Imagine starting life with a disease where the chances of reaching a fifth birthday are unlikely, let alone making it to adulthood, and the only treatments available are palliative at best. This is the reality facing millions of individuals born with a rare genetic disease. Sometimes, due to a single DNA base change – out of a possible 3 billion – occurring in the wrong place. A simple spelling mistake! However, recent years have seen the first effective gene therapies being developed, based on supplementing patient cells with functional copies of the faulty genes, or using antisense oligonucleotides or small molecules to alter pre-mRNA processing. The challenges were how to deliver genes or alter gene expression in the diseased cells and how to do it safely, without negatively affecting other endogenous genes. The answers came in the form of viruses, small non-coding RNAs and bacterial proteins, which is somewhat ironic, because we are using infectious agents or mimetics of their products to help cure diseases. With old enemies turned allies, tool sets are now being assembled to tackle the most challenging of genetic diseases. This article explores some of those tool chests in further detail, using ataxia telangiectasia, spinal muscular atrophy and several other rare diseases to highlight progress and challenges.

Chromosomal DNA encodes the genetic instructions for the maintenance, repair, growth, development and replication of cells, and subsequently any tissues and organs that they form. Each chromosome contains functional units called genes that are interspersed between non-coding DNA and regulatory elements. Genes comprise a unique sequence of deoxyribonucleotide bases that are first transcribed into pre-mRNA, which is processed into mRNA, before being translated by a ribosome into a sequence of amino acids, which normally then folds into a protein. Proteins perform functions within cells, where the function is intrinsically linked to protein structure.

Gene variants (alleles) generate diversity amongst a population. These variants are caused by subtle DNA base differences between individuals that can lead to changes in gene expression or the amino acid sequence and subsequently the protein’s structure and function. When a base change disrupts the synthesis and/or function of the resulting protein, cellular homeostasis is almost certainly negatively affected. If a negative DNA base change is inherited, that change will be present in every cell of the next generation, and some or all of those cells will suffer its deleterious effects. This may result in a genetic disease for that individual. Pathogenic DNA changes can also be spontaneously generated in parental gametes (de novo mutations), leading to the resulting baby being a carrier if the mutation produces a recessive allele, or potentially having a genetic disease if the outcome is a dominant allele.

To date, more than 6000 single gene disorders have been documented, caused by roughly 4500 separate genes. More than 10,000 single gene diseases are expected to exist. There are fewer causative genes than disorders, because different alleles of the same gene can produce different diseased phenotypes. Worldwide, 60% will suffer a disease with a genetic component, and up to 6–7% will be affected by a single gene disorder (hence the hashtag ‘#1in17’).

When a disease affects fewer than 1 in 2000 individuals, it is considered a rare disorder. Rare diseases vary in frequency from unique (single people carrying a specific pathogenic mutation not known in anyone else) to fairly common (like thalassemia or cystic fibrosis, which technically can be above the 1 in 2000 threshold). In the UK, 3.5 million people will be affected by a rare disease at some point in their lives. Globally, 300 million individuals live with a rare disease, which is roughly 4% of the world’s population. Furthermore, rare diseases disproportionately affect children, where they account for 75% of people affected, with 30% of them dying before their fifth birthday. Every year about 6000 children (referred to as ‘swans’ because they have a ‘syndrome without a name’) are born in the UK with a suspected genetic disorder for which not even state-of the-art genomic diagnostics can pinpoint the faulty gene. Over 10 years, it has been estimated that rare diseases cost NHS England more than £3.4bn.

An example of a very rare disease is ataxia telangiectasia (A-T; frequency 1:40,000–1:100,000 births), which is caused by mutations within the Ataxia Telangiectasia Mutated (ATM) gene locus. ATM encodes ATM kinase, which is a critical signalling protein within the checkpoint kinase pathway, a cellular mechanism needed for the detection and repair of DNA double strand breaks (DSBs) (Figure 1). Without this pathway working correctly, DNA DSBs are inaccurately repaired (Figure 2), resulting in three major life-limiting symptoms of the disease: progressive ataxia-causing cerebellar neurodegeneration, immunodeficiency and cancer susceptibility. Currently, no curative treatment is available, only symptom management. Disease prognosis is therefore poor, where mean life expectancy is approximately 25 years. A glimmer of hope appeared last 12 July 2023, when a report in Nature described a comprehensive search for antisense oligonucleotides (ASO) that could modify pre-mRNA processing of mutated ATM, with one experimental treatment being given to a single A-T affected person. No significant treatment toxicity was observed in this person, and there might have been a change in disease course for the better. ASOs can be considered synthetic mimetics of short non-coding RNAs, which are naturally produced by viruses and cells to affect various processes, including infection. They are particularly suited to personalized (‘n=1’) therapies because of their relatively simple design and chemical synthesis.

Figure 1

Following a DNA DSB, the MRN complex detects and holds together the two broken ends of the DNA molecule. MRN then acts as a platform for the recruitment and activation of ATM kinase, which amplifies and relays the signal onto p53. p53, along with other proteins, acts as a transcription factor to upregulate effectors, such as DNA repair enzymes.

Figure 1

Following a DNA DSB, the MRN complex detects and holds together the two broken ends of the DNA molecule. MRN then acts as a platform for the recruitment and activation of ATM kinase, which amplifies and relays the signal onto p53. p53, along with other proteins, acts as a transcription factor to upregulate effectors, such as DNA repair enzymes.

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Figure 2

Checkpoint kinase pathway without functional ATM kinase. Loss of ATM kinase results in a breakdown in communication between the MRN complex and p53. Subsequently, downstream effectors cannot be regulated through this pathway, which leads to faulty repair of DNA DSBs and the symptoms of A-T.

Figure 2

Checkpoint kinase pathway without functional ATM kinase. Loss of ATM kinase results in a breakdown in communication between the MRN complex and p53. Subsequently, downstream effectors cannot be regulated through this pathway, which leads to faulty repair of DNA DSBs and the symptoms of A-T.

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Unfortunately, most rare diseases are like A-T, in that they have no curative treatment. This is due to the sheer number of diseases, the difficulty to diagnose them, the limited research devoted to understand most of them, the scant resources that can be destined to develop treatments for each of them and the complexity of the task overall. Diseases affecting more people are likely to have stronger support groups, and the commitment and diligence of such support base can be instrumental, as we will highlight for the case of 5q spinal muscular atrophy (SMA).

The first approved gene therapy trial started in the USA in 1990, for the treatment of adenosine deaminase severe combined immunodeficiency (ADA-SCID), which is a recessive disorder that causes immunodeficiency due to mutations within the adenosine deaminase (ADA) gene. The experimental treatment was a form of ‘gene addition’, using a γ retroviral vector to genetically modify T lymphocytes harvested from the patient (an ‘autologous’ therapy), followed by reinfusion of the GM cells into the patient’s bloodstream. The vector was an engineered version of Moloney murine leukaemia virus, lacking all viral genes but including a functional, shortened copy of the ADA gene expressed from the viral long terminal repeat (LTR) promoter. The viral integrase protein then inserted the recombinant ADA gene into the genomes of the T cells, enabling long-term expression of the transgene. The trial showed that transduced cells could survive and regain ADA enzyme activity in vivo for more than 10 years. The removal of all viral genes was deemed to make the engineered vector unable to replicate and safe enough to use in humans – as we know now, the latter was not entirely correct, and further vector engineering was eventually required.

Despite these safety measures, why go through the effort of using viral vectors to deliver DNA, why not transfer plasmid DNA directly into cells? Fundamentally, viruses have evolved as specialists at infecting specific cells with their genetic payloads. Viral vectors can also be retargeted to transduce (infect) different cell types by changing the proteins on their surface. Transfecting plasmid DNA directly into cells is much less efficient, but there are some advantages, such as larger payloads and reduced immunogenicity. The chance of plasmid integration into the target cell’s genome is also significantly lower than that of integrating viral vectors, which can work as an advantage or disadvantage.

As it transpired, the first viral vectors were not that safe. This was discovered during a clinical trial for X-linked severe combined immunodeficiency (SCID-X1), another rare disease of the immune system affecting the IL2RG gene. In this case, a γ retroviral vector was used on autologous haematopoietic stem cells harvested from the patients. While the trial was the first true success of gene therapy in terms of disease correction, eventually four out of nine patients developed treatment-related leukaemia. Frantic research revealed that in some of the rare cells where vector insertion occurred at or near the LMO2 gene, a known T-cell oncogene, expression levels of this gene had been significantly increased by the vector LTR enhancer. This so-called ‘insertional mutagenesis’ became a significant stumbling block for the use of retroviral vectors.

In the meantime, lentiviral vector delivery systems had been developed based on HIV-1 (Figure 3). Lentiviral vectors have some inherently safer properties compared to γ retroviral vectors, for instance, not targeting active gene promoter sites for genomic integration. Critically, lentiviral vectors were made self-inactivating (SIN), whereby the viral vector LTR was partially deleted to remove the sequences responsible for promoter/enhancer activity. In these SIN vectors, transgene expression is controlled by a promoter inserted alongside the therapeutic gene and chosen to be devoid of enhancer activity. This also provides the opportunity for using tissue-specific promoters, limiting transgene expression to within target cells (‘transcriptional targeting’). SIN lentiviral vectors are currently considered the most effective and safe integrating vectors.

Figure 3

Lentiviral vector production. A transgene is first cloned into a transfer plasmid in between viral cis-acting sequences. These are sequences needed for the packaging of the vector genome into lentiviral virions in producer cells (and later for reverse transcription and integration in transduced target cells). The transfer plasmid is then transfected into producer cells, along with other plasmids that carry viral genes needed for the production of the lentiviral particles. Vector particles will bud out of the producer cells and can be harvested from cell culture medium. Similar production systems are available for most viral vectors.

Figure 3

Lentiviral vector production. A transgene is first cloned into a transfer plasmid in between viral cis-acting sequences. These are sequences needed for the packaging of the vector genome into lentiviral virions in producer cells (and later for reverse transcription and integration in transduced target cells). The transfer plasmid is then transfected into producer cells, along with other plasmids that carry viral genes needed for the production of the lentiviral particles. Vector particles will bud out of the producer cells and can be harvested from cell culture medium. Similar production systems are available for most viral vectors.

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Ex vivo therapies in which patient cells are harvested and genetically modified in the lab have the advantage of being amenable to quality control checks before reinfusion. Unsurprisingly, the first in vivo gene therapies, where the vector is directly administered to the patient, used non-integrating viral vectors, such as adenoviral and adeno-associated viral (AAV) vectors. These vectors produce extrachromosomal DNA elements (episomes) in the cells they transduce, with much reduced (but not entirely negligible) risk of insertional mutagenesis. Transgenes encoded as part of the vector construct are expressed from within the vector episome. This system offers transient transgene expression in dividing cells and long-term expression in non-dividing cells.

The most successful viral vector therapy is arguably Zolgensma (generic name onasemnogene abeparvovec), for 5q SMA. This disease causes progressive neuromuscular degeneration as well as other syndromic effects and is the biggest genetic killer of childhood. It presents with a range of disease severities, but the most common type is also the most severe, resulting in the death of the affected child by age 2 or earlier. It is due to mutations in the survival motor neuron 1 (SMN1) gene, and alleviated by increasing numbers of the highly related but much less effective SMN2 gene. These two genes are located next to each other in a highly plastic region of the human genome, which may explain the frequent loss of SMN1 and the copy number variation of SMN2 (Figures 4 and 5). The frequency of SMA is 1:6000–1:10,000 live births, and the carrier frequency is 1:40–1:60. It has been estimated that in the UK there are 670–1340 people living with SMA and 1.67 million carriers.

Figure 4

Expression of survival motor neuron (SMN) genes. SMN is required for all cells to remain healthy, especially motor neurons. Individuals not affected by SMA have at least one functional copy of SMN1. A paralogous gene SMN2 can also produce functional SMN, but at much reduced levels, due to a C to T mutation in exon 7 and a splice silencer (ISS-N1) in intron 7. In most pre-mRNA transcripts from SMN2, exon 7 is spliced out, producing SMN∆7 mRNA and hence truncated, non-functional SMN protein (grey). In the presence of a functional SMN1 gene, which mostly produces full-length SMN protein, this reduced expression level from SMN2 is no problem.

Figure 4

Expression of survival motor neuron (SMN) genes. SMN is required for all cells to remain healthy, especially motor neurons. Individuals not affected by SMA have at least one functional copy of SMN1. A paralogous gene SMN2 can also produce functional SMN, but at much reduced levels, due to a C to T mutation in exon 7 and a splice silencer (ISS-N1) in intron 7. In most pre-mRNA transcripts from SMN2, exon 7 is spliced out, producing SMN∆7 mRNA and hence truncated, non-functional SMN protein (grey). In the presence of a functional SMN1 gene, which mostly produces full-length SMN protein, this reduced expression level from SMN2 is no problem.

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Figure 5

Expression of SMN genes in spinal muscular atrophy (SMA). 95% of patients with SMA have deletions of their SMN1 gene. This means the cells of those individuals are totally dependent on their SMN2 gene(s) to produce sufficient amounts of SMN protein to prevent cell degeneration, especially in the motor neurons. Different individuals have naturally varying copy numbers of SMN2 present within their genomes, which result in the variety of SMA severities observed in people lacking SMN1: the more SMN2 copies, the milder the disease.

Figure 5

Expression of SMN genes in spinal muscular atrophy (SMA). 95% of patients with SMA have deletions of their SMN1 gene. This means the cells of those individuals are totally dependent on their SMN2 gene(s) to produce sufficient amounts of SMN protein to prevent cell degeneration, especially in the motor neurons. Different individuals have naturally varying copy numbers of SMN2 present within their genomes, which result in the variety of SMA severities observed in people lacking SMN1: the more SMN2 copies, the milder the disease.

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The frequency and severity of SMA have led to the creation of strong, very driven national patient associations to support people affected, and lobby and fund for research to understand the disease and develop therapies. The US SMA association, Cure SMA, has been instrumental in coordinating and funding research efforts, ultimately leading to something unique: three marketed therapies for SMA, while for most rare diseases there is only symptomatic treatment. Zolgensma is an AAV vector that delivers functional copies of the SMN1 gene. It is administered by intravenous injection as early as possible after diagnosis to maximize its efficacy. It uses a serotype of AAV, AAV9, which is able to cross the blood–brain barrier (BBB) in young individuals, critically allowing gene delivery to spinal motor neurons. It is considered to be a one-off treatment, and with a list price of £1.795m per patient in the UK, it is one of the most expensive drugs ever. Despite this, more than 3000 people have been globally treated with it.

Two other treatments are also available for SMA, Spinraza (nusinersen) and Evrysdi (risdiplam). They both alter the splicing pattern of SMN2 to promote the inclusion of exon 7, improving the production level of full-length, functional SMN protein and consequently the phenotype. Spinraza was the first drug approved for SMA; it is an ASO that is unable to cross the BBB, and hence delivered several times a year by intrathecal injection. It is very effective, but the beneficial effect is limited to the neuromuscular system, thereby not improving peripheral symptoms in other organs. Evrysdi is the most recent approval, an oral drug taken daily. Cure SMA has a drug pipeline including 16 other potential treatments in addition to the three approvals, further underscoring the importance of coordinated, well-resourced, and focused efforts to address the challenges presented by rare diseases.

AAV vectors have a narrow therapeutic index. Consequently, the doses used to achieve a therapeutic benefit for systemic diseases result in toxicity, which in some unfortunate cases has not been controlled and caused the death of a few patients. There are significant efforts in progress to improve targeting of AAV vectors by capsid engineering, although not so much is being done to improve their transgene expression efficiency. In our view, this research imbalance should be redressed. Dose reductions of more effective and targeted vectors are most likely to reduce or abrogate vector toxicity.

Gene addition therapy can be very effective, as seen with SMA and other diseases, but it is not ideal in principle. You can think of gene addition as the equivalent of taking your car to the garage because, say, the battery has stopped working. In the garage, the engineer does not remove the battery but instead produces one made from various components patched together. The engineer then proceeds to throw the battery at the car multiple times, expecting it to make the right connections, while you look on incredulously. The amazing thing is, sometimes gene addition works.

Ideally, correction of genetic diseases would be done by editing the genome to revert or eliminate pathogenic mutations, with no deleterious effects. The corrected gene would remain at its natural location and be regulated by its endogenous mechanisms, resulting in seamless function. We have been able to introduce such modifications in the genome for many years, but with very low efficiency, in a process traditionally known as ‘gene targeting’. The problem was that, while clonal cells could be painstakingly isolated that had the desired genetic modification, at a populational level the process was terribly inefficient (1:100,000–1:100,000,000 or even fewer cells successfully engineered). This all changed with the advent of chimeric nucleases, which can induce DSBs at unique DNA sequences and hence vastly promote the introduction of the desired modifications. Retargeting of most chimeric nucleases (meganucleases, zinc-finger nucleases and transcription activator-like effector nucleases, aka TALENs) requires engineering of a protein component, which is slow and cumbersome. In contrast, the leading engineered nuclease is clustered regularly interspaced short palindromic repeats (CRISPR)/Cas, which only relies on engineering of a synthetic RNA (the guide RNA or gRNA) to retarget the Cas protein component to the desired site. This improved process was rekindled as ‘genome editing’ (a more appropriate name than ‘gene editing’) and is likely to be the future of gene therapy for inherited diseases. CRISPR proteins are naturally an immune defence mechanism of bacteria against phage infections, and they have been identified in about half of bacteria known today and almost all Archaea. Yet another pathogen tool reengineered for therapy…

CRISPR/Cas technology has enabled the first clinical trials of in vivo genome editing. Counterintuitively, their aim is not to repair the target genes, but to inactivate them. The process relies on endogenous non-homologous end-joining (NHEJ) repair of the nuclease-induced DSBs in an error-prone manner, resulting in gene disruption, with a beneficial therapeutic effect. The leading targets are the Transthyretin (TTR) and BCL11A genes. TTR is mutated in the autosomal dominant disease hereditary transthyretin amyloidosis (hATTR). The mutant TTR product is prone to misfolding and deposition, causing amyloidosis and multiple symptoms. The therapeutic strategy uses a liver-targeted lipid nanoparticle to deliver a TTR-targeted gRNA and a mRNA encoding Cas9 protein. The method is not specific to the mutated allele and can knock out both TTR gene copies in the cell, but it is very successful at reducing serum levels of TTR, protein deposition and symptoms in initial clinical trials.

BCL11A is used as a target for two indications, sickle cell disease (SCD) and thalassemia. These are diseases in which haemoglobin (a tetramer of two α- and two β-globin subunits in adults) is affected by mutations in the β-globin gene HBB. The therapeutic goal is to compensate the effects of the mutation by promoting production of foetal γ-globin as a replacement for the mutated (SCD) or reduced (thalassemia) β-globin. This can be achieved by destruction of the master regulator of γ-globin gene silencing: BCL11A. The therapy involves nucleofection of haematopoietic stem cells with BCL11A-targeted gRNA and CRISPR/Cas protein, followed by reinfusion. It has proven successful in clinical trials for both diseases and is progressing in the regulatory pathway towards marketing approval.

Further refinements of genome editing are under development. (a) CRISPR/Cas and gRNA can be delivered alongside a homologous recombination template to promote homology-dependent repair (HDR) of the target gene. This process is still inefficient because HDR is much less frequently used than NHEJ for repair of DSBs, but is much improved compared to frequencies without nucleases. (b) The process is even more efficient in ‘prime editing’, whereby the Cas9 protein has been engineered to convert it into a ‘nickase’ (which now cuts only one DNA strand, generating a nick rather than a DSB) and fused to a reverse transcriptase domain. A short repair sequence template for HDR is also fused to the gRNA (here called pegRNA), which is then reverse transcribed into DNA at the site of action, resulting in enhanced frequencies of gene repair. (c) In base editing, a catalytically inactive or ‘dead’ dCas9 is fused to a choice of protein domains able to edit DNA bases around the target site, resulting in the introduction of the desired modification without any cutting of the sugar-phosphate DNA backbone. Prime editing and base editing do not involve the introduction of DSBs, which can be mutagenic per se, therefore being considered safer genome engineering methods. (d) dCas9 has also been fused to transcriptional activators or repressors, to promote or inhibit target gene transcription in other potential therapeutic strategies.

After a long maturation period from the first human trial started in 1990, gene therapy has finally delivered marketed treatments for inherited and other diseases. Viral vectors, ASOs, genetically engineered cells and other tools are providing life-saving therapies to thousands of individuals. Regrettably, the prices of these treatments are phenomenal, with each newly approved gene therapy being tagged as the most expensive drug in the world. As of today, the most expensive one approved for use in the UK is Libmeldy, for the treatment of metachromatic leukodystrophy (MLD), with a list price of £2.8m per patient. At a time when national health services are facing extreme financial pressures to deliver standard care, these prices will not be sustainable for long. We therefore run the risk of developing fantastic therapies for deadly diseases and making them only available to the few privileged people who can afford them or can have them prescribed through ever more restrictive national health services or insurance companies. There are already cases of people who move country or crowdfund to access life-saving gene therapies. We need to find a way to stop this deadly trend and make gene therapies available to all. Lives are at stake.

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R.J.Y.-M. acknowledges funding from ‘Action for A-T’ and ‘Spinal Muscular Atrophy UK’ (through the UK SMA Research Consortium) for research in our laboratory.

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Matthew Pearson is a PhD student in Professor Yáñez’s lab at the Centre of Gene and Cell Therapy, Royal Holloway University of London, where he is currently researching a novel genome editing strategy for the inherited disease ataxia telangiectasia. He has previously studied a molecular biology BSc and MRes at Royal Holloway University of London and studied and previously worked in professor Yáñez’s lab as both a Master's by research student and as a research assistant. Before this career in science, he was an electronic engineer. Email: Matthew.Pearson.2019@live.rhul.ac.uk.

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Rafael J. Yáñez-Muñoz is professor of advanced therapy at Royal Holloway University London in the UK, where he teaches genetic disease and medicine, and their laboratory (www.agctlab.org) investigates possible genetic therapies for spinal muscular atrophy, ataxia telangiectasia and other diseases. He is also the current president of the British Society for Gene and Cell Therapy, which groups UK-based scientists working in this field and people who are interested. On international Rare Disease Day, celebrated around the world on the last day of February (a rare day when a leap year), he organizes an event to highlight the importance of rare diseases (www.royalholloway.ac.uk/rdd). Twitter: @rjyanezmunoz. Email: rafael.yanez@royalholloway.ac.uk.

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