Gene therapy has had its proponents and dissidents and the recent crash out of Celadon’s cardiac therapy Mydicair at the Phase IIb stage demonstrates just how challenging this field is.
So far only two gene therapies have been approved so far. The first in China in 2003 from ShenZhen-based SiBiono Gen Tech that produced Gendicine, an adenoviral vector engineered to produce tumour supressor p53 for head neck squamous cell carcinoma. Though subject to initial skepticism, Gendicine has proven effective especially in synergy with radiation/chemotherapy against several cancer types. Only in 2012, did Europe follow suit with Glybera. An adeno-associated viral vector that delivers a lipoprotein lipase to patients suffering from a rare lipid processing disease stemming from a mutation-induced deficiency in this lipase. The US has yet to approve a gene therapy but there are currently more than 2000 clinical trials world-wide focusing on several disease areas including cancer, ocular diseases, infectious diseases and cardiac disorders.
Just what makes gene therapy so challenging? The primary factor lies in the targeted modification of host DNA as the vector transits through the host tissue->cell->nucleus->gene. The use of viruses in gene therapy comes with the nasty possibility of wrong incorporation of DNA into a non-target gene which can lead to disastrous effects such as carcinogenesis. Another major factor is the accompanying immune responses to viral vectors. The prominent case of Jesse Gelsinger, an 18yo clinical trial participant who died from multiple organ failure brought on by severe immune responses halted gene therapy research in the US for some time. Other challenges associated with gene therapy include limited DNA packaging capacity and difficulty of vector production.
The field is far from drying out though as major advances have broadened the scope as to how gene therapy is implemented. RNA for example though less stable than DNA, has reduced immunogenecity, no potential for mutagenesis and does not have to enter the nucleus to take effect. Companies are currently exploring their use to silence genes or in the case of Moderna Therapeutics, for the production of proteins in vivo. And of course CRISPR, TALENs and zinc-finger nucleases, now provide for newer methods of gene editing, sometimes with startling rapid progression.
For RNA-based therapeutics, the major hurdle to overcome is efficient systemic delivery into affected tissue due to rapid excretion of RNA and susceptibility to degradation. Current efforts avoid the use of viruses by focusing instead on polymers, liposomes and nanoparticles. Many RNA-based therapeutics target the liver as RNAs tend to accumulate there due to its high vascularity and slow elimination. Major players in RNAi therapeutics include Alnylam, Quark and Tekmira. The latter of which just obtained FDA approval for “compassionate use” of their siRNA drug in Ebola infection. The only currently FDA-approved RNAi therapeutic for official use was obtained by Isis Pharmaceuticals. It produced Vitravene, an ocularly-delivered antisense oligo used for the treatment of cytomegalovirus retinitis in AIDS patients. Big pharma bowed out of RNA-based therapeutics in 2010 due to difficulties of delivery as well as off-target effects but now with 23 siRNAs undergoing clinical trials, optimism is burgeoning in the field.
The overall advantages of gene therapy is that it promises a permanent cure and is based on good scientific rationale (i.e. replacing the protein that one is deficient in, or knocking down a toxic protein). RNA-based therapies though impermanent share the same scientific basis, are easily manufactured (RNA is a lot easier to make than monoclonal antibodies), and are better translated from cell and animal models to humans as compared to small molecules. Gene therapy is definitely a lot more complex as compared to trying to tackle proteins with antibodies/drugs. And caution is indeed warranted when it comes to messing with the human genetic code. But with the current pace of development, it provides an exciting alternative to drugs in the fight against human disease.