Gene Therapy and its Dysfunctions

Limited gene therapy approval by appropriate agencies is needed. Gene therapy is the treatment of genetic disorders by editing the mutant gene. The End Product of a gene is Protein. The defect in circulating protein is fixed by Frozen plasma or recombinant therapy. Dietary modifications can prevent phenylketonuria. Enzyme deficiency can be detected by checking the biochemical level. Gene mutations need to be studied.

Clinical Phenotype is responsible for Liver enlargement and Splenomegaly. Splenectomy is recommended.

Gene Therapy

Gene therapy is divided into two categories:

1. Ex vivo gene therapy

This therapy is outside the human body. For Example, the drug Strimvelis. It was the 1st approved gene therapy by the European Medicine Agency to treat ADA deficiency, SCID. Viral vectors are Lentivirus or retrovirus. Major trials for gene therapy are seen in X-linked SCID patients. The Outcome of the disease is the development of lymphoreticular malignancies (Insertional mutagenesis)

2. In vivo gene therapy 

This therapy is done inside the human body. The vector here is the adeno-associated viral vector (AAV). This doesn't trigger the inflammatory response. It also replicates silently, and it is the most Preferred type of therapy. For Example, Luxterna. Luxtema is the treatment for Leber congenital amaurosis (LCA). The Mutation is on the RPE 65 gene. This is the first approved Invivo gene therapy.

For Spinal muscular atrophy, the Drug of choice is Zolgensma (Using AAV). This is mainly type 1. The Mutation is on the SMN1 gene. The Product is the formation of SMN protein (Survival motor neuron)

Drugs Using Alteration in RNA Expression

Hydroxyurea

Hydroxyurea is the Drug Of Choice for Sickle cell Anemia and Spinal muscular atrophy. In Sickle cell Anemia, Hydroxyurea increases the expression of HbF (fetal hemoglobin) whereas, in Spinal muscular atrophy, Hydroxyurea increases the expression of SMN 1 gene (SMN protein)

Eteplirsen

Eteplirsen is used in the treatment of Duchenne muscular dystrophy. The mutated gene is DMD and the Final product is Dystrophin. Defect in DMD: Exon 51

Nusinersen

Nusineren is used for the treatment for spinal muscular atrophy. The two SMN genes are:

• SMN 1 (Defective gene)
  • Protein: SMN
• SMN2
  • Exon 7 is silent.

Mutant Protein

Mutant Protein can be a Structural protein or a Functional protein. Functional protein uses pyridoxine in homocystinuria. Novel strategies related to mutant protein

• Enzyme replacement therapy
• Recombinant technology is used for the synthesis of new enzymes. 
• Lysozyme storage disorders
• Glycogen storage disorders 
• Enhancing the function of existing mutant proteins

Metabolic or biochemical dysfunctions

• Genetic disorders can be tackled by
• Decreasing the substrate 
• Reduce the substrate feeding into the pathway. 
• Dietary restriction for phenylketonuria
• DM
• Replace the products. 
• Insulin replacement
• Congenital hypothyroidism: Replace thyroxine. 
• Remove the toxic products.
• New age therapies
• Substrate reduction therapy
• Miglustat
• Eliglustat 
• Both are used to treat Gaucher's disease.
• Deficiency of beta glucocerebrosidase 

• Treatment: Enzyme replacement therapy 
• Miglustat, Eliglustat will inhibit the pathway.
• Inhibit Ceramide to Glucocerebrosidase synthesis
• Enzyme: Ceramide glucosyltransferase 
• Other Name: Glucosylceramide synthase

Clinical Phenotype

Losartan

Losartan is used to treat marfan syndrome by the Upregulation of TGF Beta signaling. It is responsible for the development of aneurysm. Losartan has Anti TGF beta signaling property. It prevents aneurysms. TGF beta signaling: Responsible for cell growth and proliferation. 

Everolimus

Everolimus is an Inhibitor of mTOR pathway. It is used for the treatment of tuberous sclerosis.

• 10-15%: Has SEGA
  • SEGA: Sub ependymal giant cell astrocytomas 
• Kidney: 70% angiomyolipoma
  • Concerned with adults. 
• mTOR cascade for various growth factors
  • IG-F signaling
  • Insulin signaling
  • Growth hormone signaling
• Blockage of mTOR: Prevent the progression of SEGA and angiomyolipoma.

Vosoritide

Vasoritide is an Inhibitor of Fibroblast Growth Factor Receptor 3 signaling. It is used to treat Achondroplasia: Increased expression of FGFR pathway. 

Achondroplasia has Autosomal dominant Inheritance. Constitutively active FGFR3 receptor responsible for Premature closure of epiphysis 

Rhizomelic shortening of extremities is seen, and the Central torso is unaffected. Proximal segments are predominantly affected. 

Also Read: Pain Pathway and AMP: Pathophysiology

Frequently Asked Questions

Q: What is Another name for the treatment of genetic disorders?

Answer: Gene Therapy

Q: Glucocerebroside is produced from?

Answer: Ceramide

Q: What is the end product of a gene?

Answer: Protein

Q: What technology is used for the synthesis of new enzymes?

Answer: Recombinant technology 

Hope you found this blog helpful for your NEET SS General Medicine preparation. For more informative and interesting posts like these, keep reading PrepLadder’s blogs.