to Increase the Function of the Affected Gene or Protein

Figure 13-7 The molecular treatment of inherited disease. Each molecular therapy is discussed in the text. ADA, Adenosine deaminase; ASO, antisense oligonucleotide; ERT, enzyme replacement therapy; Hb F, fetal hemoglobin; mRNA, messenger RNA; MSD, membrane-spanning domain; NBD, nucleotide-binding domain; PEG, polyethylene glycol; SCID, severe combined immunodeficiency; siRNA, small interfering RNA.

Treatment at the Level of the Protein

Enhancement of Mutant Protein Function with Small Molecule Therapy

Small Molecule Therapy to Allow Skipping over Nonsense Codons.

Small Molecules to Correct the Folding of Mutant Membrane Proteins: Pharmacological Chaperones.

Small molecule screens to identify compounds that can serve as a chaperone to prevent misfolding and correct the ΔF508 CFTR trafficking defect in in vitro assay systems have identified lumacaftor (VX-809) as an effective, although incomplete, corrector of this specific CFTR mutant polypeptide (see Fig. 13-7). Lumacaftor interacts directly with the mutant CFTR to stabilize its three-dimensional structure, specifically correcting the underlying trafficking defect and enhancing Cl transport. Although monotherapy with lumacaftor had no clinical benefits, a recently completed Phase III clinical trial using lumacaftor together with another small molecule, ivacaftor (VX-770), discussed later, showed significant improvements in lung function in homozygous ΔF508 CFTR patients. This finding is notable because it is the first treatment shown to have a favorable impact on the primary biochemical defect in patients carrying the most common CFTR allele, ΔF508. Ongoing studies of the long-term effectiveness and safety of the lumacaftor-ivacaftor combination therapy are in progress. Irrespective of their success, this example is a milestone in medical genetics, because it establishes the principle that molecular chaperones can have clinical benefits in the treatment of monogenic disease.

Small Molecules to Increase the Function of Correctly Trafficked Mutant Membrane Proteins.


Figure 13-8 The effect of ivacaftor (Kalydeco) on lung function of cystic fibrosis patients carrying at least one Gly551Asp CFTR allele. The figure shows the absolute mean change from baseline in the percent of predicted forced expiratory volume in 1 second (FEV1) through week 48 of a clinical trial. N refers to the number of subjects studied at each time point during the trial. See Sources & Acknowledgments.

Small Molecules to Enhance the Function of Mutant Enzymes: Vitamin-Responsive Inborn Errors of Metabolism.

TABLE 13-3

Treatment of Genetic Disease at the Level of the Mutant Protein

Strategy Example Status
Enhancement of Mutant Protein Function
Small molecules that facilitate translational “skipping” over mutant stop codons Ataluren in the 10% of cystic fibrosis patients with nonsense mutations in the CFTR gene Investigational in CF: confirmatory Phase III clinical trial was begun in 2014
Small molecule “correctors” that increase the trafficking of the mutant protein through the ER to the plasma membrane Lumacaftor (VX-809) to increase the abundance of the ΔF508 mutant CFTR protein at the apical membrane of epithelial cells in CF patients Investigational: very promising improvements in lung function in ΔF508 homozygotes, when used in combination with ivacaftor; expensive
Small molecule “potentiators” that increase the function at the cell membrane of correctly trafficked membrane proteins Ivacaftor (VX-770) used alone to enhance the function of specific mutant CFTR proteins at the epithelial apical membrane FDA approved for the treatment of CF patients carrying specific alleles; expensive
Vitamin cofactor administration to increase the residual activity of the mutant enzyme Vitamin B6 for pyridoxine-responsive homocystinuria Treatment of choice in the 50% of cystathionine synthase patients who are responsive
Protein Augmentation
Replacement of an extracellular protein Factor VIII in hemophilia A Well-established, effective, safe
Extracellular replacement of an intracellular protein Polyethylene glycol–modified adenosine deaminase (PEG-ADA) in ADA deficiency Well-established, safe, and effective, but costly; now used principally to stabilize patients before gene therapy or HLA-matched bone marrow transplantation
Replacement of an intracellular protein—cell targeting β-glucocerebrosidase in non-neuronal Gaucher disease Established; biochemically and clinically effective; expensive

ADA, Adenosine deaminase; CF, cystic fibrosis; ER, endoplasmic reticulum; FDA, U.S. Food and Drug Administration; HLA, human leukocyte antigen; PEG, polyethylene glycol.


Figure 13-9 The mechanism of response of a mutant apoenzyme to the administration of its cofactor at high doses. Vitamin-responsive enzyme defects are often due to mutations that reduce the normal affinity (top) of the enzyme protein (apoenzyme) for the cofactor needed to activate it. In the presence of the high concentrations of the cofactor that result from the administration of up to 500 times the normal daily requirement, the mutant enzyme acquires a small amount of activity sufficient to restore biochemical normalcy. See Sources & Acknowledgments.

Protein Augmentation

Enzyme Replacement Therapy: Extracellular Administration of an Intracellular Enzyme

Adenosine Deaminase Deficiency.


Figure 13-10 Adenosine deaminase (ADA) converts adenosine to inosine and deoxyadenosine to deoxyinosine. In ADA deficiency, deoxyadenosine accumulation in lymphocytes is lymphotoxic, killing the cells by impairing DNA replication and cell division to cause severe combined immunodeficiency (SCID).

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on to Increase the Function of the Affected Gene or Protein

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