Andrew,
To date there is not a single approved therapeutic that contains a CPP (Tat or other).
Below is from a 2015 review on CPPs (
www.mdpi.com) Zahid et al.
It has now been over 25 years since the initial description of proteins being able to transverse cell membranes and the localization of this activity to smaller 6–30 amino acid residues known as cell penetrating peptides (CPPs) or protein transduction domains (PTDs). They have generated significant interest as to their mechanism of transduction, their diagnostic and therapeutic potential for delivering drugs, DNA, siRNA, along with various imaging agents including, but not limited to, radio-isotopes and quantum dots. Yet there are no published human studies utilizing any of the CPPs either as diagnostic or therapeutic agents, although two phase I trials of a CPP (p28) are listed at clinicaltrials.gov as ongoing for treatment of solid tumors expressing p53 and for CNS malignancies. In addition, there are several unpublished industry-sponsored Phase II clinical trials that utilize CPP for delivery (AZX100, Capstone Therapeutics, for keloid scarring; RT001, ReVance Therapeutics, for wrinkling skin; KAI-9803, KAI Pharmaceuticals, for myocardial infarction; XG-102, Auris Medical, for hearing loss). There clearly are a few hurdles to be overcome before these CPP based therapeutics can be translated into clinical utility, which will be briefly highlighted here. As peptides, CPPs are fairly expensive to synthesize and cost would be an issue, especially when it comes to upscaling for larger animal and eventually human studies. Secondly, these peptides do not have any oral bioavailability and to date have been delivered clinically either through topical, or intravenous applications. The third issue relates to the non-specific uptake of the cationic and hydrophobic CPPs. These earlier CPPs are generally potent and Molecules 2015, 20 13064 efficient transducers, but also highly non-specific, which makes non-target side effects much more likely and reduces the ratio of therapeutic to side effects. This problem can be addressed by using tissue-specific CPPs that could also, at least theoretically, reduce the dose necessary and make the side effect profile more acceptable due to less non-specific, non-target tissue uptake. Immunogenicity of these peptides, especially following chronic administration, needs to be carefully studied prior to clinical application as was observed following chronic treatment of the dog model of DMD with the Antp-NBD peptide. Given their small size, it is unlikely that the CPPs themselves would elicit an immunogenic response, but their cargo can vary in size and depending on the fusion product being delivered, adverse immune responses might occur following chronic treatment. Lastly, as with any new drug or therapeutic in development, kidney and liver toxicity, as these are usually the two major routes of elimination, needs to be carefully assessed and weighed against the therapeutic benefit.
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