Julie’s

In the Pipeline…

With Dr. Eric Siemers

Medical Advisor

Eli Lilly and Company

Clinical Associate Professor of=

Neurology, IU School of Medicine<= /st1:PlaceName>

Gene therapy inches forward with a Trojan horse<= o:p>

Gene therapy is a much discussed but not yet realized potential new treatment paradigm for Parkinson’s disease. Li= ke transplantation with fetal cells or stem cells, gene therapy for PD will re= quire a neurosurgical procedure. Un= like investigational treatments with cell transplantation, gene therapy requires only the introduction of DNA into the brains of patients with PD. During the past week, two developm= ents in gene therapy for PD have shown that this potential treatment is making progress. <= /p>

The field of gene the= rapy generally has been considered a somewhat risky approach, and the field was substantially influenced by an unfortunate circumstance in 1999 during a st= udy performed at the Universi= ty of Pennsylvania. During that study, a teenaged boy = with a rare liver disease died shortly after receiving gene therapy for the disorder. The incident = not only was a setback for gene therapy, but also called into question the enti= re informed consent process for clinical trials and the ethical considerations= of placing subjects at risk in trials for treatments in which the safety was poorly understood. An importa= nt distinction between the gene therapy for PD and gene therapy in this incide= nt and for many other diseases, is that in these other diseases the gene must = be given intravenously, and the therapy could have effects on many organs and tissues in the body. In the c= ase of gene therapy for PD, because the pathology is limited to the brain, small d= oses of the gene can be given directly into the affected brain tissue. This, along with other advances in= the technique of gene therapy, makes systemic side effects with PD gene therapy much less likely. Nevertheles= s, in early phase studies of any investigational treatment, understanding the saf= ety of the treatment is the primary goal.

In the June 23 issue = of the journal Lancet, an important paper regarding a Phase I clinical trial of ge= ne therapy for PD was reported. = The challenge that is common for all gene therapy approaches to PD is how to get the gene into brain cells. A = method that appears to be gaining ground, and the one used by the investigators in= the Lancet paper, was to use a Trojan horse, in this case a small virus known as adeno-associated virus (AAV) to take the gene into brain cells. AAV is a very small virus containi= ng only two genes, and appears only to cause actual infection when it is prese= nt along with a larger adenovirus. By injecting only the AAV, active infection appears to be avoided. The AAV inserts its genes into a v= ery specific region of a single chromosome, chromosome 19. The fact that the insertion site f= or the AAV genes is well understood means that the risk of disrupting DNA in other chromosomes is reduced.

The AAV virus in this= case was engineered to carry a gene for an enzyme known as glutamic acid decarboxylase (GAD). GAD is an enzyme that makes a neurotransmitter known as GABA, an inhibitory neurotransmitter. The AAV-GAD combination is placed in a part of the brain that is overactive in PD, the subthalamic nucleus (STN). Th= e STN is the part of the brain where electrical stimulation with deep brain stimulators is usually placed. In a sense, injecting small amounts of the GAD gene using the AAV vi= rus is like a chemical method to cause effects similar to deep brain stimulatio= n, but without the wires, battery, etc.

Because of potential = safety concerns in this Phase 1 trial, the GAD gene therapy was introduced into on= ly one side of the brain. A low, medium or high dose of AAV-GAD was given to 12 patients with advanced PD. There were no serious side effects related to the procedure or to the gene therapy. In fact, other than expected post-operative pain at the incision site, the authors did not feel there we= re any side effects related to the treatment in this small study.

While the primary pur= pose of the study was to examine safety, measures of efficacy were also studied. Gradual improvements in motor scor= es did occur over 3 months following surgery, and were then stable until the end of the study at 12 months. Additionally, a type of positron emission tomography (PET) scan that measures glucose utilization was used in the study. The improvements in motor symptoms= as assessed by clinical examination were accompanied by proportional improveme= nts in glucose utilization by the brain. In any small study in which there is no placebo group for comparison, clinical improvement could be related to a placebo response. While the change in glucose utiliz= ation by the brain does not rule out a placebo response, a change in this objecti= ve measure suggests that the clinical improvement was not a placebo response.<= span style=3D'mso-spacerun:yes'>

While these findings = are very promising, they are also very early in the development process for any new = therapy. The company developing this AAV-GAD therapy, Neurologix, announced that a larger Phase 2 study will begin later this year. =

On a related note, a = small biotech company, Ceregene, announced this week that they have partnered wit= h a larger biotech company, Genzyme, to continue development of their gene ther= apy for PD. In this case, the sam= e AAV is coupled with a different gene known as neurturin (NTN). NTN isn’t the most well know= n gene in the human genome, but is appealing for PD therapy because it appears to = have a function very similar to glial derived neurotrophic factor (GDNF). GDNF has been studied using infusi= ons of the protein into the brain. T= he results of the GDNF studies and the decision by Amgen to discontinue their research on GDNF were controversial. AAV-NTN is a similar approach, but this time implanting the gene for= NTN directly in the brain. <= /o:p>

The results of a Phas= e I/II trial of NTN were reported a= t the meeting of the American Association of Neurological Surgeons in April 2007.= This 12 month study showed safety = and improvement in motor performance similar to the AAV-GAD results above. According to the Ceregene website,= a Phase 2 study is currently underway.

A relatively large am= ount of financial information accompanied the announcement that Ceregene will partn= er with Genzyme. Genzyme will pay Ceregene $25 million dollars immediately, and may pay as much as $125 milli= on in additional milestone payments. Genzyme will also pay for 50% of the Phase 3 development costs, whic= h are likely to be hundreds of millions of dollars. In return, Genzyme would market the treatment, now known as CERE-120, in some parts of the world. The Michael J. Fox Foundation has = also contributed $1.9 million to assist with costs of Phase 2 development. Given the uncertainties in long te= rm safety and efficacy, in some respects, this is a study of high stakes poker.

Finally, Genzyme also= has the rights to a third potential gene therapy for PD using AAV. In this case, AAV is coupled to th= e gene for yet another enzyme known as aromatic amino acid decarboxylase (AADC). AADC is an enzyme that is importan= t in the production of dopamine, the brain neurotransmitter that is lost in PD a= nd that is responsible for most of the motor symptoms. This AAV-AADC treatment was being developed by a small biotech known as Avigen, and a Phase I/II study was initiated in late 2004. The s= afety in this study was also reported to be good, and a different type of PET scan showed that the gene had been taken up by the brain and was active. Avigen announced that it would tak= e a more traditional approach to drug development in April 2005, and at that ti= me licensed this therapy to Genzyme.

In these early days o= f gene therapy for PD, studies of these three genes, coupled with the same AAV sys= tem, all suggest that the Trojan horse itself seems to be safe. These positive safety assessments = will need to be confirmed with larger studies.&= nbsp; While the efficacy data and PET scan data also appear to be promisin= g, much larger studies with a longer duration of follow-up will ultimately be necessary to understand the effect of these treatments on PD progression. Stay tuned for further development= s.