Rare diseases typically have a prevalence below 0.05% and constitute around 10,000 diseases, cumulatively affecting over 5% of the global population. Although there is a large unmet need in treatment, the recent advent of gene therapy is beginning to close the gap1. On the other hand, a report in 2017 by the Global Observatory on Donation and Transplantation with data representing approximately 75% of the global population showed that the 139,024 organ transplantations performed that year barely accommodated 10% of the global need2. High hopes are on bioartificial organs to reduce the severity of this unmet need. Both fields of therapy represent a new era of biotechnology, but their role in the future of medical treatment does not solely depend on innovation alone.
Gene therapy and its current treatment landscape
The United States (U.S.) Food and Drug Administration (FDA) defines gene therapy as a technique that modifies a person's genes to treat or cure disease. Today, gene therapy is delivered through various modalities, such as vectors, chimeric antigen receptor T cell immunotherapy, and now genome editing technology3. These are often used to target rare diseases, but their high price tag challenges their longevity in the market. However, lessons gradually gathered in the past decade have paved the way for improved treatment options for patients currently facing limited options4.
Viral vectors to treat inherited retinal dystrophy
A successful case of a gene therapy technique involves in vivo DNA insertion using adeno-associated virus (AAV) vectors in Leber's Congenital Amaurosis type 2 (LCA2), a type of inherited retinal dystrophy (IRD) that was previously incurable and untreatable. IRDs are often caused by a defective gene copy, and through gene supplementation, a functional copy of the gene can be delivered to the target tissue using engineering viruses as vector delivery systems. Patients with LCA2 are blind at birth or in early childhood due to mutations in the gene coding for retinal pigment epithelium-specific 65-kilo-dalton protein (RPE65) that often results in impaired 11-cis-retinal regeneration in the visual cycle and non-functional photoreceptors.
Voretigene neparvovec (VN) is an AAV-based, recombinant, non-integrating vector gene therapy that is administered via subretinal injection with a gap of 6–18 days between each eye1. Results from the randomised, controlled, open-label, phase 3 trial showed that patients treated with VN demonstrated a strong and durable improvement in visual acuity 1 year after treatment, as well as improvements in visual field and light perception5. Moreover, results from the ongoing, 2 year, prospective PERCEIVE study was published this year with the outcomes of 103 patients treated with VN. The findings were consistent with the VN pivotal trials, but sustained improvements in full-field light-sensitivity threshold appeared better in patients aged <18 years than adult patients (Figure 1), highlighting the advantages of early treatment6.
Figure 1. Mean change from baseline in FST (white light) up to 2 years after VN administration in all patients, patients aged <18 years and those aged ≥18 years. dB, decibel; FST, full-field light-sensitivity threshold testing; n, number of eyes; VN, voretigene neparvovec. Baseline data were available for 127 eyes. Error bars represent the standard deviation6.
CRISPR comes of age with sickle cell disease
While AAV vectors are limited to somatic post-mitotic cells and short DNA segments, genome editing technologies are more versatile and have immense potential in possible applications and treatments1,10. Exagamglogene autotemcel (EA) is the first gene therapy approved by the FDA that utilises clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) techniques, and is indicated for transfusion-dependent β-thalassemia and as treatment for sickle cell disease in patients aged ≥1211. In these debilitating, hereditary, and chronic conditions, gene mutations affect haemoglobin production and function resulting in haemolytic anaemia, meaning that patients require repeated blood transfusions as frequent as once or twice a month11.
EA is a one-time, haematopoietic stem cell transplant (HSCT) where the patient’s own CD34+ cells with an erythroid lineage are modified to reduce b-cell lymphoma/leukaemia 11A (BCL11A) expression, thereby, allowing an increase in fetal haemoglobin production that has a higher affinity for oxygen compared to adult haemoglobin12. These findings were substantiated in a phase 3 clinical trial, where out of 28 patients, 89% achieved maintained a weighted average hemoglobin (Hb) ≥9 g/dL without requiring further red blood cell transfusions for over 6 and 12 months, with clinical significant improvements in quality of life13.
The challenging survival and long-term outlook of gene therapy
Even though β-thalassemia (major) and sickle cell disease are the most prevalent rare diseases, many patients are precluded from HSCT and gene therapies since the majority of newborns with the conditions live in developing countries and may never have access to such treatments14. Additionally, betibeglogene autotemcel (BA) is a lentiviral vector, stem cell-based gene therapy that was previously approved in Europe in 2019 for patients with β-thalassemia requiring regular blood transfusions. However, disagreements in the payment model led to the manufacturers withdrawing from the European market. In the United States (approved in 2022), manufacturers agreed to refund 80% of the costs to patients who fail to maintain transfusion independence up to two years later4. Newer flexible reimbursement models for gene therapies are in development, to ensure that treatments are accessible for patients.
Other techniques that build on CRISPR or that have reimagined it entirely are expanding the precision and number of targets of genome editing. For instance, whereas CRISPR/Cas9 systems can only make cuts, a newly discovered technique, known as bridge ribonucleic acids (RNAs), may enable larger-scale genome design that unifies insertion, excision and inversion (Figure 2)15.
Figure 2. A simplified schematic of the mechanism in CRISPR and Bridge RNA17.
However, when discussing the limitations of single-treatment gene therapy, Baylot et al. (2024) noted the potential risk of irreversibility if adverse events occurred and suggested to include on and off switches to prevent overexpression of deoxyribonucleic acid breaks16.
Bioartificial organs for transplants and its current treatment landscape
Bioartificial organs are conceptually structures made of biologically based materials that may functionally be analogous to natural organs, and are still being developed in pre-clinical research settings18,19. The significant growth in research on newer techniques has allowed further exploration of bioartificial organs as the ultimate avenue of hope to overcome the issues of tissue rejection, organ shortage and poor-quality donor organs found with conventional donor organ transplantation.
Lessons learned from scaffolding the bladder
The concept of developing a bioartificial organ originates from advances in tissue engineering and regenerative medicine. In 1999, Atala et al. (2006) successfully engineered an autologous bladder in seven patients aged between 4-19 with spina bifida whom did not require a complete bladder substitution. Urothelial and muscle cells were extracted from patients, cultured and seeded onto a biodegradable bladder-shaped scaffold made of collagen before being reconstructed and implanted into patients. After an intensive follow-up for an average of 46 months, they found that the bladder retained an adequate structural architecture and phenotype. Moreover, bowel function returned promptly after surgery with no subsequent metabolic consequences or urinary calculi, with normal mucus production and renal function20. This was an important stepping-stone in the field as the researchers identified the need for a scaffold to support cells to organise themselves into 3-dimensional structures (Figure 3)21.
Figure 3. Schematic of scaffold-based tissue engineering22.
The steps between bio-tissue and bio-organ
Natural, decellularised scaffolds may have better outcomes than synthetic biomaterials as they retain proteins, extracellular matrix components , and chemical and biological cues similar to the native tissue making them more compatible with the target cells23. However, the field of reconstructive urology is still challenged by the concept of replacing the entire bladder, notwithstanding to other organ systems.
Other than cellular growth, differentiation, maturation, and scaffolding, bioartificial organs should have adequate mechanical, chemical and structural properties. With the bladder, repeated coordinated bladder contractions and relaxation allows for filling, storing and emptying. And as a hollow, fluid-containing organ, sufficient structural integrity is required to avoid collapse or leakage. But as of now, replacing bladder function by using a colon conduit (i.e. an ileal conduit or neobladder generation) still remains the gold standard treatment such as in bladder cancer patients requiring a radical cystectomy, despite of a number of complications that may arise postoperatively23.
The regenerative capabilities of the liver
Solid organs are complex owing to its cell density, high oxygen requirements and multifunctionality. The liver is likely to be the first bioartificial solid organ to be developed since it has the capacity to self-regenerate and recover from disease or injury. Moreover, hepatocytes can already be engineered from induced pluripotent stem cells that are derived from normal somatic adult cells and are potentially limitless in supply19.
The potential of a bioartificial liver device has been initially tested in patients with extended liver resection. Considering that a large portion of the liver is removed, patients are at greater risk of post-hepatectomy liver failure24. Facilitated liver regeneration to support the remnant liver in these patients may provide, and insights before whole organ engineering occurs Wang et al. (2023) conducted a single-arm open-label clinical study on a bioartificial liver in seven patients with extended liver resection. The team produced hepatocytes by inducing human pluripotent stem cells, dedifferentiating hepatocytes or transdifferentiating human fibroblast, and created bioartificial liver supporting systems composed of extracorporeal bioreactors filled with hepatocytes. The initial results revealed that the liver was well-tolerated and associated with improved liver function and liver regeneration (Figure 4), meeting the primary outcome of the incidence of adverse events, including safety and tolerability up to 3 months after therapy24.
Figure 4. Assessment of liver regeneration in patients with extended liver resection by CT volumetry. The yellow box represents the tumor, and the green boxes represent the future liver remnant or liver remnant24.
Immunosuppression and the complexity of sourcing
An important consideration of bioartificial organ development are ethical and safety issues of different cell sources which were systematic review by de Jongh et al. (2022)19. For instance, allogenic cells can be used indefinitely, but unlike consenting to an organ donation, donors have less insight and control over how the cells are used. Xenogeneic cells or tissues carries a risk of zoonoses and face additional socio-cultural barriers. Moreover, when genetically modified cells are used to produce entire organs, the risks of tumour formation or epigenetic changes is exponential. Coupled with the need for immunosuppression, the authors advise on the minimal use of xenogeneic and genetically modified sources19. But if the goal is immunosuppression-free transplantation (figure 5)25 to reduce the chance of immune rejection and the dependability on immunosuppressives post-transplantation, the significant structural hurdles of harvesting and storing autologous cell sources must be overcome19.
Figure 5. Phases in the history of organ transplantation25.
To conclude, the immense pace at which gene therapy has progressed from bench to bedside or the collaboration of technologies in bioartificial organs bring immense hope for the future. But with both forms of therapy, succinct basic research must be supported by patient involvement while considering their broader implications.
References
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