Preclinical efficacy and safety studies of ADAM33 oligonucleotides as new disease-modifying asthma therapy
Lead Research Organisation:
University of Southampton
Department Name: Clinical and Experimental Sciences
Abstract
Title: Development of a new class of drug targeting the asthma gene ADAM33 as a new disease-modifying asthma therapy
The need: There are 5.4 million people with asthma in the UK and it is the most common respiratory disease in children. Although often considered controllable, on average three people still die from an asthma attack in the UK every day, and none of the current asthma treatments are able to prevent or cure the disease; therefore, the development of new treatments remains a priority.
The proposed solution: ADAM33 is an asthma susceptibility gene that is strongly associated with "twitchiness" (hyper-responsiveness) of the airways suggesting a role in the change of the structure or function of the airways. We and other groups have shown that ADAM33 is increased in the lungs of asthmatic patients and that the amount of ADAM33 found correlates with patient's disease severity and abnormal lung function. Our research group has further shown that ADAM33 is important in the development of asthma-like disease in mouse models, where mice lacking ADAM33 are protected from key aspects of the disease, including the airway "twitchiness" and allergic inflammation in the airway both of which contribute to asthma symptoms in people. Our data suggest that ADAM33 is a valid target for future, novel asthma therapies that can make a real difference in the severity of the disease.
Development plan: We have now developed a new class of asthma drug, anti-ADAM33 oligonucleotides (A33-oligos), to specifically target ADAM33 in asthma. Early investigations trialling these new therapies in our mouse models have shown that they can be given as an inhaled drug, which is highly effective for four weeks after a single inhalation and that it is very potent in reducing the amount of ADAM33 in the lungs. In first preliminary experiments we used this A33-oligo in mouse models of asthma and could suppress the "twitchiness" of the airways similar to the results in the mice that lack ADAM33 completely.
Our aim now is to develop this new class of drugs against human ADAM33 further in humanised ADAM33 mouse models of asthma. After we confirm that A33-oligo therapy is effective in treating asthma and in particular the airway "twitchiness" which is a hallmark of most cases of more severe asthma, we will perform safety studies in larger animals. If this new asthma drug is safe in these animals, we will apply for first use of A33-oligos in human trials.
We believe that ADAM33 specific oligonucleotides will allow us to target characteristics of the disease which are not treated by current asthma drugs. Thus, our ultimate aim is to develop a new asthma therapy that helps patients whose asthma doesn't respond to currently available medicines.
The need: There are 5.4 million people with asthma in the UK and it is the most common respiratory disease in children. Although often considered controllable, on average three people still die from an asthma attack in the UK every day, and none of the current asthma treatments are able to prevent or cure the disease; therefore, the development of new treatments remains a priority.
The proposed solution: ADAM33 is an asthma susceptibility gene that is strongly associated with "twitchiness" (hyper-responsiveness) of the airways suggesting a role in the change of the structure or function of the airways. We and other groups have shown that ADAM33 is increased in the lungs of asthmatic patients and that the amount of ADAM33 found correlates with patient's disease severity and abnormal lung function. Our research group has further shown that ADAM33 is important in the development of asthma-like disease in mouse models, where mice lacking ADAM33 are protected from key aspects of the disease, including the airway "twitchiness" and allergic inflammation in the airway both of which contribute to asthma symptoms in people. Our data suggest that ADAM33 is a valid target for future, novel asthma therapies that can make a real difference in the severity of the disease.
Development plan: We have now developed a new class of asthma drug, anti-ADAM33 oligonucleotides (A33-oligos), to specifically target ADAM33 in asthma. Early investigations trialling these new therapies in our mouse models have shown that they can be given as an inhaled drug, which is highly effective for four weeks after a single inhalation and that it is very potent in reducing the amount of ADAM33 in the lungs. In first preliminary experiments we used this A33-oligo in mouse models of asthma and could suppress the "twitchiness" of the airways similar to the results in the mice that lack ADAM33 completely.
Our aim now is to develop this new class of drugs against human ADAM33 further in humanised ADAM33 mouse models of asthma. After we confirm that A33-oligo therapy is effective in treating asthma and in particular the airway "twitchiness" which is a hallmark of most cases of more severe asthma, we will perform safety studies in larger animals. If this new asthma drug is safe in these animals, we will apply for first use of A33-oligos in human trials.
We believe that ADAM33 specific oligonucleotides will allow us to target characteristics of the disease which are not treated by current asthma drugs. Thus, our ultimate aim is to develop a new asthma therapy that helps patients whose asthma doesn't respond to currently available medicines.
Technical Summary
Need: Asthma affects 340 million people worldwide, triggered by interactions of genes and environment. Current therapy treats inflammation and symptoms, but no treatment targets the underlying causes of airway remodelling and associated bronchial hyper-responsiveness (BHR), a profound unmet need since asthma kills over 400,000 patients/year.
Proposed solution: ADAM33, which expresses a metalloprotease, is associated with BHR and asthma in multiple populations. ADAM33 is mainly expressed in airway fibroblasts and smooth muscle. While the protein should be membrane-anchored, an enzymatically active soluble form (sADAM33) is upregulated in the airways by gain of function in asthma patients.
Using robust genetic models, we showed that sADAM33 in allergen-naive mouse lungs initiates airway remodelling, which is reversible when sADAM33 expression is arrested. In mice challenged with low-dose allergen, sADAM33 promotes enhanced BHR and Type-2 airway inflammation. Moreover, in Adam33 knockout mice HDM challenge resulted in dose-dependent reduced airway remodelling, BHR and eosinophilic airway inflammation, compared to heterozygote and wild-type mice (JCI-I,2016). Since airway remodelling is reversible on arrest of sADAM33, and Adam33 knock-out suppresses airway remodelling, BHR and inflammation, it is a validated target for a disease modifying asthma therapy.
Development plan: We developed potent mouse/human ADAM33 silencing oligonucleotides (patent filed). In vivo experiments have shown prolonged and therapeutically meaningful suppression of Adam33 in mouse lungs. Preliminary proof of concept treatment studies before and after allergen challenge have shown BHR suppression, mirroring results in Adam33 knockout mice. We will now carry out dose-finding, duration of effect studies of therapeutic efficacy and PK/PD in humanised mice and human lung tissue. If successful we will carry out safety and toxicology studies in non-human primates to enable Phase I trial application.
Proposed solution: ADAM33, which expresses a metalloprotease, is associated with BHR and asthma in multiple populations. ADAM33 is mainly expressed in airway fibroblasts and smooth muscle. While the protein should be membrane-anchored, an enzymatically active soluble form (sADAM33) is upregulated in the airways by gain of function in asthma patients.
Using robust genetic models, we showed that sADAM33 in allergen-naive mouse lungs initiates airway remodelling, which is reversible when sADAM33 expression is arrested. In mice challenged with low-dose allergen, sADAM33 promotes enhanced BHR and Type-2 airway inflammation. Moreover, in Adam33 knockout mice HDM challenge resulted in dose-dependent reduced airway remodelling, BHR and eosinophilic airway inflammation, compared to heterozygote and wild-type mice (JCI-I,2016). Since airway remodelling is reversible on arrest of sADAM33, and Adam33 knock-out suppresses airway remodelling, BHR and inflammation, it is a validated target for a disease modifying asthma therapy.
Development plan: We developed potent mouse/human ADAM33 silencing oligonucleotides (patent filed). In vivo experiments have shown prolonged and therapeutically meaningful suppression of Adam33 in mouse lungs. Preliminary proof of concept treatment studies before and after allergen challenge have shown BHR suppression, mirroring results in Adam33 knockout mice. We will now carry out dose-finding, duration of effect studies of therapeutic efficacy and PK/PD in humanised mice and human lung tissue. If successful we will carry out safety and toxicology studies in non-human primates to enable Phase I trial application.
