Gene therapy is based upon an innovative and disruptive concept – a working copy of an appropriate and needed gene is “transferred”to the cells or specific organs of an affected patient as a long term therapy to either stabilize or reverse a disease, whether it is genetic or acquired.
We believe that one of the first human diseases that will be successfully treated by gene therapy based approaches is Pompe disease, a Lysosomal Storage Disease (LSD). Etubics gene transfer technologies were the first demonstrated to safely and rapidly forestall and/or reverse the pathology of Pompe disease, in the most severe forms of the condition and for extended periods of time after a single treatment in multiple animal models. Etubics is rapidly positioning our efforts to treat Pompe patients, which will also serve as a gateway to the potential gene therapy of many other LSDs as well.
There are approximately 50 different types of LSDs that together have a cumulative incidence estimated conservatively at 1 per 7,700 live births, although a significantly higher prevalence for each of these disorders is becoming increasingly understood (see below).1 The practical application of gene therapy approaches for use in the treatment of LSDs generally, as well liver diseases generally, can be best illustrated in understanding the potential for gene therapy based approaches to treat the prototypical LSD, Pompe disease (aka: Glycogen Storage Disease Type II, or Acid Maltase Deficiency).
Pompe disease had been traditionally estimated to affect ~1 in 40,000 individuals2, however, as detection of Pompe disease, it can now be done by simple newborn screening techniques. Recent newborn screening programs suggest that the true incidence of Pompe disease may be as high as 1 in ~8,700 live births,3 the latter translating into greater than 800,000 individuals potentially affected by Pompe disease worldwide. Pompe disease indiscriminately affects infants, teenagers and adults from all walks of life due to the inheritance ofmutations in the acid alpha glucosidase gene (GAA). Lack of sufficient GAA activity directly results in progressive accumulation of glycogen within the lysosomes of a number of organs in Pompe patients, including the liver, heart, respiratory and skeletal muscles. With every day of life, the risk of increasing weakness, wheel chair dependence, respiratory and cardiovascular failure increase, as well as death to those affected by Pompe disease.
Current treatments for Pompe disease are limited, including supportive care and enzyme replacement based therapy, the latter is a costly intervention that requires life-longweekly infusions of a limited amount of a difficult to produce, expensive, recombinant GAA enzyme produced in bioreactors using hamster cells. A better intervention is needed and, accordingly, Etubics has determined that innovative intervention for the treatment of LSDs, like Pompe disease and other liver diseases, will be achieved via gene therapy based therapeutics.
The loss of cochlear hair cells or the loss of their capacity to transduce acoustic signals is believed to be the underlying mechanism in many forms of hearing loss. Adenovirus-based vectors have been investigated as a means to deliver damaged or missing genes to certain correct auditory conditions. Adenoviruses can efficiently transduce cochlear hair cells in vivo, although early generations of Adenovirus-based vectors have demonstrated ototoxicity.
A first generation adenovirus-based vector, when slowly infused into the scala tympani of the cochlea, was found to be capable of efficiently transducing cochlear hair cells in vivo, but also resulted in severely compromised cochlear function (top panel). Etubics vector efficiently transduced the cochlear hair cells in vivo with no significant loss of function in response to auditory stimulation testing (Distortion product otoacoustic emissions (DPOAE)) (bottom panel). The gene delivered by Etubics Platform was detected in over 80% of the cochlear hair cells. The results demonstrate that the use of early-generation Adenovirus vectors can compromise cochlear function where Etubics vector did not. Development of a viral vector that infects cochlear hair cells without virus induced ototoxic effects is crucial for gene replacement strategies to treat certain forms of inherited deafness and for otoprotective strategies to prevent hair cell losses to treat progressive hearing disorders.
- J. Meikle; J.J. Hopwood; A.E. Clague; W.F. Carey. Prevalence of Lysosomal Storage Disorders. JAMA.1999;281(3):249-254.
- Martiniuk,A., Chen,A. Mack,E. Arvanitopoulos,Y. Chen,W. N. Rom,W. J. Codd,B. Hanna,P.Alcabes,N.Raben, P. Plotz. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. American Journal of Medical Genetics: Volume 79(1):69–72,1998.
- Newborn Screening for Pompe Disease: Summary of the Condition Review Workgroup Report (2013):http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/meetings/2013/first/pompediseasepresentation.pdf