Rafael J. Yáñez-Muñoz BSc PhD FHEA

Professor of Advanced Therapy 

Advanced Gene and Cell Therapy laboratory, Department of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK (AGCTlab.org)

Rafael Yáñez is the Director of the Centre of Gene and Cell Therapy in the Department of Biological Sciences, Royal Holloway University of London, UK. Prof Yáñez received his BSc and PhD in Biochemistry and Molecular Biology from the Autonomous University of Madrid, Spain, and previously held Lecturer appointments with King’s College London and University College London. Prof Yáñez has extensive experience in gene and cell therapy for both common and rare diseases. He is particularly involved in the development of safer methods, using genome editing (watch a videoclip on his genome editing research) and viral vectors modified to avoid integration in the cellular genome. His latest research is of relevance to neurodegenerative and inherited diseases ataxia telangiectasia and spinal muscular atrophy. Prof Yáñez was Editor-in-Chief of Gene Therapy 2017-2020, and Trustee (2015-2018) and then Chair of Trustees of the Genetic Alliance UK (2019-2020). He was also Treasurer (2016-2019), President-Elect (2019-2021) and then President (2021-2025) of the British Society for Gene and Cell Therapy.

[Rare Disease Dancer picture credits: design, Ramiya Lakshman; stylisation, Andrea Yáñez-Cunningham]

Long Watch - Rafael's Inaugural Professorial Lecture, With a little help from my friends, delivered on 25 Oct 2022: using photographs and art to thank the very many people who have supported him on the way to professorship, Rafael discussed career reflections, rare disease, mental health, dos and dont's in a science career... (with Introduction by Prof Klaus Dodds and Vote of Thanks by Dr Andrew Porter: 1 hour and 30 minutes)

Watch a short BBC interview with Rafael on the controversial pricing of drugs for rare diseases:

Watch a 5-minute, plain-language videoclip on our Ataxia telangiectasia research:

Watch a 2-minute, plain-language videoclip on our Spinal muscular atrophy research:

Watch a 2-minute videoclip of the Rare Disease Day event at Royal Holloway:

Rare Disease is hot on the agenda!

3,500,000. That is the number of people in England (7%) who will be affected by a rare disease in their lifetime. 20% of the Health budget will go to look after them, mostly providing symptomatic and palliative care, because there are hardly any curative treatments. And we have not started talking about the relatives who will have to stop working and become full-time carers…

How is that possible if they are rare diseases? Well, there are more than 9,600 of them (we do not have an accurate number!), and even though each disease affects fewer than 1 in 2,000 people, taken together they are a massive issue.

So why are rare diseases hot on the agenda? Because slowly but finally there is widespread understanding of their importance, and yearly Rare Disease National Plans are being published in England. International collaboration, always important in research but critical in the case of rare diseases, allowed the creation of an International Rare Disease Research Consortium (IRDiRC), with a vision to Enable all people living with a rare disease to receive an accurate diagnosis, care, and available therapy within one year of coming to medical attention. And Gene and Stem Cell Therapy research has finally provided some curative treatments, with many more in the pipeline.

Overview of current research

Our laboratory works on gene and cell therapy for common and rare (mostly inherited) diseases. Our main interest lies in the development of safer methods relying on either episomal vectors or genome editing. We mostly use novel, integration-deficient lentiviral vectors and adeno-associated viral vectors. Using episomal vectors we are particularly interested in the treatment of spinal muscular atrophy. Using genome editing we are developing treatments for ataxia telangiectasia. Haematopoietic stem cells and induced pluripotent stem cells (iPSCs) are our preferred stem cell models.

Too obscure? Try the lay description below instead.

Why use episomal lentivectors?

Many gene therapy strategies require transduction (genetic modification with a viral vector) of somatic stem cells, neurons or other cells which divide rarely or do not divide at all. HIV belongs to a class (Genus) of viruses called Lentivirus, which in turn are part of a wider Family called Retroviridae, or more commonly, retroviruses. Lentiviruses distinguish themselves from other retroviruses in several ways, including their ability to cross the nuclear membrane, which allows them to infect cells that are not dividing. However, in common with other retroviruses, lentiviruses integrate their genome into the chromosomes of the cells they infect. Retroviral and lentiviral vectors likewise integrate into the genome of the transduced cells, which can lead to unwanted effects on the genes at or near the integration site, something called insertional mutagenesis. In the worst-case scenario such negative events can lead to cancer. Furthermore, each transduced cell will have the vector integrated at a different chromosomal location, which may affect or not vector gene expression. This can cause differences in vector gene expression in different cells, what we call position effect variegation. It has long been known that lentiviral vectors can be made integration-deficient using integrase mutations, but previously observed gene expression levels in vivo were very poor in the absence of integration.

Effective gene therapy with episomal lentivectors

We originally demonstrated that lentiviral (HIV) vectors modified to prevent integration in the cellular genome (so-called integration-deficient lentiviral vectors or IDLVs) are very efficient tools for gene therapy (Yáñez-Muñoz et al., 2006). We render the vectors integration-deficient by using missense mutations altering the integrase active site. Failing to integrate in the host cell genome these lentivectors generate increased levels of episomal vector circles, which lack replication signals and get diluted out through cell division. Gene expression from the viral episomes is transient in dividing cells but long-lived and efficient in quiescent tissues, including eye, brain, spinal cord and muscle (Yáñez-Muñoz et al., 2006; Hutson et al., 2012a,b; Peluffo et al., 2013; Lu-Nguyen et al., 2014; Lu-Nguyen et al., 2015; Ahmed et al., 2018). The main advantages of these non-integrating lentivectors in gene addition strategies are their highly reduced risk of causing insertional mutagenesis and their avoidance of position effect variegation.

Genome editing

Lentiviral episomes can also be used as platforms for cassettes designed for site-specific (Moldt et al., 2008) or homologous recombination (Abdul-Razak et al., 2018) with the cellular genome. These strategies allow targeting of such cassettes to safe havens where no cellular genes will be negatively affected by the insertion event. Homologous recombination (gene targeting) can also be used for genome editing, the ideal form of gene therapy for rare inherited diseases, in which the endogenous gene is repaired (Yáñez and Porter, 1998; Popplewell et al., 2013; Rocca et al., 2014; Prakash et al., 2016; Abdul-Razak et al., 2018). The development of designer nucleases (most famously CRISPR-Cas, but also meganucleases, zinc-finger nucleases and TALENs; Prakash et al., 2016) which can cut the target gene and thus greatly boost the frequency of homologous recombination, has been a determining event to make gene repair a credible therapeutic strategy. The nuclease genes can also be delivered to cells using lentiviral episomes.