Introduction
Inherited metabolic disorders are rare and often linked to a debilitating phenotype with restricted therapeutic approaches. Standard care approaches will include diet modifications, the removal of harmful substances, enzyme and coenzyme replacement, cell and organ transplantation, and supportive therapies. Gene therapy is continuously emerging as a transformative treatment choice for individuals affected by these diseases. In the past 20 years, gene therapy has been efficiently applied to various rare disorders. The quantity of clinical trials is swiftly and constantly increasing, and certain gene therapy products have gained market authorization in Western countries.
What Are the Rare Metabolic Disorders Affecting Pediatric Patients?
Metabolic disorders are a group of disorders that affect the metabolic pathways in the body and disrupt the normal functioning of the human body. They occur as inborn errors of metabolism that usually occur due to a single gene defect, which is responsible for chemical breakdown or formation in the body. As a result of this disease, there can be problems due to the excess accumulation of these chemicals, which also potentially inhibit essential chemicals in the body. Inherited metabolic disorders are characterized by enzymatic defects in metabolic pathways, leaving single gene disorders with a calculated cumulative incidence as high as 1 out of 800 people.
Following are some of the common inborn errors of metabolism affecting the pediatric population:
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Lactase Deficiency: Also known as lactose intolerance, characterized by the inability to digest lactose which is found in dairy products mostly.
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Mitochondrial Disorders: A group of disorders affecting mitochondria, leading to symptoms like poor growth, muscle weakness, neurological problems, etc.
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Familial Hypercholesterolemia: A genetic disorder in which there can be a severe rise in serum cholesterol concentrations.
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Homocystinuria: Infrequent serious genetic condition in which there is a problem affecting the metabolism of an amino acid known as methionine.
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Metachromatic Leukodystrophy: It is a rare genetic condition and a type of lysosomal storage disease in which there can be an accumulation of certain types of fats called sulfatides.
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Congenital Disorders of Glycosylation: A large group of infrequent hereditary diseases that cause inborn errors of glycans synthesis and their attachment to lipids and proteins.
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Hyperlipoproteinemia (Types 1 and 4): Genetic disorder leading to incorrect metabolism of lipid breakdown.
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Niemann-Pick Disease (Type C): An infrequent progressive genetic disorder affecting the nervous system.
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Aminoacidopathies: These are metabolic disorders leading to defective protein synthesis.
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Fabry’s Disease: An inherited condition and a lysosomal storage disorder resulting in the build-up of fat called globotriaosylceramide in the cells.
What Are the Considerations in Gene Therapy?
Basically, gene therapy is a straightforward protocol that aims to restore normal cellular function by introducing a functional copy of the defective gene. This can be achieved by the addition of a new copy of the gene or by using tools to edit the defective gene, correcting the genetic mutation with specific vectors. Gene therapy involves the editing or transfer of genetic material to treat a disease.
Depending on the chosen delivery strategy, gene therapy can be conducted in vivo (modification of cells by directly delivering them into the patient’s body) or ex vivo (cell modification that occurs outside the patient's body), utilizing integrating and non-integrating methods. Integrating methods refers to the insertion of the therapeutic gene into the host's genome, leading to a lasting modification. For instance, lentiviral vectors are examples of this approach, as they can integrate their genetic material into the DNA (deoxyribonucleic acid) of the host cell. In contrast, non-integrating methods do not bring about permanent alterations to the host genome.
What Are the Emergent Gene Therapy Approaches for Rare Metabolic Disorders in Children?
Following are some of the recent gene therapy approaches for treating metabolic disorders in the population:
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Gene Replacement Therapy: Gene replacement therapy involves the introduction of a functional copy of a defective gene directly into the patient’s cells. This approach is particularly applicable in instances where a genetic mutation leads to a deficiency in a specific enzyme or protein. By delivering proper genetic information, the therapy aims to correct the underlying genetic anomaly, thereby facilitating the restoration of normal cellular function. Gene therapy seeks to restore the root cause of the deficiency, thereby treating genetic disorders.
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Gene Editing Techniques: This is a revolutionary method enabling highly precise modifications to the DNA sequence. In the realm of metabolic disorders, CRISPR-Cas9 can be harnessed to correct or alter the defective gene underlying the disorder, offering a targeted approach for therapeutic intervention. These innovations contribute to the continual refinement of gene editing technologies, paving the way for more effective and precise therapeutic interventions in the context of metabolic disorders and beyond.
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RNA (Ribonucleic Acid) Therapies: RNA therapies comprise diverse approaches, including mRNA (messenger RNA) therapies. In mRNA therapies, messenger RNA is employed to deliver precise genetic instructions to cells, a strategy that gained attention through the development of COVID-19 m-RNA vaccines. This innovative method facilitates the translation of genetic information into functional proteins within the cells, offering a versatile platform for therapeutic applications.
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Viral Vector Delivery Systems: Viral vector delivery systems play an important role in gene therapy, with adeno-associated viral (AAV) vectors being a prominent example. AAV vectors are widely utilized in gene therapy due to their efficiency in delivering genetic material to target cells coupled with a low likelihood of triggering immune responses. These vectors provide a reliable means of transporting therapeutic genes to specific cells, enhancing the precision of gene therapy interventions.
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Patient-Specific Approach: In the field of personalized medicine and individual treatment approaches, there is an increasing focus on customizing therapies to match individual genetic differences. This method utilizes the unique genetic traits of individuals, enabling a more accurate and targeted treatment approach. Through tailoring therapies based on the specific genetic profile of each patient, personalized medicine strives to improve treatment effectiveness while reducing potential side effects.
Conclusion
The rapid evolution of gene therapy and the incorporation of gene therapy as a viable therapeutic alternative for many rare metabolic disorders in children, as well as the adult population is an important topic to debate. This also necessitates physicians to have a comprehensive perception of these technologies to provide optimal guidance to their patients. In the past two decades, gene therapy has proved itself to be a transformative treatment for these rare disorders, potentially altering the course of the diseases.
