine fibroblasts and human hepatocytes. BMC Med Genet. 2007;8:24.
- AskBio and Selecta Biosciences Receive FDA Rare Pediatric Disease Designation for their Gene Therapy for Methylmalonic Acidemia, GlobeNewswire, Oct. 20, 2020
- AskBio and Selecta Biosciences Receive Orphan Drug Designation for MMA-101 to Treat Methylmalonic Acidemia, GlobeNewswire, Nov. 19, 2020
- Selecta Biosciences Announces Merger with Cartesian Therapeutics, GlobeNewswire, Nov. 13, 2023
- NCATS, “FDA Clears IND for Gene Therapy Candidate to Treat Rare Metabolic Disorder,” May 2026