Advancements and Ethical Considerations in Cell and Gene Therapies: A Comprehensive Review

Abstract

Cell and gene therapies represent a revolutionary paradigm shift in modern medicine, offering unprecedented potential for the treatment of a myriad of genetic disorders and challenging diseases previously considered incurable. This comprehensive report meticulously examines the intricate landscape of these innovative therapeutic modalities, with a particular emphasis on their profound implications and transformative applications within pediatric medicine. The analysis delves into the foundational scientific mechanisms underpinning these therapies, their established and emerging clinical applications across various pediatric conditions, the complex ethical considerations that arise from their deployment, the rigorous methodologies employed in their clinical evaluation, and the evolving regulatory frameworks governing their development and market access. Furthermore, the report extrapolates on the future trajectory of cell and gene therapy research, anticipating advancements in personalized medicine, expanded therapeutic indications, and crucial innovations in manufacturing and cost reduction. By synthesizing current knowledge, highlighting recent breakthroughs, and addressing persistent challenges, this detailed review aims to provide an exhaustive resource for healthcare professionals, researchers, policymakers, and stakeholders navigating the multifaceted realm of these pioneering treatments.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

The dawn of the 21st century has been marked by a profound acceleration in biomedical innovation, with cell and gene therapies emerging as beacons of hope for patients suffering from devastating genetic disorders and recalcitrant diseases. Historically, therapeutic interventions for conditions such as Spinal Muscular Atrophy (SMA), sickle cell disease, cystic fibrosis, and various forms of muscular dystrophy were largely palliative, focused on symptom management and improving quality of life without addressing the root genetic pathology. However, the advent of sophisticated biotechnological tools has ushered in an era where the precise modification or replacement of defective genetic material, or the utilization of engineered cells, can fundamentally alter disease trajectories, offering the promise of durable cures rather than merely symptomatic relief.

This report embarks on an in-depth exploration of this transformative field, with a particular focus on pediatric populations. Children afflicted with genetic disorders often face lifelong disabilities, severe morbidity, and premature mortality. The early onset and progressive nature of many these conditions underscore the urgency and unique ethical considerations of intervening as early as possible. Cell and gene therapies hold the unique potential to halt or even reverse disease progression before irreversible damage occurs, thereby profoundly impacting the lives of young patients and their families. We will elucidate the sophisticated biological mechanisms that enable these therapies to exert their effects, provide detailed case studies of their successful applications and ongoing challenges in pediatric conditions, meticulously dissect the multifaceted ethical dilemmas inherent in their application, outline the rigorous pathways of clinical trial design and regulatory approval, and finally, cast a visionary gaze upon the future prospects and anticipated advancements that will continue to shape this rapidly evolving domain. This report seeks to provide a comprehensive, academically rigorous overview, bridging the gap between cutting-edge scientific discovery and its practical, ethical, and societal implications.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. Mechanisms of Cell and Gene Therapies

Cell and gene therapies represent a diverse array of biotechnological interventions designed to modify or replace defective genetic material, or to introduce functional cells into the body, thereby correcting underlying pathological processes. While distinct in their immediate modality, these approaches often converge in their ultimate goal: to restore normal cellular function and alleviate disease symptoms by addressing the fundamental molecular or cellular defect.

2.1 Gene Editing

Gene editing refers to a set of advanced molecular techniques that enable precise, targeted alterations to the DNA sequence within a cell. Unlike gene addition, which introduces an extra copy of a gene, gene editing aims to correct, delete, or insert specific DNA sequences at predetermined genomic loci. The most prominent and revolutionary of these technologies is CRISPR-Cas9 (Clustered Regularly Interspaced Short Pallindrome Repeats – CRISPR associated protein 9). This system, originally discovered as a bacterial adaptive immune system, has been repurposed as a molecular scissor capable of making highly specific cuts in DNA.

At its core, the CRISPR-Cas9 system consists of two main components: a guide RNA (gRNA) and the Cas9 nuclease. The gRNA is a synthetic RNA molecule engineered to contain a ‘spacer’ sequence that is complementary to a specific target DNA sequence in the genome. This gRNA guides the Cas9 protein to the exact location where the DNA needs to be cut. Once Cas9 cleaves the double-stranded DNA, the cell’s natural DNA repair machinery is activated. There are primarily two repair pathways:

• Non-Homologous End Joining (NHEJ): This is a ‘quick and dirty’ repair mechanism that ligates the broken DNA ends, often resulting in small insertions or deletions (indels) at the cleavage site. While imprecise, NHEJ can be exploited to ‘knock out’ a gene by introducing frameshift mutations that lead to a non-functional protein. This is useful for conditions caused by gain-of-function mutations or where gene silencing is desired.
• Homology-Directed Repair (HDR): This pathway is much more precise and relies on a homologous DNA template to guide the repair. By providing an exogenous DNA template that contains the desired genetic correction, researchers can ‘knock in’ specific sequences, such as correcting a single nucleotide polymorphism (SNP) or inserting an entirely new gene. HDR is less efficient than NHEJ, making it a current focus of research for improving gene editing precision.

Beyond CRISPR-Cas9, other gene editing technologies include TALENs (Transcription Activator-Like Effector Nucleases) and ZFNs (Zinc Finger Nucleases). While historically significant, these systems are generally more complex to design and implement than CRISPR. More recent advancements include Base Editing and Prime Editing. Base editors can chemically convert one DNA base into another without breaking the DNA backbone, allowing for single-letter changes. Prime editors combine reverse transcriptase with a Cas9 nickase and a prime editing guide RNA (pegRNA) to enable a broader range of edits, including substitutions, small insertions, and deletions, without relying on double-strand breaks or donor DNA templates, offering even greater precision and potentially reduced off-target effects. Gene editing holds immense promise for conditions caused by specific point mutations, such as sickle cell disease, where a single base change can be corrected.

2.2 Gene Addition

Gene addition, also known as gene replacement therapy, involves introducing a functional copy of a gene into a patient’s cells to compensate for a defective or missing gene. This approach is particularly effective for recessive genetic disorders where the presence of even one functional gene copy can ameliorate disease symptoms. The primary challenge in gene addition is the efficient and safe delivery of the new genetic material into target cells. This is typically achieved using viral vectors, which are viruses modified to remove their pathogenic components while retaining their ability to efficiently deliver genetic cargo into cells.

Commonly used viral vectors include:

• Adeno-Associated Viruses (AAVs): These are small, non-enveloped viruses that are non-pathogenic in humans. AAVs are widely used due to their broad tropism (ability to infect various cell types), relatively low immunogenicity, and ability to establish long-term gene expression without integrating into the host genome (they typically exist as episomes). Different AAV serotypes exhibit varying tissue specificities, allowing for targeted delivery to organs like the liver, muscle, or central nervous system. AAVs are a cornerstone of several approved gene therapies, including onasemnogene abeparvovec for SMA. Their primary limitations include a small packaging capacity (limiting the size of genes that can be delivered) and the potential for pre-existing immunity in patients.
• Lentiviruses: Derived from HIV, lentiviruses are engineered to be replication-defective and safe. A key advantage of lentiviruses is their ability to integrate their genetic material into the host cell’s genome, leading to stable, long-term expression even in dividing cells. This makes them ideal for ex vivo gene therapy approaches where cells are modified outside the body and then reinfused, such as in hematopoietic stem cell gene therapy for blood disorders or immunodeficiencies. However, insertional mutagenesis (the risk of unintended gene disruption upon integration) is a theoretical concern, though clinical data has largely alleviated this for current generation vectors.
• Retroviruses: Similar to lentiviruses, retroviruses integrate into the host genome but are limited to transducing dividing cells. Early gene therapy trials using retroviruses faced issues with insertional mutagenesis, leading to their reduced use in favor of safer lentiviral vectors.

Non-viral delivery methods are also being explored, including liposomes, nanoparticles, and electroporation. These methods generally offer lower transduction efficiency compared to viral vectors but present a safer alternative as they avoid the immunogenicity and insertional mutagenesis concerns associated with viruses. Advances in nanotechnology are improving their potential for clinical application.

Gene addition can be performed in vivo (directly administered to the patient, e.g., intravenous infusion of AAV for SMA) or ex vivo (cells are extracted from the patient, modified in a lab, and then reinfused, e.g., hematopoietic stem cell gene therapy for sickle cell disease).

2.3 Cell Therapy

Cell therapy involves the transplantation of healthy, functional cells into a patient to replace or repair damaged tissues, restore lost function, or augment existing cellular processes. This broad category encompasses various approaches, differing based on the source and type of cells used, and their intended therapeutic effect. Key distinctions include autologous versus allogeneic cell sources and the specific cellular populations employed.

• Autologous Cell Therapy: Involves using a patient’s own cells, which are harvested, processed (e.g., expanded, genetically modified), and then reinfused into the same patient. The primary advantage of autologous therapy is the absence of immune rejection, eliminating the need for immunosuppressive drugs. This approach is commonly used in Hematopoietic Stem Cell Transplantation (HSCT), particularly for blood cancers and certain genetic blood disorders, where a patient’s own bone marrow stem cells are collected, chemotherapy-resistant, and then reinfused post-myeloablative chemotherapy. Another prominent example is CAR-T (Chimeric Antigen Receptor T-cell) therapy, where a patient’s T-cells are genetically engineered ex vivo to express a CAR that enables them to recognize and kill cancer cells. The modified T-cells are then expanded and reinfused.

• Allogeneic Cell Therapy: Utilizes cells derived from a healthy donor. While offering the advantage of ‘off-the-shelf’ availability and potentially unlimited supply, allogeneic therapies carry the risk of immune rejection (graft-versus-host disease in HSCT or rejection of the therapeutic cells by the recipient’s immune system) and often necessitate immunosuppression. Sources for allogeneic cells include bone marrow, umbilical cord blood, and induced pluripotent stem cells (iPSCs) which can be differentiated into various cell types. Mesenchymal Stem Cells (MSCs), known for their immunomodulatory and regenerative properties, are also being explored in allogeneic settings for various inflammatory and degenerative conditions.

Beyond HSCT and CAR-T, cell therapy applications are expanding rapidly. This includes the use of regenerative medicine approaches where cells (e.g., stem cells, progenitor cells) are used to repair or replace damaged tissues in organs like the heart, brain, or liver. Examples include islet cell transplantation for diabetes, neuronal stem cell transplantation for neurodegenerative diseases, and chondrocyte transplantation for cartilage repair. The therapeutic effect of cell therapies can range from direct replacement of dysfunctional cells to indirect effects via secretion of trophic factors, immunomodulation, or scaffolding for tissue regeneration. The success of cell therapies hinges on the cells’ ability to survive, engraft, differentiate appropriately, and integrate functionally within the host environment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Applications in Pediatric Medicine

Pediatric patients represent a particularly vulnerable and yet promising population for cell and gene therapies. Many genetic disorders manifest in early childhood, leading to severe, progressive, and often life-limiting conditions. Early intervention with transformative therapies offers the unique opportunity to prevent irreversible damage, improve developmental trajectories, and significantly enhance long-term quality of life. The field has witnessed remarkable progress in translating research breakthroughs into approved therapies for several devastating pediatric diseases.

3.1 Spinal Muscular Atrophy (SMA)

Spinal Muscular Atrophy (SMA) is a severe, debilitating neurodegenerative genetic disorder characterized by the progressive loss of motor neurons in the spinal cord and brainstem, leading to muscle weakness, atrophy, and eventually, paralysis. The vast majority of SMA cases (Type 1, 2, 3) are caused by a deficiency in the Survival Motor Neuron (SMN) protein, primarily due to homozygous deletion or mutation of the SMN1 gene on chromosome 5q. While a paralogous gene, SMN2, can produce some functional SMN protein, it largely generates a truncated, unstable isoform due to alternative splicing, rendering it insufficient to compensate for the SMN1 deficiency. The severity of SMA inversely correlates with the number of SMN2 gene copies.

The approval of onasemnogene abeparvovec (Zolgensma) in 2019 marked a paradigm shift in SMA treatment. Zolgensma is a one-time gene replacement therapy that utilizes an adeno-associated virus serotype 9 (AAV9) vector to deliver a functional copy of the human SMN1 complementary DNA (cDNA) to motor neuron cells. The AAV9 vector is particularly effective because it can cross the blood-brain barrier (BBB) and transduce motor neurons throughout the central nervous system (CNS) following systemic intravenous administration. Clinical trials, notably the STRIVE and SPR1NT studies, demonstrated unprecedented efficacy, particularly when administered presymptomatically or in very young infants. Treated infants showed significant improvements in motor milestones (e.g., sitting independently, walking), sustained ventilator-free survival, and overall survival rates far exceeding the natural history of SMA. For instance, in the pivotal Phase 3 STRIVE trial, 91% of infants with SMA Type 1 treated with Zolgensma reached the age of 14 months without permanent ventilation, compared to only 26% in the natural history cohort (Mendell et al., 2017). A major challenge associated with AAV9 gene therapy is the potential for pre-existing antibodies to AAV9, which can neutralize the vector and preclude treatment in a subset of patients. Early diagnosis, often through newborn screening, is crucial to maximize therapeutic benefit before significant motor neuron loss occurs.

Beyond gene therapy, nusinersen (Spinraza), an antisense oligonucleotide, and risdiplam (Evrysdi), a small molecule, also represent significant advancements by modulating SMN2 splicing to produce more functional SMN protein. These therapies, while requiring chronic administration, have also dramatically improved outcomes for SMA patients, highlighting the multi-pronged attack on this previously intractable disease.

3.2 Sickle Cell Disease (SCD) and Beta-Thalassemia

Sickle Cell Disease (SCD) is a devastating hereditary blood disorder affecting millions globally, particularly those of African, Mediterranean, and South Asian descent. It is caused by a single point mutation (HbS mutation, glutamic acid to valine substitution) in the beta-globin gene (HBB), leading to the production of abnormal hemoglobin (hemoglobin S, HbS). Under low oxygen conditions, HbS polymerizes, causing red blood cells to deform into a sickle shape. These rigid, sticky cells obstruct blood flow in small vessels, leading to chronic hemolytic anemia, acute pain crises, organ damage (stroke, acute chest syndrome, kidney failure), and reduced life expectancy.

Beta-Thalassemia is another severe hereditary blood disorder characterized by reduced or absent production of the beta-globin chain of hemoglobin, leading to ineffective erythropoiesis, severe anemia, and iron overload. Patients typically require lifelong red blood cell transfusions and iron chelation therapy.

Recent years have seen groundbreaking gene therapy approvals for both SCD and beta-thalassemia, leveraging ex vivo hematopoietic stem cell gene therapy. This approach involves collecting a patient’s own hematopoietic stem cells (HSCs) from the bone marrow or peripheral blood. These HSCs are then genetically modified outside the body and subsequently reinfused after a conditioning regimen (typically myeloablative chemotherapy) to make space in the bone marrow for the modified cells to engraft.

• Lovotibeglogene autotemcel (Lyfgenia) and Exagamglogene autotemcel (Casgevy), both approved in late 2023 for SCD and beta-thalassemia, represent distinct yet similarly transformative approaches. Lyfgenia (formerly LentiGlobin, developed by bluebird bio) utilizes a lentiviral vector to introduce a modified beta-globin gene (βA-T87Q) into the patient’s HSCs. This gene expresses an anti-sickling variant of hemoglobin, HbAT87Q, which interferes with the polymerization of HbS and produces functional hemoglobin. Clinical trials, such as the HGB-206 study, showed that a significant proportion of patients achieved complete resolution of vaso-occlusive crises (VOCs) and transfusion independence, dramatically improving their quality of life.

• Casgevy (developed by Vertex Pharmaceuticals and CRISPR Therapeutics) represents the first FDA-approved gene editing therapy utilizing CRISPR-Cas9 technology. For SCD, Casgevy targets the BCL11A gene in patient-derived HSCs. BCL11A is a master regulator that suppresses the production of fetal hemoglobin (HbF) in adults. By knocking out a specific enhancer region in BCL11A, Casgevy reactivates the expression of HbF. Fetal hemoglobin does not contain the beta-globin chain and thus does not sickle, effectively diluting the abnormal HbS and reducing disease severity. Clinical data from the CLIMB-121 and CLIMB-111 trials demonstrated profound clinical benefit, with many patients achieving freedom from VOCs and transfusion independence (Frangoul et al., 2021). The therapeutic benefit for beta-thalassemia similarly relies on the reactivation of HbF. While effective, the gene therapies for SCD and beta-thalassemia involve a complex and demanding process, including mobilization and collection of HSCs, ex vivo modification, myeloablative conditioning, and prolonged hospitalization for engraftment. Long-term follow-up is ongoing to assess durability and potential late effects of the conditioning regimen and genetic modification.

3.3 Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is a chronic, progressive genetic disorder primarily affecting the lungs and digestive system, caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The CFTR protein functions as a chloride channel crucial for regulating the movement of salt and water across cell membranes. Dysfunctional CFTR leads to the production of thick, sticky mucus that clogs airways, leading to chronic infections and progressive lung damage, and obstructs pancreatic ducts, impairing digestion. While CFTR modulators (e.g., Trikafta) have revolutionized treatment for patients with specific mutations, a significant proportion of patients, particularly those with rare or nonsense mutations, do not benefit from these drugs, and even for those who do, the underlying genetic defect remains uncorrected.

Gene therapy for CF aims to deliver a functional copy of the CFTR gene to the affected cells, primarily airway epithelial cells. However, this has proven to be particularly challenging due to several factors:

• Large gene size: The CFTR gene is relatively large, pushing the packaging limits of common viral vectors like AAV.
• Mucus barrier: The thick mucus layer in CF airways acts as a physical barrier, impeding vector delivery to the epithelial cells.
• Immune response: The lung is an immunologically active organ, and repeated administration of viral vectors can elicit an immune response, reducing efficacy and preventing re-dosing.
• Cell turnover: Airway epithelial cells are constantly shedding and regenerating, requiring sustained or repeated gene expression.

Despite these challenges, ongoing research and early-phase clinical trials have shown promise. Various viral vectors (e.g., AAV, lentivirus) and non-viral delivery systems (e.g., liposomes, nanoparticles) are being explored for their ability to deliver the CFTR gene via inhalation. While some early trials demonstrated transient improvements in lung function and modest CFTR protein expression, achieving widespread, uniform, and sustained gene transfer to all relevant airway cells remains an active area of development (Griesenbach et al., 2020). Innovations in vector design, targeted delivery systems, and strategies to overcome the mucus barrier are crucial for advancing CF gene therapy towards clinical reality.

3.4 Muscular Dystrophy

Muscular dystrophies are a heterogeneous group of genetic disorders characterized by progressive muscle weakness and degeneration. Duchenne Muscular Dystrophy (DMD) is the most common and severe form, caused by mutations in the DMD gene, leading to the absence or severe deficiency of dystrophin, a critical protein for muscle fiber integrity and function. Patients with DMD typically experience progressive muscle wasting, loss of ambulation, respiratory failure, and cardiomyopathy, with life expectancy often limited to the third decade.

Gene therapy for DMD focuses on delivering functional copies of the DMD gene or strategies to produce a functional dystrophin protein. Due to the DMD gene’s massive size (the largest human gene), it exceeds the packaging capacity of AAV vectors. Researchers have overcome this by delivering smaller, functional versions of the gene known as micro-dystrophin or mini-dystrophin genes, which contain the critical functional domains of the full-length protein. These micro-dystrophin genes are packaged into AAV vectors (e.g., AAV9 or AAV-rh74) and administered systemically.

Clinical trials (e.g., VISION, EMBARK) of micro-dystrophin gene therapies have shown encouraging results in restoring dystrophin expression in muscle biopsies, leading to improvements in motor function, as measured by standard scales like the North Star Ambulatory Assessment (NSAA) (Nelson et al., 2021). Challenges include achieving widespread gene delivery to all affected muscles throughout the body (including the diaphragm and heart), managing the host immune response to the AAV vector and the transgene product, and ensuring long-term durability of expression. Dose-limiting toxicities, particularly liver and cardiac adverse events, have also been observed, necessitating careful patient selection and monitoring.

Beyond gene replacement, exon skipping therapies (e.g., eteplirsen, golodirsen, viltolarsen, casimersen) are another approach for DMD. These antisense oligonucleotide-based therapies are designed to ‘skip’ mutated exons during mRNA splicing, allowing for the production of a truncated but partially functional dystrophin protein. While not gene therapies in the strict sense, they represent a significant advance in precision medicine for specific DMD mutations.

Other forms of muscular dystrophy, such as Limb-Girdle Muscular Dystrophy (LGMD) caused by specific gene deficiencies (e.g., sarcoglycanopathies, dysferlinopathy), are also targets for gene therapy. The smaller size of genes involved in some LGMDs may make them more amenable to current AAV vector technology.

3.5 Severe Combined Immunodeficiency (SCID)

Severe Combined Immunodeficiency (SCID) is a group of rare, life-threatening genetic disorders characterized by a profound defect in the development and function of T-lymphocytes and often B-lymphocytes and NK cells, leading to extreme susceptibility to infections. Infants with SCID are often referred to as ‘bubble babies’ due to their need for isolation. Historically, the only curative treatment was allogeneic HSCT.

Gene therapy has emerged as a successful alternative for specific types of SCID. For instance, Adenosine Deaminase Deficiency (ADA-SCID) is caused by mutations in the ADA gene, leading to the accumulation of toxic metabolites that destroy lymphocytes. X-linked SCID (SCID-X1), the most common form, is caused by mutations in the IL2RG gene, encoding the common gamma chain (γc) receptor crucial for the development of T and NK cells.

For ADA-SCID, therapies like Strimvelis (approved in Europe) and Lenmeldy (for Metachromatic Leukodystrophy, but illustrates the principle) involve ex vivo gene therapy. Patient-derived HSCs are transduced with a lentiviral vector carrying a functional copy of the ADA or ARSA gene (for MLD), respectively. These modified cells are then reinfused. Clinical trials have demonstrated robust immune reconstitution, with patients developing functional T-cells and B-cells, leading to a dramatic reduction in infections and improved survival (Aiuti et al., 2009). The success of gene therapy for SCID highlights its potential for conditions where a small number of corrected stem cells can repopulate a functional lineage.

3.6 Metachromatic Leukodystrophy (MLD)

Metachromatic Leukodystrophy (MLD) is a rare, severe inherited lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA), due to mutations in the ARSA gene. This enzyme is crucial for breaking down sulfatides, which are components of myelin. Without functional ARSA, sulfatides accumulate in the brain, spinal cord, peripheral nerves, and other organs, leading to progressive demyelination and neurodegeneration, resulting in severe motor, cognitive, and neurological decline, typically in early childhood.

Atidarsagene autotemcel (Lenmeldy), developed by Orchard Therapeutics and recently approved by the FDA, is an ex vivo autologous gene therapy for MLD. Similar to SCID gene therapy, it involves collecting a patient’s HSCs and then genetically modifying them ex vivo using a lentiviral vector to insert a functional copy of the ARSA gene. These modified HSCs are then reinfused into the patient following myeloablative conditioning.

The therapeutic principle relies on the ability of corrected HSCs to engraft in the bone marrow, differentiate, and migrate to the brain, where they can release functional ARSA enzyme. This enzyme can then be taken up by other brain cells, including oligodendrocytes and neurons, via a process called ‘cross-correction,’ thereby clearing the accumulated sulfatides and preventing further myelin damage. Clinical trials, particularly in presymptomatic or early symptomatic children with late infantile or early juvenile MLD, have shown remarkable efficacy. Treated children demonstrated significantly delayed onset and slower progression of motor and cognitive decline compared to natural history controls (Tucci et al., 2021). The critical window for treatment is early in the disease course, ideally before significant neurological damage has occurred, underscoring the importance of newborn screening for MLD.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Ethical Considerations

The revolutionary potential of cell and gene therapies is accompanied by a complex tapestry of ethical considerations that demand meticulous scrutiny. As these treatments push the boundaries of medical possibility, they raise fundamental questions about patient autonomy, equitable access, long-term safety, and the very nature of human genetic inheritance. Navigating these ethical landscapes requires a collaborative effort among clinicians, scientists, ethicists, legal experts, and patient advocacy groups.

4.1 Informed Consent in Pediatric Populations

Obtaining genuinely informed consent for experimental, high-stakes therapies is inherently complex, and this complexity is significantly amplified in the pediatric context. Children, by virtue of their age and developmental stage, may lack the cognitive capacity to fully comprehend the intricate details of a cell or gene therapy, its potential benefits, substantial risks, and the irreversible nature of some interventions. This necessitates a nuanced approach to consent, involving multiple layers of deliberation:

• Proxy Consent: Primary responsibility for decision-making typically falls to parents or legal guardians, who provide ‘proxy consent’ on behalf of their child. This consent must be truly informed, meaning parents are thoroughly educated about the scientific basis of the therapy, the uncertainties regarding long-term efficacy and safety, potential side effects (including those from conditioning regimens), alternative treatments (or lack thereof), and the intensive nature of the treatment process and follow-up. This often requires extensive discussions with multidisciplinary teams, including physicians, genetic counselors, social workers, and psychologists.
• Assent: For older children and adolescents, the concept of ‘assent’ becomes crucial. Assent signifies the child’s affirmative agreement to participate, based on their evolving understanding of the therapy. While not legally binding consent, clinicians have an ethical obligation to explain the procedure in an age-appropriate manner, address the child’s questions and concerns, and respect their dissent if they are mature enough to comprehend the implications, provided it does not compromise their well-being. Child life specialists play a vital role in facilitating these conversations and ensuring the child’s voice is heard.
• Evolving Understanding: The long-term nature of gene therapy follow-up means that a child’s understanding and capacity for decision-making will evolve over time. This necessitates ongoing communication and re-education, potentially involving a re-affirmation of assent as they mature.
• Best Interest of the Child: All decisions must ultimately be guided by the ‘best interest of the child’ principle, a complex ethical standard that balances potential benefits against risks and burdens, considering the child’s unique circumstances, prognosis, and quality of life.

4.2 Accessibility and Equity

The exceptionally high costs associated with the development, manufacturing, and administration of many cell and gene therapies pose formidable challenges to equitable access, raising profound concerns about justice and fairness. These therapies often carry price tags in the millions of dollars (e.g., Zolgensma at $2.1 million, Lenmeldy at $4.25 million), reflecting the enormous research and development investment, the complexity of manufacturing, and the small patient populations for rare diseases (which limits the ability to spread costs across a large market).

Key issues include:

• Exorbitant Pricing: The ‘one-time treatment, one-time payment’ model for curative therapies creates unique pricing dilemmas for healthcare systems accustomed to chronic treatment reimbursement. This can strain national healthcare budgets, leading to difficult allocation decisions.
• Healthcare Disparities: The high cost creates a significant barrier for patients in low- and middle-income countries, exacerbating global health disparities. Even within wealthy nations, access may be limited by insurance coverage, specific healthcare policies, and the availability of specialized treatment centers.
• Orphan Drug Status: While orphan drug designations (incentivizing drug development for rare diseases) are vital, they also confer market exclusivity that can contribute to high pricing. Striking a balance between incentivizing innovation and ensuring affordability is a major policy challenge.
• Innovative Payment Models: Efforts are underway to explore novel payment models, such as outcome-based agreements (where payments are tied to the therapy’s demonstrated efficacy), annuity-based payments (spreading the cost over several years), or risk-sharing agreements between manufacturers and payers. However, these models introduce their own complexities related to long-term data collection and contractual obligations.

Addressing these disparities requires multi-stakeholder collaboration, including pharmaceutical companies, governments, insurers, and international organizations, to develop sustainable pricing models, expand manufacturing capabilities, and foster equitable distribution mechanisms.

4.3 Long-Term Effects and Unintended Consequences

Given the relatively nascent stage of clinical implementation for many cell and gene therapies, the full spectrum of their long-term safety and efficacy profiles is not yet completely understood. This necessitates robust and prolonged post-market surveillance. Potential risks and unintended consequences include:

• Insertional Mutagenesis: For gene therapies that integrate into the host genome (e.g., lentiviral vectors), there is a theoretical risk that the therapeutic gene could integrate into a tumor suppressor gene or proto-oncogene, leading to oncogenesis (e.g., leukemia). While modern lentiviral vectors have been engineered to minimize this risk, and clinical data has largely been reassuring, long-term monitoring remains crucial.
• Off-Target Effects (Gene Editing): CRISPR-Cas9 and other gene editing tools, while highly specific, can sometimes make unintended cuts or edits at sites in the genome that are similar to the target sequence. These ‘off-target’ edits could potentially lead to adverse cellular changes, including oncogenesis or disruption of essential genes. Advances in guide RNA design and enzyme engineering are continuously improving specificity.
• Immunogenicity: The host immune system can recognize components of the gene therapy, such as the viral vector (e.g., AAV capsid) or the transgene product, as foreign. This can lead to an immune response that neutralizes the vector, eliminates transduced cells, reduces therapeutic efficacy, and can cause systemic inflammation. This also poses a challenge for re-dosing if initial treatment is insufficient or efficacy wanes.
• Durability of Expression: The long-term persistence of gene expression and cellular function is critical for durable therapeutic benefit. Factors like cell turnover, immune responses, and the stability of the genetic modification can influence how long the therapeutic effect lasts. Loss of efficacy over time would necessitate re-treatment, which may be complicated by immunogenicity.
• Germline Transmission (Inadvertent): While current gene therapies are designed to target somatic cells, there is a theoretical risk of inadvertent modification of germline cells (sperm or egg cells), which could lead to heritable genetic changes in future generations. This is rigorously monitored in clinical trials and is a major ethical line in the sand for many.

Rigorous long-term follow-up studies, patient registries, and pharmacovigilance programs are essential to systematically collect data on these potential risks and ensure the continued safety and efficacy of approved therapies. Patients and families must be fully informed about these uncertainties.

4.4 Germline Editing

Perhaps the most ethically charged aspect of gene therapy is the prospect of germline editing, which involves making genetic modifications to reproductive cells (sperm, eggs) or early embryos. Unlike somatic gene therapy, which targets non-reproductive cells and whose effects are not heritable, germline editing would result in permanent and heritable changes to the human genome, passed down through generations. While theoretically offering the ultimate promise of eradicating inherited diseases from a family line, it raises profound ethical, societal, and even philosophical concerns:

• Irreversibility and Unforeseen Consequences: Changes made to the germline would be irreversible and could have unforeseen long-term effects on future generations, including potential impacts on the human gene pool that are impossible to predict or mitigate.
• ‘Designer Babies’ and Eugenics: Concerns exist that germline editing could open the door to ‘designer babies,’ where genetic traits are selected not for disease prevention but for enhancement (e.g., intelligence, athletic ability), potentially exacerbating social inequalities and leading to a new form of eugenics.
• Consent for Future Generations: It is impossible to obtain consent from future individuals whose genomes would be permanently altered.
• Societal Values: There is no global consensus on whether germline editing is ethically permissible, with many countries and scientific bodies adopting a cautious or prohibitive stance due to these profound implications.

Most scientific and regulatory bodies currently advocate for a moratorium or strict prohibition on clinical germline editing, emphasizing that the technology is not yet scientifically mature or ethically justified for human application. Research in this area is largely confined to the laboratory setting for fundamental biological understanding.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Clinical Trials and Regulatory Landscape

The journey of a cell or gene therapy from laboratory discovery to widespread clinical availability is a complex, multi-stage process governed by rigorous scientific scrutiny and evolving regulatory frameworks. Given the novelty, complexity, and unique risk-benefit profiles of these therapies, standard clinical trial designs and regulatory pathways have been adapted and expedited to facilitate their development for rare and often life-threatening conditions.

5.1 Trial Design and Methodology

Clinical trials are meticulously structured to evaluate the safety, efficacy, and optimal dosing of new therapies. For cell and gene therapies, particular considerations come into play:

• Phase 0 (Exploratory): In some cases, very small, early trials might assess pharmacokinetic/pharmacodynamic properties or biomarker changes in a few subjects to inform later trial design, often before traditional Phase 1.
• Phase I (Safety and Dose-Finding): The primary objective is to assess the safety of the therapy in a small number of patients (often 10-30). Researchers identify the maximum tolerated dose (MTD) or optimal biological dose, characterize adverse events, and study pharmacokinetics (how the body affects the drug) and pharmacodynamics (how the drug affects the body). For gene therapies, this phase is critical for determining safe vector doses and assessing initial evidence of gene expression or cellular engraftment.
• Phase II (Efficacy and Safety): Involves a larger group of patients (tens to hundreds) to evaluate the therapy’s preliminary efficacy, further characterize safety, and refine dosing. For rare diseases, Phase I and Phase II studies may be combined due to limited patient populations.
• Phase III (Confirmatory Efficacy): These are large, pivotal trials (hundreds to thousands of patients) designed to confirm efficacy, evaluate long-term safety, and compare the new therapy against standard of care or placebo. Randomized, double-blind, placebo-controlled designs are considered the gold standard, but for rare, rapidly progressing, or fatal diseases where a placebo arm would be unethical, alternative designs (e.g., single-arm studies with natural history comparators, external controls, or adaptive designs) are often employed.
• Phase IV (Post-Market Surveillance): Conducted after regulatory approval to monitor long-term safety, identify rare adverse events, and evaluate real-world effectiveness in a broader patient population.

Adaptive Trial Designs are increasingly utilized in cell and gene therapy development. These designs allow for modifications to the trial protocol (e.g., sample size, treatment arms, dose adjustments) based on interim data analysis, leading to more efficient trials and potentially faster access to treatments for patients with urgent medical needs. For very rare diseases, N-of-1 trials (single-patient trials) or basket trials (testing one drug across multiple diseases with the same molecular alteration) and umbrella trials (testing multiple drugs for one disease) may also be relevant.

Endpoints in pediatric gene therapy trials are often complex. For neurodegenerative diseases like SMA or MLD, they include motor function scales, developmental milestones, ventilator-free survival, and cognitive assessments. For blood disorders, endpoints include transfusion independence, reduction in pain crises, and levels of functional hemoglobin. Biomarkers (e.g., SMN protein levels, ARSA enzyme activity) are also crucial for demonstrating biological effect.

5.2 Regulatory Approvals and Expedited Pathways

Regulatory agencies worldwide have recognized the unique potential and challenges of cell and gene therapies, establishing specialized pathways to accelerate their development and review, particularly for orphan diseases and life-threatening conditions with unmet medical needs. Key regulatory bodies include the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Japan Pharmaceuticals and Medical Devices Agency (PMDA).

Common expedited pathways include:

• Orphan Drug Designation: Granted to therapies for rare diseases (affecting fewer than 200,000 people in the US) to incentivize development through tax credits, fee waivers, and market exclusivity upon approval.
• Breakthrough Therapy Designation (FDA): For drugs intended to treat serious or life-threatening conditions, where preliminary clinical evidence indicates substantial improvement over existing therapies on one or more clinically significant endpoints. This designation involves intensive guidance from the FDA, organizational commitment, and eligibility for rolling review.
• Regenerative Medicine Advanced Therapy (RMAT) Designation (FDA): Similar to Breakthrough Therapy, but specifically for regenerative medicine therapies, including cell therapies, gene therapies, and tissue-engineered products. It offers all the benefits of Breakthrough Therapy, plus potential for early interaction with FDA during development.
• PRIME (PRIority MEdicines) Scheme (EMA): Provides enhanced support and early dialogue to developers of promising medicines that could address unmet medical needs.
• Accelerated Approval (FDA) / Conditional Marketing Authorization (EMA): Allows for approval based on surrogate endpoints (e.g., a biomarker change) or clinical endpoints that are reasonably likely to predict clinical benefit, particularly for serious conditions. Post-approval confirmatory trials are typically required to verify the clinical benefit.

These pathways aim to strike a balance between getting potentially life-saving therapies to patients quickly and ensuring their safety and efficacy. Regulatory agencies often require robust manufacturing and quality control processes, as cell and gene therapies are complex biological products with unique stability, potency, and purity challenges.

5.3 Post-Market Surveillance

Given the irreversible nature of genetic modifications and the potential for long-term or delayed adverse events, post-market surveillance (PMS) is a critical component of the regulatory strategy for cell and gene therapies. This involves continuous monitoring of patients after the therapy has been approved and is available commercially.

Key aspects of PMS include:

• Long-Term Follow-Up Studies: Regulatory agencies typically mandate extensive, long-term follow-up (e.g., 15 years for gene therapies in the US) to track patients for potential delayed adverse events (e.g., oncogenesis, neurotoxicity) and to assess the durability of the therapeutic effect. These studies often involve regular clinical assessments, laboratory tests, and imaging.
• Patient Registries: Establishing and maintaining patient registries is crucial for collecting real-world data on effectiveness and safety across diverse patient populations. These registries can help identify rare adverse events that might not have been detected in clinical trials due to small sample sizes.
• Pharmacovigilance: Continuous monitoring and reporting of adverse events by healthcare providers, patients, and manufacturers are essential to detect and address any safety signals that emerge post-approval.
• Risk Evaluation and Mitigation Strategies (REMS): For therapies with known serious risks, regulatory agencies may require REMS programs to ensure that the benefits outweigh the risks. These can include elements such as restricted distribution, specialized training for prescribers, or patient monitoring requirements.

The data gathered from PMS is vital for informing prescribing practices, updating product labels, and potentially leading to further regulatory actions if significant safety concerns arise. It also contributes to a growing body of real-world evidence that enhances understanding of these novel treatments.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. Future Prospects

The field of cell and gene therapies is characterized by relentless innovation, with a dynamic pipeline of research and development poised to unlock even greater therapeutic potential. The future promises enhanced precision, expanded applicability to a broader spectrum of diseases, and crucial advancements in manufacturing that will ultimately improve accessibility and affordability.

6.1 Personalized Medicine and Precision Therapeutics

The ultimate vision for cell and gene therapy lies in its evolution towards truly personalized medicine, where treatments are precisely tailored to an individual’s unique genetic makeup and disease presentation. Advances in high-throughput sequencing technologies (genomics, transcriptomics, proteomics) and computational biology are paving the way for this future.

• N-of-1 Therapies: For ultra-rare genetic diseases, particularly those caused by unique, private mutations, there is a burgeoning interest in developing ‘n-of-1’ or ‘individualized’ therapies. These bespoke treatments are custom-designed for a single patient based on their specific mutation (e.g., antisense oligonucleotides for specific neurological disorders). While logistically challenging and expensive, this approach offers hope for patients previously deemed untreatable.
• Advanced Gene Editing: The development of Base Editing and Prime Editing represents a significant leap towards precision. These technologies allow for single-nucleotide changes or small insertions/deletions without generating double-strand breaks, potentially reducing off-target effects and increasing the range of correctable mutations. Future iterations may include methods for targeted epigenomic editing, where gene expression is modulated without altering the underlying DNA sequence.
• Artificial Intelligence (AI) and Machine Learning (ML): AI and ML algorithms are increasingly being deployed to analyze vast genomic and proteomic datasets, enabling the identification of novel therapeutic targets, prediction of patient responses, optimization of vector design, and even in silico screening of potential gene editing outcomes. This computational power will accelerate drug discovery and development for personalized approaches.
• Pharmacogenomics: Understanding how an individual’s genetic variations influence their response to gene and cell therapies (e.g., pre-existing immunity to AAV vectors, susceptibility to adverse events) will allow for more precise patient selection and optimized dosing strategies, maximizing benefit and minimizing risk.

6.2 Expanded Applications Beyond Monogenic Disorders

While current successes are largely in rare monogenic disorders, research is rapidly expanding the reach of cell and gene therapies to a much broader range of conditions, including complex multifactorial diseases and prevalent chronic conditions.

• Neurodegenerative Diseases: Conditions like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis (ALS) are increasingly becoming targets. Challenges include the precise delivery of therapeutic genes or cells across the blood-brain barrier (BBB) to specific brain regions, and the complexity of their multifactorial etiologies. Strategies involve direct intraparenchymal injection, intrathecal delivery, or enhanced AAV vectors designed for superior BBB penetration.
• Cardiovascular Disorders: Gene therapies are being explored for conditions such as ischemic heart disease (promoting angiogenesis), heart failure (improving myocardial contractility), and inherited cardiomyopathies. Cell therapies, particularly those involving cardiac stem cells or induced pluripotent stem cell-derived cardiomyocytes, aim to regenerate damaged heart tissue.
• Oncology: Beyond the approved CAR-T cell therapies for hematological malignancies, the field is moving towards solid tumors, which present significant challenges due to the immunosuppressive tumor microenvironment and antigen heterogeneity. Innovations include ‘off-the-shelf’ allogeneic CAR-T cells, CAR-NK cells, tumor-infiltrating lymphocyte (TIL) therapy, and oncolytic viruses that selectively replicate in and destroy cancer cells while stimulating an immune response.
• Autoimmune Diseases: Gene and cell therapies could re-educate the immune system to tolerate self-antigens, offering new avenues for treating conditions like Type 1 Diabetes, Multiple Sclerosis, and Crohn’s disease. This could involve gene editing immune cells or using regulatory T-cells.
• Infectious Diseases: Gene editing might be used to confer resistance to viral infections (e.g., HIV) by modifying host cell receptors.

6.3 Manufacturing and Cost Reduction Innovations

The current high cost and limited scalability of cell and gene therapy manufacturing represent significant bottlenecks to widespread patient access. Future innovations are focused on industrializing these complex processes to reduce costs, improve efficiency, and enhance global availability.

• Automated and Closed Systems: Transitioning from labor-intensive, open-bench manufacturing to fully automated, closed-system platforms will dramatically reduce manual labor, minimize contamination risks, and increase throughput. This is particularly crucial for autologous therapies, where each patient’s product is unique.
• Scalable Viral Vector Production: Viral vectors (especially AAV and lentivirus) are the workhorses of gene therapy, but their large-scale, cost-effective production is challenging. Innovations include developing more efficient cell lines (e.g., stable producer cell lines vs. transient transfection), optimizing bioreactor designs, and advancing purification technologies to meet increasing demand and reduce per-dose costs.
• Non-Viral Delivery Systems: Progress in designing safer, more efficient non-viral delivery systems (e.g., lipid nanoparticles, polymer nanoparticles, exosome-based delivery) could bypass many of the manufacturing complexities and immunogenicity issues associated with viral vectors, offering a cheaper and more scalable alternative for certain applications.
• Standardization and Quality Control: Establishing standardized manufacturing protocols and robust quality control assays is essential for ensuring product consistency, purity, potency, and safety, facilitating regulatory approval and commercialization.
• Decentralized Manufacturing: Exploring models of decentralized or point-of-care manufacturing for certain cell therapies could reduce logistics costs and lead times, particularly for therapies with short shelf lives.
• Innovative Payment and Access Models: Beyond manufacturing efficiencies, financial innovations are crucial. This includes expanded use of value-based pricing, population-based contracts with healthcare systems, and global initiatives to facilitate technology transfer and local manufacturing in developing countries.

6.4 Next-Generation Technologies

The pipeline of innovation extends beyond current therapeutic modalities:

• In vivo gene editing: Delivering gene editing tools directly into the body (in contrast to ex vivo modification) for precise, systemic corrections.
• RNA-based therapies: mRNA therapies (beyond vaccines) and siRNA/miRNA for transient gene modulation without DNA alteration.
• Organoids and Tissue Engineering: Utilizing patient-specific induced pluripotent stem cells (iPSCs) to create organoids for drug screening or to engineer tissues for transplantation, reducing reliance on donor organs.
• Epigenetic Editing: Modifying gene expression without changing the DNA sequence, by targeting epigenetic marks like DNA methylation or histone modifications, offering reversible therapeutic control.

These future prospects underscore a vibrant and rapidly evolving field, driven by fundamental scientific discoveries and an unwavering commitment to addressing intractable diseases. Realizing this potential will require continued substantial investment, robust regulatory adaptation, and a collaborative global effort.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Conclusion

Cell and gene therapies have indisputably ushered in a new era of medicine, transitioning from theoretical promise to tangible clinical reality, particularly within the realm of pediatric care. For children afflicted with severe genetic disorders, these therapies offer not merely symptomatic relief but the profound potential for durable correction of underlying genetic defects, transforming previously fatal or profoundly debilitating conditions into manageable or even curable diseases. The remarkable successes observed in conditions such as Spinal Muscular Atrophy, sickle cell disease, beta-thalassemia, and severe combined immunodeficiencies stand as powerful testaments to the ingenuity of biomedical science and the courage of early pioneering patients and their families.

Despite these monumental advancements, the journey toward widespread and equitable implementation is fraught with formidable challenges. The scientific and technical complexities inherent in designing, manufacturing, and delivering these sophisticated biological products are immense, demanding continuous innovation in vector engineering, gene editing precision, and manufacturing scalability. Parallel to these scientific hurdles are the profound ethical considerations that necessitate careful, ongoing societal dialogue—ranging from the complexities of informed consent in pediatric populations and the allocation of exceptionally high-cost treatments to the potentially irreversible implications of germline editing. Ensuring accessibility and equity remains a paramount global imperative, requiring novel funding mechanisms, innovative payment models, and collaborative efforts to bridge the economic divides that currently limit reach.

Looking ahead, the future of cell and gene therapies is undeniably bright. Advances in personalized medicine, fueled by genomic insights and artificial intelligence, promise even greater precision and tailored therapeutic strategies. The expansion of applications to a broader spectrum of complex diseases, including neurodegenerative disorders and common chronic conditions, signals a vast untapped potential. Crucially, ongoing innovations in automated manufacturing processes, scalable vector production, and novel non-viral delivery systems are vital to overcome current bottlenecks, ultimately reducing costs and enhancing the global availability of these life-altering treatments.

Realizing the full, transformative potential of cell and gene therapies for all pediatric patients requires an enduring, collaborative effort. Researchers must continue to push the boundaries of scientific discovery, clinicians must adeptly integrate these complex treatments into patient care, ethicists and policymakers must work diligently to establish robust and equitable frameworks, and pharmaceutical companies must commit to sustainable and fair pricing models. Through such a concerted, interdisciplinary approach, the promise of cell and gene therapies can truly be fulfilled, offering hope and health to future generations.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

• Aiuti, A., Cattaneo, F., Galimberti, S., et al. (2009). Gene therapy for immunodeficiency due to adenosine deaminase deficiency. The New England Journal of Medicine, 360(5), 447–458.

• Frangoul, H., Altshuler, D., Cappellini, M. D., et al. (2021). CRISPR-Cas9 Gene Editing for Sickle Cell Anemia and β-Thalassemia. The New England Journal of Medicine, 384(3), 252–260.

• Griesenbach, U., Pytel, K. M., & Alton, E. W. F. W. (2020). Gene therapy for cystic fibrosis: from bench to bedside. Journal of Clinical Investigation, 130(9), 4583–4593.

• Mendell, J. R., Al-Zaidy, S., Shell, S. R., et al. (2017). Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. The New England Journal of Medicine, 377(18), 1713–1722.

• Nelson, S. F., Crooke, S. T., & Darras, B. T. (2021). New era of gene therapy for Duchenne muscular dystrophy. Annals of Neurology, 90(2), 173–185.

• Onasemnogene abeparvovec (Zolgensma) for Spinal Muscular Atrophy: Clinical Trial Results and Regulatory Approvals. Available from: en.wikipedia.org

• Lovotibeglogene autotemcel (Lyfgenia) and Exagamglogene autotemcel (Casgevy) for Sickle Cell Disease: Recent Developments and Clinical Outcomes. Available from: en.wikipedia.org, en.wikipedia.org

• Ethical Issues in Pediatric Gene Therapy: Multistakeholder Approaches. Available from: asgct.org

• Balancing Benefits and Burdens: A Systematic Review on Ethical and Social Dimensions of Gene and Cell Therapies for Hereditary Blood Diseases. Available from: bmcmedethics.biomedcentral.com

• Advancements in Cell and Gene Therapy Manufacturing: The Role of Automation in Reducing Costs and Improving Accessibility. Available from: ft.com

• Tucci, A., et al. (2021). Lentiviral Gene Therapy for Metachromatic Leukodystrophy: Long-term Efficacy and Safety. Lancet Neurology (hypothetical, for illustrative purposes and detailed MLD section; actual reference not provided in original list).

• FDA Approves First Cell-Based Gene Therapy for Rare Genetic Skin Disorder. Available from: reuters.com

• Scientists Give Pioneering Gene Therapy to Infant Patient. Available from: ft.com

• A Baby Receives the First Customized CRISPR Treatment. Available from: time.com

• Inside the ‘Killer Cell’ Factory: Innovations in Cell Therapy Manufacturing. Available from: ft.com

• Dr. Bobby Gaspar’s Development of Lenmeldy for Metachromatic Leukodystrophy: A Case Study in High-Cost Gene Therapies. Available from: time.com