Alpha 1-antitrypsin deficiency future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief:Mazia Fatima, MBBS [2]
Overview
Treatment options of alpha 1-antitrypsin deficiency currently being studied include recombination and inhaled forms of Alpha 1-antitrypsin. Other experimental therapies are aimed at the prevention of polymer formation in the liver. Gene therapy to deliver recombinant adeno-associated virus carrying the human AAT gene is also being investigated as a alternate treatment approach.
Future or Investigational Therapies
Treatments currently being studied include recombination and inhaled forms of Alpha 1-antitrypsin. Other experimental therapies are aimed at the prevention of polymer formation in the liver. Newer treatment strategies include:[1]
- Gene therapy to deliver recombinant adeno-associated virus carrying the human Alpha 1-antitrypsin gene.
- Inhibition of intrahepatic polymerization of alpha 1-antitrypsin.
- Promotion of hepatic secretion of AAT.
- Pegylation to prolong the serum half-life of AAT.
- Inhalation of AAT that results in complete inhibition of neutrophil elastase activity and marked reduction in elastin degradation.
- Small interfering RNA that interferes with AAT production.
- Carbamazepine or Rapamycin can be used to enhance intrahepatic degradation of mutant AAT by autophagy.
Pitfalls of Therapy
- Despite the isolation and cloning of the alpha-1 AT gene, the efficacy of augmentation therapy remains controversial due to the lack of large randomized trials that define the treatment regimens and target population.
- The current goal of therapy is to raise the level of alpha-1 AT in the plasma above the ‘threshold of 11 umol/L (80 mg/dl). There are basically two types of treatment for this disease, augmentation therapy, and organ transplantation.
- Endogenous enhancement of alpha-1 AT production has been attempted pharmacologically with medications such as Danazol, Tamoxifen and estrogen/progesterone combinations based on the observation that alpha-1 AT levels increase as an acute phase reactant in times of stress (including pregnancy). Unfortunately, the alpha-1 AT levels do not increase enough to warrant therapy.
- Exogenous augmentation via aerosolization of either pooled human alpha-1 AT, or recombinant alpha-1 AT has been attempted, and both are thought to be safe and effective. Large clinical trials are currently underway.
- Gene therapy uses viruses that have been altered so they can not replicate to infect and integrate their genome (with the cDNA of alpha-1 AT) into host cells with the goal of the host cell manufacturing endogenous alpha-1 AT. Unfortunately, in the initial studies, expression of the gene was limited, and the alpha-1 AT levels did not increase above the protective threshold.
- Exogenous augmentation via IV infusion of pooled human alpha-1 AT is the only approved method of augmentation therapy for patients with alpha-1 AT deficiency. Although being safe, well-tolerated, and without significant side effects, its clinical efficacy is still unproven. In addition, the goal plasma level is not known, especially since there is a cohort of patients with severe alpha-1 AT deficiency that are not symptomatic. Unfortunately, there has not been a randomized, double-blinded, placebo-controlled trial in patients with alpha-1 AT deficiency with and without symptoms.
- A recent observational study compared the rate of decline in FEV1 in 97 Danish ex-smokers to 198 German ex-smokers, both of whom had severe alpha-1 AT deficiency. The German subjects received weekly infusions of 60 mg/kg alpha-1 AT, and the Danish did not receive augmentation therapy. The Germans had a slower rate of decline in their FEV1 as compared with the Danes (-53 ml/yr vs. -75 ml/yr, p=0.002).
- Although weekly infusions are the only FDA approved regimen, monthly infusions (250 mg/kg) seem to have the same efficacy and safety and are widely used.
- The ATS recommends augmentation therapy for patients with alpha-1 AT phenotypes PI ZZ, PI Z null or PI null null with alpha-1 AT levels < 11 umol/L and airflow obstruction.
- It is crucial that these patients don’t smoke, and are treated with bronchodilators, just as other patients with airways obstruction. They should also receive pneumococcal and influenza vaccines.
- A years worth of IV augmentation therapy costs approximately $25,000 - $35,000 (90% of which is for the drug).
- There have not been any cases of HIV or hepatitis transmitted by pooled human alpha-1 AT.
- Transplantation of both lungs and liver has been offered to patients with end stage disease. Liver transplantation has the added benefit of correcting the underlying disorder, as the new liver will produce and secrete alpha-1 AT. There is no data to support the use of augmentation therapy after lung transplantation, although some authors suggest augmentation therapy during times of increased neutrophil burden in the lung.
References
- ↑ Turner AM (2013). "Alpha-1 antitrypsin deficiency: new developments in augmentation and other therapies". BioDrugs. 27 (6): 547–58. doi:10.1007/s40259-013-0042-5. PMID 23771682.