TREATMENT OF INDEX CASE
Genetic disorders cannot be cured and treatment is largely supportive, including physiotherapy, blood transfusions, e.g. haemolytic anemia, surgical treatment of malformations, incl.
However, recent therapeutic advances in the management of these rare diseases have be able to prevent the severe morbidity or at least slow down the progression of disease, with following measures:• Dietary manipulations to reduce the intake of substances which cannot be adequately metabolized in a genetic defect, specially if they are potentially toxic, e.g. removal of galactose (milk) from diet in galactosemia.
• Enhancing urinary excretion of toxic metabolites by drugs, e.g. sodium benzoate in urea cycle defects, penicillamine in Wilson disease or desferrioxamine in thalassemia.
• Enzyme inducers and coenzymes to augment deficient enzymes in certain defects, e.g. phenobarbitone for Crigler-Najjar syndrome. Desmopression in haemophilia. Administration of mega doses of vitamins have been successful in some defects to bypass enzymatic block, e.g. biotin in biotinidase deficiency, pyridoxine in homocystinuria
• Enzyme replacement therapy (ERT) is available for many lysosomal disorders at present, e.g. Gaucher disease, Niemann-Pick disease, Hurler syndrome and some other mucopolysaccharidoses, Pompe disease, Fabry disease, etc., though at a prohibit cost. Factor VIII therapy in hemophilia is another example of enzyme replacement therapy.
• Avoidance of precipitating factors: Symptoms of many IEMs are precipitated by prolonged fasting, heavy exercise, sun-exposure or exposure to certain drugs, e.g. primaquine in G6PD deficiency or Barbiturates in porphyria, which can be avoided.
• Removal of disease organ, e.g. splenectomy in hereditary spherocytosis of thyroidectomy in multiple endocrinal dysplasia.
• RNA Modulators, i.e. antisense oligonucleotides (ASO) therapy, e.g.
Nusinersen (Spinal muscular dystrophy), Eteplirsen (Duchenne muscular dystrophy), etc.• Stem-cell transplant is the ultimate therapy for many genetic defects, e.g. thalassemia major, Hurler syndrome and some primary immunodeficiencies. Liver transplant may be useful in many urea cycle defects.
• Molecular targeted therapy is available for certain disorders, e.g. Ivacaftor or Lumacaftor for cystic fibrosis, Nusinersen or risdiplam for spinal muscular atrophy and exon-skipping drugs for Duchenne muscular dystrophy and Imatinib for chronic myeloid leukemia.
• Gene therapy is possible for some disorders, e.g. SMA, Metachromatic leukodystrophy and some cancers, discussed as below.
Gene therapy aims 'to replace an identified abnormal gene with a normal gene, i.e. recombinant DNA, to modify or manipulate cell function and correct the genetic defect.' It is emerging as an exciting option to cure many single gene defects and multifactorial disorders, e.g. cancers. However, medical and ethical issues support use of gene therapy only in rare and serious life-threatening disorders, for which no effective therapy are known.
Gene therapy involves: (a) isolation of recipient's plasmid, (b) selection of normal donor/recombinant gene for replacement from established gene libraries, (c) insertion of the normal gene into recipient's plasmid, (d) facilitating the multiplication of recombinant plasmid to yield multiple copies of new gene and (e) delivery of the recombinant DNA to the target cell nucleus. Direct insertion of a gene into cultured mammalian cells is also possible, if the candidate gene is introduced along with its promoter.
Depending on the type of recipient cell, gene therapy may be divided into: (a) somatic cell therapy, i.e. transfer of recombinant DNA into somatic cells, e.g. muscle cells
TABLE 11.13: Common disorders for gene therapy
• Spinal Muscular atrophy (Zolgensma)
• #946;-thalassemia (Zynteglo)
• Hemophilia A (Hemgenix)
• Retinal dystrophy (Luxturna)
• cerebral Adrenoleukodystrophy (Skysona)
• Adenosine deaminase deficiency (ADA)
• Alpha-1 antitrypsin deficiency (A1AT)
• Cystic fibrosis (CFTR)
• Familial hypercholesterolemia (LDL receptor)
• Gaucher's Disease (acid #946; glucosidase)
• Phenylketonuria (PAH)
• Neuroblastoma (IL-2)
in Duchenne muscular dystrophy or bone marrow for thalassemia; and (b) germ-line therapy, i.e.
transfer of recombinant DNA into germ cells for transmission to future generations. Germ-line therapy, is considered as unethical for human use, though has been successfully adopted for obtaining #945;-glucosidase enzyme from rabbit milk for treatment of Pompe's disease.Various de livery systems are used to insert donor gene into the recipient's plasmid including physical methods, e.g. gene-gun technology, viral vectors, e.g. retroviruses, adenoviruses and non-viral vectors, e.g. liposomes, DNA- ligand complexes and vaccines.
Gene therapy has shown promising results in many disorders and has been approved by USFDA for over 30 conditions (Table 11.13).
11.5.2