Small-molecule gene therapy nearing trials

New Jersey-based PTC Therapeutics has asked the US Food and Drug Administration for approval to start the trials of the lead candidate, dubbed PTC124, in its Small Molecule Modulation of Read-Through (SMMRT) programme.

Inherited diseases are attributable to mutations in an individual's DNA. A common type of mutation, occurring in approximately 10 to 30 per cent of the cases of, leads to the synthesis of a messenger RNA (mRNA) that contains an inappropriate stop codon - known as a nonsense codon - within its protein-coding region.

This nonsense mutation causes the ribosome that reads the sequence and assembles the protein to stop prematurely, producing a non-functional protein. For example, in cystic fibrosis, the mutation prevents the formation of a fully-functional protein called CFTR that is involved in ion balance in the lungs and other organs.

PTC's drug is an orally-bioavailable small molecule that is designed to prevent this inappropriate termination of protein production. The programme stemmed from prior research showing that the antibiotic gentamicin could restore the usual 'read through' of the gene, resulting in the expression of full-length CFTR protein.

The company has developed a compound that shares these properties but avoids the side effects of gentamicin, which make its use in a chronic disease difficult, as well as the antibiotic's parenteral route of administration.

The company​'s chief executive Stuart Peltz told DrugResearcher.com​ that the approach was akin to "gene therapy using a small molecule."​ If approval to start trials is given, PTC plans to start off with single- and multidose studies in healthy volunteers, followed by a Phase II trial in CF patients in 2005.

The trials will look at surrogate markers for CFTR function in the patients, as well as some assessment of the ability of patients to carry out their usual daily activities. A second Phase II programme involving patients with Duchenne muscular dystrophy will also be started before the end of next year, he said.

The approach could be of use in a range of other diseases, including cancers, which are thought to originate from nonsense mutations, said Peltz.

Broad drug target in proliferative disorders​

In other news, researchers at PTC have identified a new biochemical pathway that could lead to a new generation of small-molecule drugs to treat proliferative orders, including malignancies and psoriasis.

The company has discovered an enzyme complex that underlies the metabolism of mRNA and a related molecule - transfer RNA (tRNA) - that is integral to the process of cell proliferation.

Peltz said that the discovery, published in the journal Cell (30 April issue) could lead to new treatments for haematological and solid malignancies and inflammatory diseases such as psoriasis.

"Overexpression of tRNA and mRNA is a key factor in the deregulation of translation that allows cancer cells to grow uncontrollably,"​ according to Christopher Trotta, senior scientist at PTC.

The finding relates to the discovery of an endonuclease enzyme that is involved in the splicing of tRNA. Splicing is a common control mechanism that is used in the cell to regulate RNA function, with portions of the sequence cut off to turn a non-active tRNA into a mature, functional molecule.

In many cancer cells, there are elevations in tRNA and ribosomal RNA, the cellular machinery used to synthesise proteins in the cell. The identification of the specific endonuclease complex suggests that it will be possible to design small-molecule drugs that can switch off this process in replicating cells, without affecting the actions of tRNA/mRNA etc in non-replicating cells.

"This important finding adds to our repertoire of post-transcriptional mechanisms of RNA processing and illustrates our expertise in RNA biology,"​ said Peltz. PTC has filed worldwide patent applications to protect its discovery.