Build backwards: A framework for rare disease gene therapy development

AUTHORs: Nicholas Ostrout Ph.D., VP Corporate Development & Strategy AND Farzin Farzaneh Ph.D., CSO, ViroCell Biologics; Hilary Schultz, M.S., CEO, Persephoni Biosciences LLC.

To deliver on the promise of gene therapy for rare diseases, developers must move beyond traditional linear models and begin building backwards — starting instead with the clinical, regulatory, and patient access endpoints they intend to reach. Developers need to reorient rare disease programs around success metrics defined at the outset. From modular vector platforms and early stakeholder alignment to smarter regulatory narratives and flexible academic licensing, structural changes are needed to make rare disease innovation scalable and sustainable. A more disciplined, collaborative, and outcome-driven approach will not only make development more efficient but also enable therapies to reach more of the patients who need them.

A need to rethink the development model

Gene therapy development traditionally follows a linear progression: scientific discovery, preclinical validation, investigational new drug (IND) application, and eventual clinical evaluation. While this model has yielded transformative therapies, it often breaks down when applied to rare diseases. These programs face unique constraints — small patient populations, insufficient animal models, fragmented funding, and limited commercial incentives — that amplify the risks of deferring key decisions around clinical feasibility, regulatory strategy, and manufacturing until after preclinical proof of concept. While the science is sound, many promising therapies falter because they were misaligned with the practical realities of current paradigms in translational medicine development.

A more sustainable approach is emerging. One that begins with the end in mind. This building backwards framework starts by defining clinical, regulatory, and commercial goals from the outset and aligns every development decision, from unique license models, to vector design, to streamlined alternatives to animal model testing, to trial planning and synergistic collaborations, with those endpoints.

This shift also encourages a rethinking of how rare diseases are categorized and pursued. Many belong to genetically or mechanistically related families. Developing each as a standalone program may be inefficient. By identifying shared features — such as delivery routes, tissue targets, or regulatory requirements — developers can build unified platforms that serve multiple conditions. This model enables shared safety data, coordinated manufacturing, and more compelling arguments for funding and reimbursement.

The opportunity ahead is not only to innovate, but to do so strategically. It is important that we design rare disease gene therapy programs from the beginning that are scientifically robust and built for approval, access, and lasting impact.

Defining “building backwards” in rare disease

As described in Building Backwards to Biotech: The Power of Entrepreneurship to Drive Cutting Edge Science to Market, by Stephanie Wisner, the key to driving successful translation of treatments to patients is to start with the desired endpoint and build solutions to get there – the opposite approach, the “solution looking for a problem,” is unfortunately well ordained in many academic labs and is not sufficient in rare disease development. To build backwards is to begin with clarity: a rare disease gene therapy program must be designed to demonstrate scientific feasibility and to meet the full spectrum of success criteria that determine whether a therapy will ultimately reach patients. These criteria include regulatory approvability, clinical relevance, safety, manufacturability, scalability, and long-term accessibility.

In practice, this means defining success metrics before initiating vector design and preclinical studies. Some of the questions to define success criteria may include: What levels of expression are needed in the target tissue? What safety profile will regulators expect based on mechanism of action and delivery method? Are there ways to reduce or remove costly animal safety testing? What manufacturing complexity is feasible in a cost-sensitive rare disease context? What is my dose, and how much material do I need? How will the therapy be delivered, and by whom?

These are not questions to defer until IND filing or commercialization — they must guide development from the outset. A well-conceived program works backward from the point of intended use, ensuring that each technical decision serves the end goal: a therapy that is not only innovative, but viable across regulatory, clinical, and logistical dimensions.

This framework demands rigorous, cross-functional thinking. Scientific ambition must be balanced with regulatory realism. Programs that fail to proactively align design with downstream expectations — whether from regulators, clinicians, or payers — may falter, even if the core technology is sound.

Building backwards does not constrain innovation — it channels it. It challenges developers to define what success looks like for patients, and to make every design decision in service of that outcome.

The power of early multistakeholder collaboration

In rare disease gene therapy, early decisions have lasting consequences. Vector selection, tissue targeting, and preclinical model choices all shape a program’s regulatory pathway, manufacturing feasibility, and clinical relevance. Making those decisions wisely — especially within the constraints of rare disease development — requires early and sustained collaboration.

The most effective programs bring all stakeholders to the table from the start. Patient advocacy groups and families contribute urgency and real-world insight. Academic researchers offer mechanistic depth and translational experience. Contract research organizations (CROs) can provide scientific and study design insights for elucidating the direct mechanism of action, which helps define the quality target product profile (QTPP). CROs can also provide critical knowledge on requirements for safety/toxicology studies. Contract development and manufacturing organizations (CDMOs) help define manufacturability of the product and its scalability. Regulatory experts guide data generation toward approvability. These contributors are most effective not when consulted in sequence, but when engaged concurrently, aligned around shared therapeutic goals.

When this coordination happens early, it leads to smarter vector choices, fewer setbacks, better regulatory communication, and more realistic timelines. Its absence is often visible in programs that stall — not for lack of innovation, but due to misaligned expectations or avoidable technical and regulatory delays.

Ultimately, the key to success isn’t just expertise — it’s alignment. A unified team can anticipate downstream needs, manage risk more sustainably, and build programs engineered to succeed from concept through commercialization.

As Hilary Schultz, M.S., CEO of Persephoni BioPartners, explains: “When you have a family with a microphone to draw attention on a rare disease, researchers that have a viable candidate to pursue, a patient advocacy organization that's going through the exercises of finding and identifying the patients and developing natural history and real-word data, a development team that has executed, and the right investors in the room — that’s where I’ve seen the magic happen.”

Clarifying disease relationships through genetic screening

A solid approach to increase funding opportunities and decrease spending across various therapies for related diseases is to build a family or network of disease families. However, as developers increasingly pursue platform-based strategies across families of rare diseases, assumptions of genetic or mechanistic similarity must be rigorously validated. Too often, conditions are grouped based on shared symptoms or legacy classifications rather than confirmed biological alignment. Without precision in genetic screening, modular vector platforms or shared delivery systems may be deployed across disease subtypes that are, in fact, molecularly distinct, leading to inconsistent outcomes, regulatory complications, and wasted resources.

“Sometimes… there are multiple subtypes of a disease that probably mean they’re just different diseases or catch-all buckets, but nobody has enough genetic information to really nail it down,” notes Hilary Eaton, Ph.D., Chief Business Officer at Profluent.

This is not a rhetorical point; it defines the feasibility of basket trials, shared toxicology, and the entire premise of scalable gene therapy platforms. Building backwards requires that developers begin with a clear understanding of the genomic and mechanistic basis of the conditions they intend to treat. Only with that clarity can they design vectors, define targeting strategies, and construct regulatory arguments that are scientifically and clinically defensible. Genetic screening is not merely a diagnostic tool — it is a strategic prerequisite for any development program hoping to extend its reach across multiple indications.

Designing for platformability: The case for modular vectors

For many rare diseases, the burden of development is disproportionately high. Each new indication often requires its own bespoke vector, delivery system, manufacturing protocol, and regulatory dossier. While this one-disease-at-a-time model may be viable in more common conditions, it is often unsustainable in the rare disease space, both scientifically and economically.

A more efficient approach is emerging through platform-based development: designing a flexible, modular vector system that can serve as a foundation — or backbone — for multiple related indications. This model enables developers to pursue a family of rare diseases with shared delivery needs or biological mechanisms using a single, adaptable platform.

The foundation of such a system is a common vector backbone, optimized for manufacturability, regulatory compliance, and general safety. Onto this backbone, modular components can be integrated, including:

• Promoters to control tissue-specific expression;

• Tropism-modifying elements, such as envelope pseudotypes or ligand-directed targeting domains, to direct the vector to relevant cells; and

• Genes of interest (GOIs) tailored to each specific disease within the broader family.

This modular strategy not only improves scalability, but it also opens the door to regulatory and operational efficiencies, potentially allowing for reused safety data, streamlined toxicology, and basket trial designs that support multiple programs at once.

As Eaton notes, “If we could get a set of guidance that enabled us to be slotting in different genes of interest, and that was all viewed as the common delivery system, it would greatly simplify the path forward.” This flexibility is not theoretical — it is essential for enabling development at a speed and scale that rare disease patients demand.

Schultz added, “In rare disease indications, building technologies that have the ability to leverage across multiple indications and patient stratification is critical, but just as important, is building the foundation of the corporate and business development strategies in such a way to make a stronger business case for investors. At Persephoni, we leverage the technical capabilities of partners like ViroCell to enhance our venture studio — grounded in building backwards, maximizing the utility of assets, and fast tracking to the clinic.”

One example of the successful approval of a platform approach is Sarepta’s rAAVrh74 viral vector platform that recently received platform technology designation by the US FDA. The use of the platform allows multiple drug candidates to leverage data from previous studies, which will lead to faster approvals for new therapies targeting rare diseases using the same platform. Although Sarepta’s Platform Technology Designation was recently revoked, the core concept behind the platform designation is sound.

Sarepta’s case is a learning experience for future developers to ensure the correct and appropriate guardrails are put around the platform designation request so that if one of the drugs comes back with safety concerns, it does not derail the entire platform, but rather can be traced back to the specific mechanism of action, promoter, or tropism modifying element from the gene of interest within an individual vector. As a field, we will need to work closely with the regulators to ensure our platform definition is broad enough to serve the purposes of the multiple diseases the platform will target, but flexible enough to prevent platform revocation should one derivative of the platform show safety concerns.

Regulatory strategy as narrative construction

In rare disease gene therapy, regulatory success depends not only on data, but on the strength of the development narrative. Regulators must assess safety, efficacy, and manufacturing quality — but they do so through the lens of a story: Why this vector? Why this design? Why this route of administration? The rationale must be both scientifically sound and clearly communicated.

As Maryam Mokhtarzadeh, M.D., Senior Director of Regulatory Strategy at RegenXBio, puts it: “Writing the narrative and making it easy for reviewers to find the yes definitely helps your case.” That insight captures a central principle of building backwards — regulatory alignment starts at the design table, not the submission deadline.

Especially in rare diseases — where data may be limited, models imperfect, and tradeoffs inevitable — developers must proactively frame how each design decision supports safety, efficacy, and real-world feasibility. A clear, intentional narrative helps reviewers contextualize risk, understand rationale, and align with the sponsor’s logic.

More than defensibility, this is about demonstrating forethought. A program that anticipates clinical translation, commercial constraints, and patient access signals to regulators that the sponsor understands the full implications of their design. In rare disease, where every approval may set a precedent, clarity isn’t just helpful; it’s essential.

Rethinking licensing structures in academia

The path from academic discovery to clinical impact often begins with technology transfer, but for rare disease therapies, this step can become a roadblock. Licensing models built for high-revenue, large-market therapeutics may impose terms that are misaligned with the realities of ultra-rare indications. As a result, promising innovations can stall before they ever reach a sponsor or CDMO.

At the heart of this challenge is a tension between mission and margin. Academic institutions, especially those with histories of high-value deals, may default to licensing terms that prioritize revenue: royalties, equity, aggressive milestones. But rare disease programs operate under fundamentally different constraints. With limited patient populations and modest commercial upside, they require leaner economics and greater risk tolerance.

Rethinking licensing isn’t about lowering standards — it’s about recalibrating expectations to reflect therapeutic and societal value. A modest return on a rare disease therapy that reaches patients can represent far greater clinical and ethical impact than a rich licensing deal that never results in a product.

Flexible models — such as deferred royalties, non-exclusive rights within a disease family, or milestone relief — can lower the barrier to entry for startups, nonprofits, and first-time sponsors. Institutions that adopt such structures position themselves not just as generators of innovation, but as true partners in making that innovation real.

Toward a shared industry playbook

As rare disease gene therapy matures, the case for shared infrastructure and standardized practices grows stronger. While each condition presents unique biological challenges, the core development activities — vector design, toxicology, regulatory planning, and manufacturing — often follow common patterns. Capturing and codifying those similarities is key to making the field more scalable, efficient, and inclusive.

The Bespoke Gene Therapy Consortium (BGTC) exemplifies this approach. By developing templates for toxicology, manufacturing, and regulatory engagement, BGTC reduces duplication, promotes regulatory familiarity, and lowers barriers to entry for new programs.

As Sadik Kassim, Ph.D., CSO of Genomic Medicines at Danaher, explains, “Initiatives like the BGTC and the Foundation for the National Institutes of Health help develop a platform around AAV gene therapy for rare disorders where you have a playbook — you deploy it and reduce it to practice across up to eight indications… and then this playbook becomes open to others.”

The impact of such frameworks need not be limited to BGTC participants. Across the sector, open communication and knowledge-sharing can help avoid reinventing the wheel. When sponsors, CDMOs, and regulators align around proven approaches, programs move faster and with greater confidence.

This playbook mentality also helps democratize innovation. Academic groups, first-time sponsors, and mission-driven foundations often lack access to institutional knowledge that larger developers take for granted. A shared framework levels the playing field, enabling more ideas to reach the clinic based on scientific value, not just financial or operational muscle.

To truly fulfill its promise, gene therapy must balance tailored solutions with codified pathways. Not every program requires a bespoke framework. In many cases, a reusable structure — adapted thoughtfully — may be the most efficient way to deliver safe, impactful therapies to patients with rare diseases.

Conclusion: Begin with the end in mind

Rare disease gene therapy demands more than innovation; it demands intention. The traditional development path, which postpones practical considerations until after scientific and clinical proof of concept, is no longer tenable in a space defined by urgency, complexity, and constrained resources.

A backward-built model — one that begins with clinical goals, regulatory realities, and delivery constraints — offers a path to therapies that are not just scientifically promising but truly deliverable. It calls for early alignment, disciplined design, and shared infrastructure. But above all, it requires a shift in mindset: from proving what's possible to planning for what’s necessary.

In this next phase, success won’t hinge on isolated breakthroughs. It will be measured by how reliably we turn those breakthroughs into treatments that reach patients: across diseases, across systems, and across the finish line.

The industry is ready to evolve. What comes next isn’t less bold — it’s more deliberate. We don’t just need to show that gene therapy can work. We need to build it to succeed.

July 2025