Objective
The objective of PRIME is to develop, optimize, and validate a pre-transplant graft conditioning strategy that accelerates blood vessel recruitment into transplanted islets before the damaging avascular period can take hold, and to establish the scientific and manufacturing foundation required to bring this strategy into clinical practice.
The core technology is a molecule that selectively enters insulin-producing cells and temporarily activates their natural blood vessel-recruiting signal before transplantation. This means the graft begins attracting a blood supply from the moment it is placed in the body, compressing the window of vulnerability rather than waiting for stress to trigger the response naturally. The signal is transient, switching itself off within days, and leaves no permanent modification to the cells.
PRIME will determine precisely how much conditioning is needed, and whether that amount can be calculated reliably from the size of the graft and the weight of the recipient, which is a critical step toward a standardized clinical dosing framework. This will be tested across multiple transplantation sites in mice, moving from the most controlled experimental setting to sites that more closely resemble where human transplantation is heading. Findings will then be validated in pigs, whose size and physiology make them the appropriate bridge between mouse experiments and human application.
Alongside the biological studies, the program will develop a manufacturing process that meets the quality standards required for clinical use. It will also validate two complementary imaging tools that allow the health and vascularisation of a graft to be monitored over time without surgery or tissue removal. The first uses a fluorescent-labelled version of the same targeting molecule to measure how many insulin-producing cells remain viable in a living animal without retrieving the tissue, which has not previously been possible. The second uses MRI to localise the graft and assess whether its new blood vessels have matured into a functional supply. Together, these tools address a longstanding blind spot in transplant medicine: currently, clinicians have no non-invasive way to know whether a graft is thriving or failing until metabolic function deteriorates. Establishing validated imaging readouts in this program creates a direct path toward graft monitoring in future clinical trials. Finally, PRIME will test whether the same conditioning approach works for islets from suboptimal donors and for insulin-producing cells grown in the laboratory from stem cells, considered the two sources most likely to expand the supply of transplantable tissue in the future.
Background Rationale
Type 1 diabetes is an autoimmune disease in which the body's own immune system destroys the insulin-producing beta cells of the pancreas. Without these cells, blood sugar cannot be regulated, and patients face a lifetime of insulin injections, continuous glucose monitoring, and the constant risk of dangerous blood sugar swings. For most patients, modern insulin therapy manages the condition effectively. But for those with the most severe forms of the disease, where life-threatening hypoglycemic episodes occur without warning and cannot be controlled by any other means, a different solution is needed.
Transplanting donor insulin-producing cells, called islets, directly into the patient offers the closest thing to a biological cure currently available. A successful transplant can restore the body's ability to sense and respond to blood sugar naturally, freeing patients from insulin dependence. Yet despite decades of progress in transplant medicine, outcomes remain frustratingly inconsistent. The reason comes down to a problem that occurs in the very first days after transplantation.
When islets are placed in the body, they do not immediately connect to a blood supply. For the first one to two weeks, they must survive without active delivery of oxygen or nutrients, relying entirely on passive diffusion from surrounding tissue. This is an extraordinarily stressful period, and many islets do not survive it. By the time new blood vessels grow in to perfuse the graft, a large proportion of the transplanted cells have already been lost irreversibly. The body does have a natural mechanism for recruiting blood vessels: a signalling molecule called VEGF-A. However VEGF-A is triggered naturally only by cellular stress, meaning the signal only switches on after damage has already begun. It is reactive rather than preventive, and it is slow.
Current clinical practice compensates for this predictable early loss by transplanting far more islets than the patient theoretically requires. This works, but it consumes scarce donor tissue, and limits how many patients can be treated from a single donor, and does nothing to address the underlying biological problem. Existing research strategies to improve early vascularization have not overcome this limitation: they are difficult to standardize, carry regulatory complexity, or fail to demonstrate a clear benefit to functional beta cell mass at clinically relevant doses. A fundamentally different approach is needed; one that acts before the damage begins.
Description of Project
Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing β-cells, leaving patients dependent on exogenous insulin for life. Islet transplantation can restore natural glucose sensing, but clinical outcomes are constrained by a fundamental biological problem: a large proportion of transplanted islets are lost before the graft is ever perfused with blood. After transplantation, islets survive by diffusion alone during an obligate avascular period; by the time blood supply is established, substantial irreversible damage has already accumulated. It is the timing of revascularisation, not its ultimate occurrence, that determines how much functional graft survives.
PRIME addresses this bottleneck directly. The program is built on a novel graft conditioning technology: an aptamer–small activating RNA (saRNA) chimera that targets β-cells and induces transient VEGF-A expression prior to transplantation, without activating the stress cascades that normally gate angiogenic signalling. By initiating pro-angiogenic drive before the graft is implanted, the platform compresses the avascular window and accelerates host vascular recruitment from outside the stress pathway entirely. In both mouse and human islets, this approach produces robust, early VEGF-A secretion that peaks at approximately 96 hours and resolves by day 8, with no evidence of sustained vascular expansion or aberrant angiogenesis. Primed islets establish host vascular perfusion within one week compared to two weeks for controls, with earlier perfusion translating directly into greater functional β-cell mass retention and improved metabolic outcomes.
The program pursues three interconnected objectives. The first establishes a quantitative, bodyweight-scaled priming framework in immuno-compromised mice, evaluating human islet engraftment across four clinically relevant transplantation sites: kidney capsule, under the skin, intramuscular, and epididymal fat pad. A central challenge in islet transplantation research is that graft survival has historically been impossible to measure in a living animal without removing the tissue, meaning the same graft cannot be tracked over time. PRIME addresses this through a validated non-invasive imaging platform in which β-cell–targeted aptamers carrying fluorescent or MRI contrast labels accumulate at the graft site in proportion to viable β-cell mass, enabling continuous longitudinal tracking of graft size and vascular integration. This platform is itself a translatable tool for monitoring graft health in future clinical trials where tissue access is unavailable.
The second objective advances the programme to a porcine transplantation model, validating that the bodyweight-scaled priming framework established in mice translates to clinically relevant anatomical scale. Studies are conducted at both omental and intrahepatic sites within the same animal, enabling direct cross-site comparison of revascularisation kinetics and, in the hepatic arm, comprehensive profiling of the inflammatory response to intraportal islet delivery. A GMP-transferable manufacturing and quality testing framework is established in parallel, defining the release criteria required for eventual clinical translation.
The third objective tests the breadth of the platform by evaluating priming efficacy in marginal donor islets and stem cell–derived islet preparations, the two sources most likely to expand transplantable graft availability at scale, and the populations where early engraftment failure is most consequential.
If successful, PRIME will establish the preclinical and manufacturing foundation for a modular, non-integrative ex vivo conditioning step that can be incorporated into existing islet transplantation workflows without redesigning the transplant procedure, immunosuppression protocol, or manufacturing pipeline. By reducing early β-cell attrition, the platform has the potential to lower the donor tissue burden required per recipient cure. The same conditioning step may prove equally critical for stem cell–derived islet therapies, where manufacturing scale is achievable but early engraftment losses remain a key barrier to realising their full potential, thus making robust early vascularisation a shared requirement across both the donor and the cell-therapy routes to a cure.
Anticipated Outcome
By the end of the program, PRIME is expected to deliver four interconnected outcomes that together constitute a translational package ready for advancement to human trials.
The first is a validated, bodyweight-scaled dosing framework, which should lead to a quantitative understanding of how much graft conditioning is required as a function of graft size and recipient metabolism, tested across multiple transplantation sites in mice and confirmed in pigs. This framework will provide the dosing logic needed to design a first-in-human trial and will establish whether the conditioning benefit is preserved across the range of clinical transplantation contexts currently under investigation.
The second is a GMP-transferable manufacturing process, which should lead to a production and quality testing workflow for the conditioning molecule that meets the regulatory standards required for clinical application. This includes defined criteria for identity, purity, potency, and safety that can be evaluated lot by lot before any material is used in a transplant, providing the manufacturing infrastructure that regulatory agencies will require.
The third is a validated non-invasive imaging platform, which should lead to a set of tools that allow the mass and vascularization of islet grafts to be measured over time without surgery, in both small and large animals. This platform will generate the preclinical imaging data needed to support trial design and will provide a framework for monitoring graft health in future clinical studies where tissue biopsy is not feasible.
The fourth is evidence of platform breadth and would demonstrate that the conditioning strategy works not only for high-quality primary donor islets, but also for islets from suboptimal donors and for stem cell-derived insulin-producing cells. This will directly inform which patient populations and which graft sources the technology can realistically serve, and will identify any source-specific adjustments needed before clinical deployment.
Together, these outcomes will position PRIME for a first-in-human feasibility study in which conditioned and unconditioned islets from the same donor are compared within the same clinical cohort, enabling a controlled early assessment of benefit under standard-of-care transplantation conditions.
Relevance to T1D
The most direct relevance of PRIME to people living with type 1 diabetes is straightforward: if graft conditioning reduces early beta cell loss, fewer donor islets are needed to achieve the same clinical outcome. That means more patients treated per donor, lower effective cost per cure, and a meaningful step toward making islet transplantation accessible to a broader population and not only those with the most extreme disease burden.
At present, islet transplantation is reserved for a narrow group of patients with severe, medically refractory disease, largely because the donor tissue requirement per patient is high and the supply of suitable donors is limited. A technology that reliably improves engraftment efficiency would shift the cost-benefit calculation for a wider group of patients, potentially expanding eligibility criteria and reducing the number of transplant procedures required to achieve insulin independence.
The relevance extends beyond donor-derived islets. The stem cell-derived islet field is advancing rapidly, with multiple groups now producing functional insulin-secreting cells in the laboratory. If these cells face the same early engraftment challenge as donor islets, then a conditioning strategy validated across both sources would be directly applicable to the next generation of beta cell replacement therapies. PRIME explicitly evaluates this, positioning the platform as relevant not only to transplantation as it exists today but to the cell therapy landscape as it is developing.
For the broader T1D community, PRIME addresses one of the most persistent gaps between what islet transplantation can achieve biologically and what it delivers consistently in practice. The goal is not a new therapy from scratch, but a modular improvement to a therapy that already works: one that integrates into existing clinical workflows without requiring new surgical approaches, new immunosuppression regimens, or new manufacturing infrastructure. If the preclinical programme succeeds, the path to clinical evaluation is short, and the potential to improve outcomes for patients who have exhausted all other options is immediate.