Genomic testing can help rare disease patients obtain a diagnosis, which can open doors to targeted treatments and gene therapy. This resource provides an overview of the various approaches and clinical applications.
Settings
Save and close
Genomic testing can help rare disease patients obtain a diagnosis, which can open doors to targeted treatments and gene therapy. This resource provides an overview of the various approaches and clinical applications.
Gene therapy is a treatment method that involves modifying genes or the expression of genes to treat or prevent disease.
Condition | Gene therapy method | Delivery | Mechanism |
|---|---|---|---|
Leber congenital amaurosis | Gene replacement | In vivo, retinal cells | Introduces a healthy copy of the gene, which allows for normal regeneration of visual pigments in photoreceptor cells, restoring vision. |
Hemophilia A | Gene replacement | In vivo, liver cells | Delivery of a functional gene enables the patient's body to produce clotting factor, reducing prolonged bleeding, easy bruising, and severe joint pain. |
Sickle cell anemia | Gene replacement | Ex vivo, modified stem cells | Reactivated production of fetal hemoglobin (HbF), which oxygen and reduces amount of sickle hemoglobin (HbS). |
Beta thalassemia | Gene replacement | Ex vivo, stem cells | Red blood cells produce a functional hemoglobin. |
Spinal muscular atrophy | ASO | In vivo, intrathecal injection into cerebrospinal fluid | Increases the amount of full-length SMN protein, decreasing the loss of motor neurons. |
Familial hypercholesterolemia | RNAi | In vivo, subcutaneous injection | Blocks production of a protein that degrades LDL receptors on liver cells, resulting in more receptors to remove LDL from the bloodstream. |
Targeted therapies involve tailoring medical treatments to address specific genetic mutations (pathogenic variants) in a patient's DNA. By identifying these genetic factors and affectedbiochemical pathways, targeted therapies aim to deliver effective treatments with minimal side effects. Many epilepsies, for example, have established targeted treatments based on the genetic variants and underlying pathophysiology.
Condition | Targeted therapy approach | Mechanism |
|---|---|---|
Hemophilia A | Alhemo (concizumab-mtci), a monoclonal antibody | Binds to and blocks a protein that normally inhibits clotting factors, preventing or reducing bleeding episodes. |
Tuberous sclerosis | Everolimus, an mTOR inhibitor | Reduces the hyperactivity of the mTOR pathway in the brain, leading to a decrease in TSC-associated seizure frequency and severity. |
Dravet syndrome | Fenfluramine | Serotonin-releasing agent that reduces seizure frequency. |
When caring for patients receiving gene therapy:
Be prepared to discuss:
Genomic Testing for Diagnosis (CME|CNE). Practice identifying patients who may benefit from genomic testing and communicating with patients, families, and genetic experts about testing.
Genetic Testing in Pediatric Neurology (CME|CNE). Practice identifying when further value might be added by a molecular diagnosis and choosing the best genetic tests for the clinical context.
Bateman-House A. Somatic Gene Therapy: Ethics and Access. Annu Rev Genomics Hum Genet. 2024 Aug;25(1):421-438.
Brooks PJ, Urv TK, Parisi MA. Gene-Targeted Therapies: Overview and Implications. Am J Med Genet C Semin Med Genet. 2023 Mar;193(1):13-18.
Crooke ST, Baker BF, Crooke RM, Liang XH. Antisense Technology: An Overview and Prospectus. Nat Rev Drug Discov. 2021 Jun;20(6):427-453.
Fermaglich LJ, Miller KL. A comprehensive study of the rare diseases and conditions targeted by orphan drug designations and approvals over the forty years of the Orphan Drug Act. Orphanet J Rare Dis. 2023 Jun 23;18(1):163.
Guerrini R, Balestrini S, Wirrell EC, Walker MC. Monogenic Epilepsies: Disease Mechanisms, Clinical Phenotypes, and Targeted Therapies. Neurology. 2021 Oct 26;97(17):817-831.
Jonker AH, O'Connor D, Cavaller-Bellaubi M, Fetro C, et al. Drug repurposing for rare: progress and opportunities for the rare disease community. Front Med (Lausanne). 2024 Jan 17;11:1352803.
Lechuga L, Franz DN. Everolimus as adjunctive therapy for tuberous sclerosis complex-associated partial-onset seizures. Expert Rev Neurother. 2019;19(10):913-925.
Papaioannou I, Owen JS, Yáñez-Muñoz RJ. Clinical applications of gene therapy for rare diseases: A review [published correction appears in Int J Exp Pathol. 2024 Jun; 105(3):114]. Int J Exp Pathol. 2023; 104(4):154-176.
Schambach A, Buchholz CJ, Torres-Ruiz R, et al. A new age of precision gene therapy. Lancet. 2024 Feb 10;403(10426):568-582.
Tambuyzer E, Vandendriessche B, Austin CP, et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead [published correction appears in Nat Rev Drug Discov. 2020 Apr;19(4):291.]. Nat Rev Drug Discov. 2020; 19(2):93-111.
Zhang Y, Wu ZY. Gene therapy for monogenic disorders: challenges, strategies, and perspectives. J Genet Genomics. 2024 Feb;51(2):133-143.
All information in this resource is provided for educational purposes only.