Reneurish Technology
We are developing a genetically engineered Neural Progenitor Cell (NPC) line that overexpresses Brain-Derived Neurotrophic Factor (BDNF). This factor is critical for promoting neuronal survival, enhancing synaptic plasticity, and facilitating brain tissue repair.
Utilising advanced synthetic biology techniques, we have optimised a novel expression system that allows for the transient expression of BDNF within our NPCs. This patent-pending system is integrated into an adeno-associated virus (AAV) vector, enabling episomal transfection. This approach facilitates precise control over BDNF production during the critical six-week period following transplantation, thereby minimising potential toxicity associated with overexpression.
Our methodology begins with the use of human induced pluripotent stem cells (hiPSCs), which are subsequently transfected and differentiated into NPCs. The final therapeutic product consists of these BDNF-enriched NPCs, which are administered via intracerebral injection directly into the affected brain tissue. This targeted delivery promotes the restoration of damaged neuronal circuitry and extends the beneficial effects of the therapy.
Key Stakeholder Pain Points in Stroke Recovery
The following outlines critical challenges faced by patients, healthcare providers, healthcare systems, and companies in addressing stroke recovery.
Our project is feasible, as demonstrated by our proof of concept in vitro, which shows that genetically modified NPCs can successfully express BDNF and sustain this overexpression. While we acknowledge that an in vitro proof of concept does not guarantee future success, it serves as a crucial first step toward validating our approach in animal models.
We leverage iPSC-derived NPCs that are primed to differentiate into cortical neurons, making them highly suitable for treating ischemic stroke. Unlike multipotent neural stem cells (NSCs), which can differentiate into astrocytes and oligodendrocytes—potentially increasing glial scarring—our NPCs are specifically directed towards neuronal differentiation.
Our approach utilises AAV vectors for transient BDNF expression, effectively addressing challenges related to BDNF’s short half-life. By expressing BDNF on our Reneurish cells, we are also addressing problems related to blood-brain barrier permeability of this molecule. This method allows for localised and controlled BDNF release, maximising therapeutic efficacy while minimising risks.
To mitigate teratogenicity, our four-day priming process ensures complete NPC differentiation, significantly reducing the risk of tumour formation. Additionally, our non-integrating AAV vectors enhance safety and reliability, as supported by clinical validations.
While intracerebral administration of NPCs poses technical challenges, it allows for precise targeting of injury sites, thereby maximising NPC survival and integration. Numerous studies and clinical trials have employed this delivery method, illustrating that, despite its higher costs and logistical complexities, it remains the optimal choice for enhancing patient outcomes—our primary objective [12] [13]. A meta-analysis of 55 studies utilising mesenchymal stromal cells demonstrated that intracerebral injections significantly improved neurobehavioral outcomes and reduced lesion volume compared to intravenous injections [14].
Historically, direct brain injections of cell therapies faced considerable challenges related to cell integration. Upon transplantation, these cells struggled to survive in ischaemic environments, with only a small fraction remaining at the injection site within days [15]. Research has shown that BDNF can enhance cell engraftment and survival. By employing BDNF-modified NPCs, we aim to address this critical bottleneck in cell therapy.
Our laboratory results indicate that BDNF-transfected NPCs exhibit improved integration into brain tissue, providing a promising pathway for subsequent in vivo models. For detailed findings, please refer to the results section.
Our solution is expected to be highly scalable, thanks to the production of iPSC-derived NPCs, which can be generated in large quantities and stored until needed. The use of CRISPR-Cas9 to create universal donor cells minimises the risk of immune rejection, enhancing the potential patient pool, making them immunologically compatible with >90% of the world's population [16]. Our optimised differentiation and freezing processes allow for efficient batch production, ensuring that NPCs can be activated rapidly upon patient identification.
Additionally, our exit strategy focuses on pursuing an acquisition by a major pharmaceutical company after phase II clinical trials. This partnership will provide access to substantial resources and infrastructure, significantly enhancing our scalability. The broad applicability of our technology in neurodegeneration further supports market expansion opportunities in the future.
While the concepts of stem cell therapy and neurotrophic factor regulation are not new, our approach is highly inventive. We uniquely utilise iPSC-derived NPCs that have been specifically primed for differentiation into cortical neurons. This process, known as cortical priming, distinguishes our NPCs from other stem cell types, which may lead to unwanted cell types like astrocytes or oligodendrocytes that can hinder therapeutic outcomes by exacerbating the glial scar [17].
Additionally, our innovative time-controlled gene expression system for BDNF production allows us to regulate neurotrophic factor levels precisely during critical recovery periods, addressing the well-documented risks of neurotrophic factor toxicity associated with prolonged exposure [18].
Moreover, the application of CRISPR technology to generate universal iPSC lines is a significant advancement in the field. While universal donor cells are becoming more common in some areas, their use in neuroregenerative medicine remains limited. By combining these innovative techniques, we offer a uniquely adaptable therapy with the potential to address various neurological conditions beyond ischaemic stroke.
SWOT
We have thought about our strengths, weaknesses, opportunities, and threats, which can be
seen in the SWOT analysis.
Competition analysis
Unique Selling Proposition (USP) and competitive advantages
Neural progenitor cells (NPCs) stand out as the only stem cells capable of differentiating and proliferating within brain tissue after transplantation, facilitating direct neural repair [19]. Unlike competitors utilising mesenchymal stem cells (MSCs) or multipotent adult progenitor cells (MAPCs), which lack this neural regenerative ability, our therapy is specifically designed to replace damaged cells and restore neurological function [20].
The strategic application of brain-derived neurotrophic factor (BDNF) plays a crucial role in supporting the survival, differentiation, and integration of NPCs, thereby enhancing neuroplasticity [21]. Reneurish ensures precise regulation of BDNF expression, which minimises associated risks while maximising therapeutic outcomes. This level of control is often absent in competing therapies .
Reneurish employs CRISPR technology to knock out human leukocyte antigen (HLA) genes, effectively reducing the risks of immune rejection [22]. This allogeneic approach presents significant advantages in terms of scalability and accessibility compared to more costly autologous solutions like NurOwn, which necessitate complex, patient-specific procedures.
The method of intracerebral delivery allows for the accurate placement of NPCs directly into damaged brain regions, thereby enhancing therapeutic efficacy. While competitors may opt for simpler intravenous or intrathecal methods, Reneurish’s approach justifies its higher cost by significantly improving cell engraftment and promoting neural regeneration [23].
Reneurish integrates multiple safety measures into its therapeutic framework, including a novel temporal BDNF expression system, adeno-associated virus (AAV)-based gene delivery, and cell priming post-thawing. These strategies are designed to ensure therapeutic safety and mitigate risks such as uncontrolled growth or tumour formation. Such comprehensive safety mechanisms further validate the premium pricing associated with Reneurish’s therapy, emphasising long-term patient safety and efficacy.
Pricing strategy
Based on discussions with industry experts and comparisons with existing therapies, we anticipate pricing our treatment within the range of €50,000 to €70,000 per patient. This pricing is justified by several critical factors that underscore the therapy's unique value proposition:
Superior therapeutic outcomes
Our therapy is specifically designed to enhance neural regeneration and functional recovery while minimising toxicity risks during essential therapeutic windows. This strategic approach results in significant long-term benefits, including lower long-term healthcare costs, reduced rehabilitation expenses, and a decreased likelihood of stroke recurrence.
Competitive comparison
Competitors like Stempeucel offer therapies priced around €20,000; however, these alternatives lack the targeted precision and regenerative potential that define Reneurish’s methodology. Our advanced treatment offers distinct advantages, warranting the premium pricing.
Market context
The pricing landscape for cell therapies in Europe varies significantly. For instance, Zolgensma, a gene therapy for spinal muscular atrophy, is priced at €2.1 million. This demonstrates the market's readiness to invest in high-cost treatments that yield life-altering results.
While our preliminary pricing strategy is robust, several external factors may influence the final price point:
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Healthcare system dynamics
Our pricing must align with the Spanish healthcare system, where treatments for severe conditions like stroke are typically covered by the Sistema Nacional de Salud (SNS) [24]. High-cost therapies are subject to scrutiny, necessitating possible negotiations to accommodate public health budgets.
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Partnership opportunities
Our intention to pursue mergers and acquisitions with larger pharmaceutical companies could also impact our pricing strategy. Collaborating with established partners may lead to strategic adjustments based on market access considerations.
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Inclusion of surgical costs
Our proposed pricing range must consider the costs associated with the intracerebral delivery procedure, which can range from €15,000 to €30,000 [25] in Spain. Ensuring that our pricing reflects these operational expenses is crucial for maintaining competitiveness.
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Reimbursement and access strategies
To maximise access to our therapy, we plan to engage with both the SNS and private insurers, potentially offering conditional reimbursement arrangements. This approach may lead to further pricing adjustments aligned with reimbursement structures.
We aim to establish Reneurish as a high-value, single-dose treatment, providing a transformative solution compared to competitor’s recurring therapies. By setting our pricing between that range, we not only highlight the unique benefits and long-term value of our therapy but also ensure that healthcare providers pay based on its effectiveness through outcome-based pricing models. Our pricing strategy will be refined through continuous evaluations of healthcare dynamics, partnership opportunities, and regulatory requirements. This approach ensures our therapy remains competitive and accessible to patients in Spain while delivering enhanced long-term benefits for healthcare systems.