Advances in the Treatment of Alpha1-antitrypsin Deficiency
In animal studies, intramuscular injections of recombinant adeno-associated virus serotype-2 (rAAV2) containing the normal AAT gene were shown to be safe and result in significant expression and increased serum levels of AAT.78,79
In the first Phase I trial of
The vector DNA sequence was detected in blood by PCR on days one and three in most subjects receiving the higher doses. However, only a low level of transgenic M-AAT was transiently detected in the serum of one subject.
intramuscular injections with this vector on 12 subjects with PiZZ AATD, four different doses were tested and no significant side effects were observed.80
In order to improve efficiency, the same researchers used a different carrier, namely a rAAV serotype 1 capsid, which had a similar safety profile and a more sustained AAT expression in mice.78,81
There are promising animal data in transgenic mice suggesting that such approach can reconstitute the liver’s ability to produce normal human AAT.83
Bone marrow cells where isolated and infected with Lenti-CB-hAAT, rAAV1-CB-hAAT, and rAAV8-CB-hAAT. After re-injection, significant levels of transgenic product h-AAT were detected in liver and serum, especially with the rAAV8 vector. Studies in humans have not been reported.
AATD continues to be a very challenging condition. Screening and early detection continues to be crucial as prompt diagnosis may lead to more effective risk factor modifications that may prevent the development of lung disease.
In this study,
three different dose groups were tested in nine PiZZ individuals. Sustained, but still subtherapeutic, expression of M-AAT was observed for at least one year in two subjects and 90 days in a third, who received the highest dose. T-cell immune responses did not cause the complete elimination of the vector.82
These trials are the basis for continued explorations of the possibility of gene therapy for AATD. The safety and feasibility of the injections along with a controlled immune response is encouraging. Gene therapy trials are under way to try to maintain a constant production of AAT at protective levels. Current trials aim to discover whether higher dosing or more injection sites provide higher and sustained AAT expression.
Stem Cell Therapy
Stem cells have been used in patients in need of for cell replacement therapy (i.e., bone marrow transplantation in cancer patients). Stem cells have the ability to differentiate into different, functional cells with normal gene expression. In AATD, the goal is to establish new hepatocytes that produce normal AAT.
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Although specific data are scarce, subjects with AATD and lung disease should be treated according to COPD guidelines with drugs such as long-acting bronchodilators and inhaled steroids. Disease management programmes have been shown to be effective in improving quality of life and healthcare utilisation in this population. There is an imperative need for better targeting of the group of patients that will mostly benefit from augmentation therapy as well as trials a need for determining AAT’s optimal dosage.
Several potential therapeutic strategies exist to target the different pathophysiological mechanisms of the disease, for both the liver and lung manifestations. To augment AAT levels, these strategies include alternate routes of administration (inhaled), gene therapy and stem cell therapy. To decrease intracellular AAT polymerisation, AAT secretion and the formation of extracellular AAT polymers, strategies that block polymerisation with small molecules or increase autophagic degradation are under way with promising results. These new strategies will need to be validated in larger clinical trials. n
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EUROPEAN RESPIRATORY DISEASE
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