Girija and I had a lengthy conversation with Dr. Barbara Waszczak last week and she updated us on the current status of her fascinating research for treating Parkinson's disease using a non-invasive, gene therapy via intranasal administration of GDNF. Barbara explained how her intranasal gene therapy worked and gave us details on the differences in her approach and the more widely known AAV2-GDNF. We also spent time discussing her next steps in required pre-clinical research before a submission of an IND to the FDA to begin human studies.

There are several differences between Dr. Waszczak's approach to GDNF therapy and that which is currently taking place using viral vectors encoding GDNF, known as AAV2-GDNF. The most obvious difference is the method of administration. GDNF is a protein that activates survival and growth-promoting pathways, protects dopamine neurons from injury, and restores their function. However, GDNF not cross the blood-brain barrier (BBB), so its use would require surgical injection into the brain. Barbara is investigating pGDNF encoded with DNA nanoparticles (NPs) which by-pass the BBB and allow for the brain to continuously produce its own GDNF. AAV vector research requires GDNF to be surgically implanted into the exact area needed in the substantia nigra and hope that the protein uptakes to the still living neurons. Success would still likely require multiple lifetime surgeries to maintain the GDNF production. Alternatively, administration of intranasal pGDNF allows for uptake throughout the brain and causes the cells to continuously produce their own GDNF over a long time period. Essentially, the viral vector approach surgically inserts an encoded GDNF protein. The intranasal approach inserts an encoded GDNF gene which allows cells that line blood vessels throughout the brain to begin to produce their own renewable source of GDNF.

Please keep in mind that all of her research has been on rodents. That being said, the results of those studies have been great and offer some excitement as she moves forward.
One week after intranasal administration, GDNF levels were significantly increased throughout the brain. The transfected cells were largely adjacent to capillaries, suggesting they may be pericytes. Most importantly, intranasal GDNF NPs provided significant neuroprotection of dopamine neurons in a standard rat model of PD.

I have clearly simplified matters in this brief summary. If anyone is interested, Barbara has given us a copy of a poster-board for a conference in which she will be presenting her latest, not yet released, research results. I would be happy to send this out if you're interested.

So, where do things stand today? One more rodent study is needed for dosing purposes. Then a primate study is probably required, before she can submit the IND. What we need to do now, as a community, is to make sure she gets the funding required to move forward. Girija and I have offered to assist in getting the PD community involved. How much does she need? All of $100,000. If you believe in advancing this research, we need to get the normal early research funders (i.e. MJFF, PDF, NPF, NIH, etc.) to cut a check. MJFF has funded her previous research, so I am hoping that this will go through their funding committee quickly and be approved again. However, my general point is that many people on this site, and others, complain about how slow the research process is. We complain about big pharma. We want more say in the research process. This is our time to step up. All you have to do is tell your local support groups to support this research. Contact the larger organizations (e.g. MJFF) and tell them we want our donations to get this study started immediately. Basically, it's time to act, if you want to see intranasal GDNF research move forward. Understand, no one else in the world can conduct this research. Northeastern and their corporate partner, Copernicus Therapeutics, own the patent rights to the drug. I can't imagine how it could be difficult to fund $100,000. Finally, anyone on this board that would like to assist me and Girija are more than welcome.

If we are successful getting this done, we can find more relevant research and help move it along. It's up to us PWP to take more control by advising, assisting, and twisting arms where necessary.

Tupelo3,

Thank you and Girija for looking into this.

The approach is exciting.

I have many questions. Most can wait. But one needs answering quickly. You write:
"Understand, no one else in the world can conduct this research. Northeastern and their corporate partner, Copernicus Therapeutics, own the patent rights to the drug."

Supposing that this approach works, what is your understanding of their pricing strategy?

John

John, I'm really not sure about the answer to your question as Barbara's main focus now is just to get into human trials. Honestly, Barbara is a genius when it comes to the biology and chemistry of human brain cells. However, she isn't very knowledgeable, yet, on the drug approval process. So, I would think that pricing a future drug, if approved, is way down her list of priorities. I also think that Copernicus has more say in that regard, and we haven't spoken with them yet, although I do intend too. If I get the chance, I will definitely ask that question.

Gary

• Intranasal delivery directly targets the brain, does not require surgery, and could be used in patients ineligible for surgery.

• The intranasal route bypasses the BBB. Only a small percentage of the administered dose reaches the brain, but small amounts of GDNF may be sufficient (due to its high potency on dopamine neurons), and desirable (due to side-effects associated with too much GDNF in brain).

• Intranasal delivery limits distribution outside the brain, and therefore limits potential side-effects in other tissues, an advantage over intravenous administration.

• Copernicus’ plasmid DNA nanoparticles successfully transfect cells in the brain after nasal delivery, making them capable of producing GDNF within the brain

1. Copernicus’ DNA nanoparticles are safe and non-immunogenic. They have been given via the nose for other applications, such as to deliver the gene for cystic fibrosis to the lungs
2. AAV vectors can be immunogenic and they integrate into the host cell DNA, so production is lasting and hard to regulate.
3. Plasmid DNA does not integrate with the host cell DNA, so transfection is time limited
4. GDNF production is scalable, and nasal re-dosing is possible and easy. If adverse effects develop, dosing could be terminated and production would eventually stop.
5. The time course of GDNF production can be modified by design of the plasmid
6. The time course of production still needs to be determined for intranasal pGDNF NPs. New funding is sought for this work.
7. Dose-response relationships must be determined to see if giving more yields proportionally more GDNF production. Funding is also sought for this

Dr. Waszczak's Progress and future plans:

• Research in the Waszczak lab has shown that intranasal pGDNF NPs significantly reduce dopamine cell loss in the rat 6-OHDA model of Parkinson’s disease.

• The next step (after time course and dose-response studies in rats) is testing in a large brain primate to determine if intranasal pGDNF NPs are likely to work in humans. A major grant from the NIH (or other source) will be needed.

• If the primate study is promising, Copernicus and Northeastern University will pursue an IND for a clinical trial. Funding prospects uncertain.

• MRI-guided focused ultrasound (FUS) may enrich delivery of intranasal pGDNF NPs to the target brain areas (substantia nigra and striatum).
o FUS is non-invasive; it is a brief, focused application of low energy sonication to areas where pGDNF NP delivery is desired. FUS would be done just before or after the intranasal dose is given.
o A new grant awarded to the Waszczak lab and collaborators at Harvard Medical School and Copernicus Therapeutics will allow us to investigate whether FUS increases delivery to the target brain areas.

Expression of GDNF Throughout Rat Brain After Intranasal Delivery of hGDNF Plasmid Nanoparticles

http://www.fasebj.org/content/29/1_S...20.10.abstract

AAV2-GDNF for Advanced Parkinson s Disease
This study is currently recruiting participants.

https://clinicaltrials.gov/ct2/show/...rm=gdnf&rank=1