Gene Therapy for Neurofibromatosis - the Path to a Cure


Despite huge unmet need and relatively high prevalence, there are still no cures for any form of Neurofibromatosis (NF) – nor even a significant choice of effective disease-modifying therapies. Ameliorating the genetic defect underlying these tumour predisposition syndromes with a gene therapy offers curative and preventative potential for patients. Yet the challenge is complex and multifaceted – encompassing a range of technical, commercial and regulatory constraints. We believe now is the right time to solve them – exploiting the recent emergence of new tools, modalities, datasets, knowledge and clinical precedence. In partnership with the Children’s Tumor Foundation – a global leader driving forward solutions for NF patients – we are assembling a world-class founding team to lead this mission of curing NF1 and NF2 with gene therapy. Will you join us?

NF What?

You have probably never heard of neurofibromatosis (NF). And therein lies the problem. Despite being among the most common genetic disorders worldwide, and more prevalent than better-known diseases like cystic fibrosis (for which there are eight approved drugs), the NF field has sadly been overlooked for decades. Yet it is difficult to understand why, given the large and multidimensional burden that NF poses – greatly impacting the quality and duration of patients’ lives, while incurring disproportionately high costs to healthcare systems due to the frequent need for complex, life-long, multi-specialist care.

The Challenge

The main challenge? NF is complex and variable. In fact, NF is three distinct diseases, all of which cause tumours to form on nerves, often alongside a constellation of other debilitating symptoms*. Yet despite being monogenic disorders with 100% penetrance, defects in the eponymous genes encoding neurofibromin (NF1) and merlin (NF2) are clinically and biologically heterogeneous. This complexity is thought to arise at least in part due to the segmental, mosaic or generalised distributions of NF1 or NF2 mutations across germ layers (where they have differential effects) – and is a consequence of the large proportion of de novo (non-inherited) cases of NF. This creates an imperfect correlation between genotype and clinical severity, which can complicate patient stratification, trial design and healthcare economics. And the challenge is compounded by the fact that NF is a multi-system disease, meaning that an effective therapy would ideally reach all affected sites – which sit across several distinct biological tissues including the peripheral and central nervous systems, the bone, and the skin. Furthermore, the delivery of tumour-suppressor genes like NF1 or NF2 comes with unique safety and efficacy considerations related to ‘over-delivery’ and ‘under-delivery’ of the vector, respectively. When you add to this the complication that gold-standard AAV gene therapy vectors – which are achieving great success in other rare diseases – can simply not accommodate the enormous size of the NF1 gene’s exons, it soon becomes clear why there is such a need for innovative new strategies.

And therein lies the opportunity. To fully seize it, we have partnered with the Children’s Tumor Foundation – the world’s leading non-profit dedicated to NF research – to build a new venture whose mission will be to create curative gene therapies for patients with NF1- or NF2-driven tumour syndromes. Fortunately we are not alone: the NF community is a very special, cohesive and collaborative environment comprised of patients, researchers, clinicians and funders, all relentlessly pursuing their mission to create transformative new therapies for NF. Our work will therefore be building off the excellent initiatives and works of others in this space, namely the Gilbert Family Foundation and the Neurofibromatosis Therapeutic Acceleration Program (NTAP).

Why Deep Science Ventures?

The DSV methodology involves working backwards from desired outcomes to map the systemic constraints described above (in a process we call ‘scoping’) – before iteratively devising solutions that fulfil, circumvent or solve those constraints. In other words, we do not start with a specific vector, technology or target in mind – but take an unbiased systems-view of the factors holding back progress within a given area, and remain agnostic to the (combinations of) technologies required to achieve the desired outcome. This scoping process, led by a Founder-in-Residence with support from the DSV team, culminates in novel therapeutic approaches which are then triaged by their tractability, novelty, and impact – leading to the formation of high quality companies with defensible IP strategies that spin-out of DSV with the pre-seed investment and co-founding team required to prove experimental concepts and attract further investment.

Our approach of outcomes-led venture creation is unusual, but we believe it is the antidote for many of the systemic challenges in deeptech innovation – from knowledge silos and bureaucracy, to ‘technology-push’ approaches and fractured value chains. Over the past 5 years, we have built 35 companies and have a track record of success in the life sciences sector, with portfolio companies that have generated impact and gone on to raise significant funding. In 2021 alone, we created three oncology companies with CRUK: Enedra, Neobe and Stratosvir. Specifically within the rare disease space, we partnered with the Cystic Fibrosis Foundation (CFF) to build a curative and multi-system gene therapy platform to cure CF patients, including the 10% of patients who do not respond to current therapies (company launching Q3 2023).

Why now?

So why is now the right time to act? Firstly, because we are in urgent need of innovative approaches for NF patients. NF2-driven disease still has no approved therapy, and NF1-driven disease has only one: the MEK inhibitor, selumetinib, which slows or modestly reverses tumour growth in some patients, but carries significant side effects, and as many as 30% of patients do not respond at all. In contrast to disease-modifying therapy which does not address the underlying genetic defect, gene therapy offers both curative and preventative potential for patients. Secondly, recent advances in our understanding of NF, paired with the emergence of powerful technologies and an ever-expanding armamentarium of therapeutic vectors – together – make this an ideal moment to pursue more ambitious approaches with transformative potential. 

Unanswered Questions

Delivery of the NF1 and NF2 genes poses overlapping but distinct challenges – from differential constraints on cargo size, cell/tissue tropism and market size, to common constraints of high cellular uptake and homogeneity of expression. How can we exploit the recent emergence of new tools, modalities, datasets, knowledge and clinical precedence to overcome these constraints, and develop curative therapies for NF patients? What can we learn from the clinical successes and failures of gene therapies to date – or from the commercial challenges faced by incumbent gene therapy companies – and how can we incorporate such learnings into the next generation of approaches? How do we move away from achieving incremental improvements gained by tweaking the classical vectors, towards achieving step-changes in performance by considering alternative strategies? Can we devise optimal and novel gene delivery approaches that not only provide superior and life-long benefit for NF patients, but generalise into platform technologies applicable beyond NF?

These are among the many questions we urgently want to answer – and we are seeking a passionate, impact-driven and entrepreneurial gene therapy expert to help us do this. If you’re interested in the intersection of neurology, oncology and rare disease; if you’re frustrated by the way we currently treat genetic diseases, and deeply motivated to change that by building a company that will develop novel gene therapy vectors – we would love to hear from you. To find out more or to apply for the Founder-in-Residence role, please see the Job Description.

*including vision & hearing loss, chronic pain, musculoskeletal disfigurement, cognitive defects, psychosocial difficulties, increased risk of various cancers, and benign but disfiguring skin tumours (sometimes >100 in a patient).