Abstract

Gene therapy works differently depending on which virus is used to deliver it and how that virus is given to the patient. This paper looks at four genetic diseases – hemophilia B, spinal muscular atrophy (SMA), leber congenital amaurosis (LCA) and Rett syndrome (RTT) – to see how these two factors affect how well the treatment works. In all four diseases, the adeno-associated virus (AAV) is used to carry the therapy. However, the way the virus is delivered changes based on which part of the body needs treatment. For hemophilia B and SMA, the treatment is primarily given through an IV so it can travel through the blood to reach the liver (for hemophilia B) or spread through the nervous system (for SMA). Some SMA research shows that injecting the treatment around the spinal cord can work at a much lower dose and cause fewer side effects. LCA is treated differently, with a small injection directly into the eye, which works well because the eye does not react strongly to foreign substances. This allows a much smaller dose to be effective. Rett syndrome treatments are still being tested, but the main course of treatment includes either injections into the brain or IV delivery. Each method has its own results and side effects. Overall, this paper shows that the type of virus and the way that it is delivered work together to determine how safe and effective a gene therapy is, meaning that each disease requires its own tailored approach in order to be the most successful it can be.

Introduction

Viral vectors are, at their core, safe, lab-changed viruses that act as vehicles designed to deliver and integrate a payload of genetic information into specific (often designated) cells of the body. These viruses are non-pathogenic as prior to their use as viral vectors, all their genetic information is removed and replaced with the wanted, therapeutic genetic information (Naso, 2017; ASGCT, 2025). Viruses are used in this way as they have proven to be very effective at making their way into cells and their nuclei, which achieves the vector’s purpose to deliver and integrate genetic information into the cell. Viral vectors make use of the shell of the modified virus in order to use the virus’ ability to seek out and transport itself into specific cells of the body (Pillay, 2018). 

There are many different factors that may have an effect on the effectiveness of these genetic therapies, which is to say their potency. These factors namely include the vector type and the delivery method used to administer said vector. There are many different types of viral vectors, each derived from viruses and different strands of said viruses. There isn’t necessarily a single “best viral vector” that would provide the most effective treatment for each condition, but instead different vectors are used for different jobs as they all serve separate purposes. For example, adeno-associated vectors are smaller load bearing vectors, around 4-5 kb (Naso, 2017), that do not permanently affix genetic information into the chromosomes, but allow for long lasting gene expression as the genetic information is integrated separately from the chromosomes. They are also able to effectively target and navigate through the circulatory system towards liver and muscle cells, making them more effective for non-invasive, safe genetic therapies regarding those areas (Naso, 2017). On the other hand, lentivirus is a slightly higher load bearing virus (around 7-8 kb) that permanently affixes genetic information into the chromosomes for a permanent therapy. However, it is not able to navigate as effectively as AAV and so it is more popular for ex vivo treatments such as CAR-T therapy. 

This paper will explore these factors when applied to hemophilia B, spinal muscular atrophy (SMA), leber congenital amaurosis (LCA) and Rett syndrome (RTT) in order to demonstrate these factors’ effect on the effectiveness of the genetic therapy in question.

Hemophilia B

Hemophilia B is a rare inherited bleeding disorder caused by a deficiency or lack of clotting factor IX, a protein that helps the blood clot properly. It is usually caused by a change, or mutation, in the F9 gene and is most commonly inherited through the X chromosome, meaning it mainly affects males, although females can also have symptoms (Killeen et al., 2026). People with hemophilia B can experience prolonged bleeding after injuries, surgery or dental procedures, as well as spontaneous bleeding into joints and muscles in more severe cases. Repeated bleeding into joints can cause pain and long-term joint damage if it is not treated. The severity of hemophilia B depends on how much factor IX a person’s body produces. Treatment usually involves replacing the missing factor IX through injections, either regularly to prevent bleeding or when bleeding occurs. Other treatments may also be used depending on the individual’s needs. With appropriate treatment and medical care, most people with hemophilia B can manage their condition and live active, healthy lives. 

Gene therapy for hemophilia B has become increasingly effective due to improvements in both viral vector design and delivery methods. There have been multiple treatments for this condition using slightly different variants of the adeno-associated virus (AAV), which is able to effectively target cells. AAV is also not integrating, meaning that the genetic information it carries to the cell remains outside the chromosome as an episome in the nucleus. This avoids possible complications or unwanted alterations to the host’s original genetic information. 

An early study used a self complementary adeno-associated virus type 8 (AAV8) to administer treatment (Nathwani et al., 2014). The delivery method consisted of an intravenous infusion, allowing the virus to efficiently and effectively enter the blood stream and circulate towards the liver. At the highest dose (which proved the most effective), factor IX expression reached approximately 5% more than normal levels (Nathwani et al., 2014). Although the improvement in expression was relatively minimal across patients, this shows that the AAV8 vector is able to successfully deliver the F9 gene to liver cells. Furthermore, long-term follow ups showed long-term effectiveness from this treatment (Reiss et al., 2025). 

Later studies used a single stranded AAV vector to deliver the factor IX padua variant (George et al., 2017). The factor IX padua variant has higher clotting activity than the naturally occurring factor IX. This treatment resulted in an approximate 33.7% increase in factor IX activity compared to original levels (George et al., 2017), proving to be a substantial improvement on the previous study and resulting in over 600% more effectiveness. This proves that it is not only the viral vector type that has an impact on the success of the treatment, but also the gene which it carries. However, that is not to say that the viral vector type does not have an impact. 

A later study using hemophilia B treatment known as etranacogene dezaparvovec (also using the padua factor IX variant) used an AAV5 vector (Pipe et al., 2023). This treatment resulted in a 36.2% increase in factor IX expression compared to original levels (Pipe et al., 2023), proving that the adeno-associative vector type (which falls under the reach of viral vector type in general) also has a great effect on the effectiveness of the treatment. 

Overall, the evidence suggests that viral vector type and delivery have a substantial impact on the effectiveness of the treatment for hemophilia type B. The majority of the studies conducted on the use of viral vectors for the treatment of this condition use adeno-associative vectors as they have proven to be the most consistently effective and safest vectors when used on hemophilia type B (Nathwani et al., 2014; George et al., 2017; Pipe et al., 2023). This is due to their ability to efficiently target liver cells (if carrying a gene expression matching those of the liver), to safely be administered via intravenous infusion (instead of needing a direct injection into the organ) and to infect both dividing and non-dividing cells, making them a more suitable candidate for liver cells (which are not quite considered non-dividing but rather stable or quiescent) over other vectors (Kwon et al., 2008). The studies also show that the sub-type of vector has an influence, with AAV5 vectors proving to be more effective than AAV8 vectors for this treatment, with the use of AAV5 vectors resulting in the expression of factor IX of approximately 2.5% more (of the original factor IX expression levels) than the use of AAV8 vectors (Nathwani et al., 2014; Pipe et al., 2023). 

Spinal Muscular Atrophy

Spinal muscular atrophy is a genetic disorder characterised by the progressive degeneration of motor neurons in the spinal cord and brainstem, leading to muscle weakness (Kolb et al., 2016). The condition is most commonly caused by mutations or deletions in the survival motor neuron 1 (SMN1) gene (Kolb et al., 2016). This gene is responsible for producing a protein essential to the survival and function of motor neurons. Without adequate SMN protein, motor neurons deteriorate, disrupting the communication between the nervous system and muscles. In order for an individual to inherit SMA, they must receive a defective copy of the gene from both parents (Kolb et al., 2016). SMA is estimated to affect about 1 in 11,000 live births worldwide. SMA presents across a spectrum of severity (0 – 4) (Kolb et al., 2016). The most severe and common form, Type 1, usually appears within the first six months of life and can greatly affect breathing, swallowing and more if left untreated. Milder forms of SMA may not appear until late childhood or adulthood, with symptoms such as difficulty walking, frequent falls or lower stamina. Common symptoms across all types of SMA include muscle weakness, reduced muscle tone and tremors. In severe cases, there can be respiratory complications, magnifying the importance of early diagnosis and intervention. 

Evidence from clinical and preclinical studies of spinal muscular atrophy type 1 (SMA1) gene therapy demonstrates that effectiveness depends heavily on the interaction between the AAV and delivery route, rather than on vector choice alone. Because SMA1 is from motor neuron loss distributed throughout the spinal cord and brainstem, an effective vector must be capable of crossing the blood-brain barrier and achieving broad transduction of the central nervous system rather than a single localised site. The crucial clinical trial of onasemnogene abeparvovec established that a single intravenous infusion of self complementary AAV9 could rescue SMA1 infants from almost certain permanent ventilation or death (Mendell et al., 2017). This is possible because AAV9 is uniquely capable of crossing the blood-brain barrier and transducing motor neurons throughout the spinal cord following systemic administration, while simultaneously reaching the peripheral tissues affected by SMN deficiency (Mendell et al., 2017). This systemic route proved both clinically practical, because it required only a single infusion in fragile infants, and physiologically practical, given SMN protein’s universal role beyond the nervous system (Mendell et al., 2017). 

Subsequent preclinical work investigating this same scAAV9-SMN construct found that the delivery route is, itself, a major determinant of dosing efficiency and biodistribution (Meyer et al., 2015). It was found that direct cerebrospinal fluid delivery achieved widespread spinal cord transgene expression in both mice and non-human primates. It transfers more than half of motor neurons across all spinal cord segments, at a dose ten times lower than that required for intravenous administration. Meyer et al. also found that positioning animals in a head-down orientation, also called the Trendenlenburg position, during CSF injection further improved viral distribution (Meyer et al., 2015). This finding indicates that CSF based delivery can substantially reduce the systemic vector burden, and by doing so, reduce the risk of off-target hepatotoxicity without sacrificing central nervous system transfer efficiency. 

Clinical follow up on the approved AAV9 product confirmed the durability of the systemic delivery approach, confirming that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA (Al-Zaidy et al., 2019), while also situating AAV9-based gene replacement alongside a non-viral alternative (Ogbonmide et al., 2023). This alternative, called nusinersen, was an intrathecal and oral antisense oligonucleotide that binds SMN2 pre-mRNA to increase translation of functional SMN protein (Ogbonmide et al., 2023). Taken together, these findings show that within SMA gene therapy, the choice of AAV9 as a blood-brain barrier piercing serotype, combined with careful selection between systemic and CSF directed delivery, shape both the efficiency of motor neuron transduction and the safety of treatment (Al-Zaidy et al., 2019; Ogbonmide et al., 2023).

Leber Congenital Amaurosis

Leber congenital amaurosis is a group of inherited retinal disorders that are known to cause very serious visual impairment from infancy, with one of the most prominent subtypes originating from mutations in the RPE65 gene. RPE65 encodes an isomerase enzyme required for the retinoid, or visual, cycle within the retinal pigment epithelium. If the gene RPE65 was to not function, photoreceptor cells would not be able to regenerate the light-sensitive pigment necessary for the host to have vision. The condition is inherited in an autosomal recessive pattern, which means that patients require two defective copies of the gene. Typically, this mutation presents itself within the first few months of life through severe loss of vision, nystagmus and a diminished pupillary response to light.

Gene therapy is a fitting treatment for this disease as even though RPE65-deficient photoreceptors are dysfunctional, they usually maintain their structure for years, therefore meaning that the retina is frequently still anatomically capable of responding to gene replacement. The preservation of the structure, combined with the retina’s small size and physical accessibility, makes LCA one of the earliest and most successful targets for direct, localised gene therapy when compared to hemophilia and spinal muscular atrophy (Cideciyan et al., 2010). 

This distinction is clear in the combination used to deliver LCA treating vectors. The approved therapy, voretigene neparvovec (Luxturna), uses the AAV2 vector to deliver a functional copy of the RPE65 gene (American Academy of Ophthalmology, 2017). In contrast to the hemophilia B, hemophilia A and SMA therapies, Luxturna does not rely on a single peripheral intravenous infusion to distribute the vector. Instead, it is distributed through subretinal injection, a surgical procedure placing the vector between the neural retina and the retinal pigment epithelium, focusing on reaching a small and localised target rather than distributing to the whole body (Huang et al., 2025). It is also important to mention that the choice of route that this vector takes is crucial regarding almost every downstream aspect of the therapy including its dosing, safety and mechanism of treatment. 

The choice of subretinal delivery is best explained by the eye’s unique anatomy. The retina is shielded by a blood-retina barrier and lacks a conventional lymphatic drainage network. Instead, the eye contains local anti-inflammatory mechanisms that produce what is often called “immune privilege” (Alsalloum et al., 2024). These features allow a vector that is newly introduced into the subretinal space to remain largely contained within the eye which then minimises systemic immune exposure, therefore reducing the chance of the body mounting an antibody or T-cell response against the AAV capsid. This has a direct practical consequence because the vector does not need to be diluted throughout the entire circulatory system. Only a very small volume is required which is typically just 1–2 µL of AAV solution delivered directly into the target tissue. This directly contrasts the IV-delivered hemophilia B therapies where high-dose patients received total vector doses on the order of 2×10^11 vg/kg. This disparity in required dose size is strong evidence that delivery method directly shapes how a gene therapy must be formulated, dosed and administered, rather than being interchangeable and maintaining the same function. 

The effectiveness of this delivery strategy was further demonstrated in the pivotal Phase 3 randomised controlled trial by Russell et al. (2017). The trial initially included 31 participants (21 treated and 10 untreated controls) though after two early withdrawals, the analysed population at one year consisted of 20 treated and 9 control participants. Treated patients showed a significant improvement on the multi-luminance mobility test, which included a functional test requiring the participants to navigate an obstacle course under varying light conditions, compared with control trials conducted at one year after the treatment. The treated group could navigate the course at rooms 1.8 light levels dimmer on average than they could before treatment, compared with only a 0.2 light-level improvement in the control group, a difference of 1.6 light levels that was statistically significant (95% CI 0.72–2.41, p=0.0013) (Russell et al., 2017). Additionally, 65% of treated participants were able to pass the course at the dimmest light level tested, which was a steep contrast with none of the control participants being able to pass (Russell et al., 2017). The significance of this treatment was further underscored when voretigene neparvovec received FDA approval on 19th December 2017, becoming the first gene therapy approved in the United States for an inherited disease, proving that the therapy’s benefits were robust enough for real-world clinical use, not just statistical significance in a controlled trial setting (US Food and Drug Administration, 2017).

Rett Syndrome

Rett syndrome is a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2), which is essential for the normal function of nerve cells. This genetic illness usually affects females as it is caused by disruption of the MECP2 gene located on the X chromosome. Affected females have two X chromosomes, usually one with the disrupted gene and one with the healthy gene. Having some healthy MeCP2 protein allows females to survive but at the expense of severe impairment that comes with RTT. Since males only have the one X chromosome, they have no healthy MECP2 at all. These boys typically have a more severe form of the disease and often die in early childhood.

RTT occurs in roughly 1 in 15,000 live births. The early symptoms of this disease are slow brain growth, low muscle tone, loss of eye contact and interest, and difficulty developing normal skills for a young toddler such as sitting or crawling. Later on, from the ages of 1-4, they lose purposeful hand-use, communication skills, have uncoordinated movements and experience trouble socialising. In the later years, more medical issues develop, such as epilepsy, GE-reflux, muscle rigidity, difficulty breathing and prolonged QTc. Many children diagnosed with RTT have reduced brain volume compared to healthy individuals. Reduced brain volume is largely due to small neuronal body size and a denser packing of cells, specifically in the third and fifth of the cerebral cortex, thalamus, substantia nigra, basal ganglia, amygdala, cerebellum and hippocampus. 

Despite multiple scientific discoveries, the mechanism by which MECP2 mutations cause RTT symptoms remains largely unknown. As a result, there are not many current treatments for patients, but some are in development. 

The first published gene therapy paper for RTT was in 2013. Using mice models, it showed that “intracerebral administration of a single‐strand AAV9‐MECP2 vector in a neonatal MECP2‐KO mouse induced MeCP2 expression in brain structures and ameliorated the mouse phenotype”. This injection unfortunately caused the mice to develop hepatotoxicity (chemical-driven liver damage), but improved the survival of treated mice. The AAV, which was injected into the tail vein, was mostly transduced into the liver, then the heart, spleen, kidney and central nervous system.

Genome editing is also a popular way to treat this disease as it allows researchers to add, remove or fix genetic material at exact spots in the genome, rather than changing DNA at random. The CRISPR-Cas9 system, which is composed of the Cas9 enzyme and a synthetically engineered guide RNA (gRNA), is the most used gene editing method. Cas9 and gRNA form a ribonucleic complex capable of recognising and cleaving a target sequence. The cut is then repaired either by non‐homologous end joining (NHEJ) or by homology‐directed repair that allows precise genome repair against a donor DNA template. However, there are limits to its use in gene therapy. The first is off‐target modifications on sequences that differ by only a few nucleotides from the target sequence, which can cause alteration of essential genes; second, to co‐express Cas9 and gRNA, it is necessary to transfer the same cell with two different AAVs, the encapsidation (packing viral genetic material into a protein coat) size of one being insufficient. 

For RTT, two techniques of genome editing are in development. Firstly, Beam therapeutics is targeting single point mutations. A study in patients’ fibroblasts and neurons derived from induced pluripotent stem cells showed the success of this approach to correct the T158M mutation. There, the Cas9 expression was limited by adding a sequence recognised by Cas9 between its own sequence and its promoter to allow for its self‐cleavage. This two‐vector approach allowed editing of about 45% of the cells on average. On the other hand, Jonathan Watt’s team at the University of Massachusetts is performing exon editing by replacing exons 3 and 4. This approach would allow, with the same technology, for correcting 97% of RTT‐causing mutations. A first in vitro study conducted by another team showed 20-30% efficacy in cell lines derived from patients with RTT for mutations located in exon 4. However, Neurogene, a clinical-stage biotechnology company that creates genetic medicines and gene therapies for rare and severe neurological diseases, announced their Rett syndrome gene therapy programme, NGN-401, in 2022. NGN-401 delivers a full-length MECP2 gene with a novel technology, called EXACT, that allows the amount of protein made by the gene to be regulated in order to avoid high levels. NGN-401 is administered via injection into the ventricles of the brain. 

Limitations

Although gene therapy is an extremely innovative and useful way to treat rare genetic diseases, it has its limits.

Firstly, there are issues pertaining to the body’s immune response. NAbs are neutralising antibodies that recognise viral vectors as pathogenic viruses, since the viral vector uses the same structure (Tsaregorodtseva et al., 2025). Typically, the body does not already have the antibodies to destroy the viral vector, but in the cases where it needs to be reinjected or the body previously had a similar virus and therefore has the antibodies, the viral vector is destroyed before reaching the desired spot. 

Secondly, there are genomic risks, meaning the probability of developing inherited health conditions due to gene changes: for example, insertional mutagenesis, which is the process where an extra piece of DNA breaks into a host cell’s genome. There is also genotoxicity, which is the ability of chemical, physical or biological agents to damage the genetic material (DNA or RNA) within a cell. 

Thirdly, there are capacity constraints, such as the small packaging limits of AAVs which limit the delivery of large genes, as well as delivery constraints, with vectors entering non-targeted organs/locations. 

Finally, there is significant production complexity to consider as there are high biosafety requirements and difficult purification steps, which makes large-scale manufacturing expensive and variable.

Conclusion

Taken together, the evidence from hemophilia B, spinal muscular atrophy, leber congenital amaurosis and Rett syndrome all show that the vector type and delivery method work dependently on each other to help determine how safe and effective a gene therapy ultimately is.  

Across all four diseases discussed in this paper, AAV remains the best vector choice due to its low immunogenicity and non-integrating nature, meaning that AAV vectors avoid unwanted changes to the host’s genetic material. However, the delivery method of  this vector varies drastically depending on the location of the affected cells. For hemophilia B, the most common method is IV delivery, which successfully targets the liver to restore clotting factor IX production, and newer transgene variants such as padua show that pairing an effective delivery route with an optimised gene can always outperform simply making changes to the vector type. In SMA, the delivery method of choice is usually IV-delivered AAV9, which crosses the blood-brain barrier to treat both the central nervous system and peripheral tissues in one single infusion, while CSF-directed delivery achieves a similar broad motor neuron transduction at a smaller, more localised dose, therefore reducing the systemic side effects. LCA offers the clearest example of treatment tailored to its target tissue. Furthermore, the small size of the eye and its immune-privileged environment allow for a localised subretinal injection which achieves strong functional improvement while also using a fraction of the systemic dose required for hemophilia. However, this introduces localised surgical risks which are not seen in IV delivery methods. Rett syndrome, which is still earlier in gene therapy development, shows the challenges of treating a widespread, brain-based disorder with both IV and intracerebral delivery methods. Similarly to LCA, this treatment shows both functional benefits and risks such as hepatotoxicity, meaning that the choice of delivery method shifts the balance between efficacy and safety significantly even within a single disease. 

Overall, these four case studies suggest there is no universally superior vector or delivery method in gene therapy. In the case of the diseases that were discussed, the effectiveness of the treatment always depends on the anatomical, immunological and physiological characteristics of the target tissue of each disease, therefore meaning that a method that may be superior in one context, such as localised injection for the eye, may be unsuitable for a disease that requires whole-body treatment/spread. Therefore, gene therapy pathways and design must be tailored to each disease’s specific demands rather than universally optimised.

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