Clinical potential of a rationally engineered enzyme for treatment of cocaine dependence: Long-lasting blocking of the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine

Abstract

It is a grand challenge to develop a truly effective treatment of substance use disorder (SUD), particularly for cocaine and other drugs without an FDA-approved treatment available, because a truly effective therapy must effectively block the drug's physiological and reinforcing effects during the entire period of treatment in order to achieve the long-time abstinence required by the FDA. Whether a biologic, such as monoclonal antibody, vaccine, or therapeutic enzyme, can be truly effective for SUD treatment or not has been the subject of extensive debate. The main debate question is whether a biologic, particularly an exogenous enzyme, can effectively block the drug's reinforcing effect. In this report, we demonstrate that a modest dose of a recently redesigned longacting cocaine hydrolase, CocH3-Fc(M6), can be used to effectively block the psychostimulant, discriminative stimulus, and reinforcing effects of cocaine for a sufficiently long period of time. For example, a dose of 3 mg/kg CocH3-Fc(M6) completely blocked the discriminative stimulus and reinforcing effects for 24/25 days and continued to significantly attenuate/decrease the cocaine effects for at least 29 days in rats. All the animal data consistently suggest that the long-acting cocaine hydrolase is a truly promising candidate of enzyme therapy for treatment of cocaine use disorder.

Recovery of dopaminergic system after cocaine exposure and impact of a long‐acting cocaine hydrolase

“…It has been demonstrated that these proteins are capable of accelerating cocaine metabolism, rapidly detoxifying cocaine and its toxic metabolites 22,27–30 . A single dose of the CocH‐Fc can effectively block the physiological and reinforcing effects of cocaine for a long period of time (weeks) 25,27,31 . Specially, we have also demonstrated that CocH‐Fc can also block cocaine‐induced DAT trafficking in cocaine‐naïve rats 11 .…”

“…Furthermore, Fc‐fused CocHs can block cocaine‐induced hyperactivity, cocaine discrimination and cocaine self‐administration (associated with i.v. infusion of cocaine) 31 . In particular, CocH3‐Fc(M3) was proved capable of effectively limiting the brain cocaine concentration and preventing cocaine‐induced hyperactivity and DAT trafficking to plasma membrane from acute cocaine exposure 11 .…”

Cocaine hydrolase blocks cocaine‐induced dopamine transporter trafficking to the plasma membrane

“…The locomotor data are plotted as the mean ± SEM metres travelled in 5-min bin during locomotor activity for 7 h. Particularly for the lethal dose (60 mg/kg), in addition to the hyperactivity, 60-mg/kg cocaine induced convulsion in six out of eight rats, with two rats died after convulsion, 37 Particularly for treatment of cocaine abuse, previous studies 20,23,30,37,41,43 demonstrated that an exogenous CocH (known as a BChE mutant with at least 1000-fold improved catalytic efficiency against cocaine compared to wild-type BChE) can powerfully rescue rats by rapidly detoxifying cocaine and its toxic metabolites 25,27,29,44 at any time point as long as rats are still alive, and also effectively block cocaine-induced hyperactivity. 23,28,30,37,45 However, it was unknown whether an enzyme can also effectively block cocaine-induced DAT trafficking to plasma membrane. According to the animal data with CocH3-Fc(M3) treatment, the enzyme is capable of effectively preventing cocaine from reaching the brain and limiting the brain cocaine concentration to be lower than the threshold (2.0 ± 0.8 μg/g) even with a lethal dose of 60-mg/kg cocaine (ip).…”

“…Particularly for treatment of cocaine abuse, previous studies 20,23,30,37,41,43 demonstrated that an exogenous CocH (known as a BChE mutant with at least 1000‐fold improved catalytic efficiency against cocaine compared to wild‐type BChE) can powerfully rescue rats by rapidly detoxifying cocaine and its toxic metabolites 25,27,29,44 at any time point as long as rats are still alive, and also effectively block cocaine‐induced hyperactivity 23,28,30,37,45 . However, it was unknown whether an enzyme can also effectively block cocaine‐induced DAT trafficking to plasma membrane.…”

“…Further, we have also designed and discovered a long‐acting form of the CocH (denoted as CocH‐Fc) 23,24 through protein fusion with the Fc fragment (wild‐type or mutant) of human immunoglobulin G1 (IgG1). It has been demonstrated that these CocHs and CocH‐Fc proteins are capable of accelerating cocaine metabolism, rapidly detoxifying cocaine and its toxic metabolites, 25–29 and that a single dose of the CocH‐Fc protein can effectively block the physiological, discriminative stimulus and reinforcing effects of cocaine for a long period of time (weeks) 23,28,30 . It would be interesting to know whether a CocH‐Fc protein can also block cocaine‐induced DAT trafficking while blocking cocaine's physiological effects.…”