User:Droflet/Sandbox/GDNF

GDNF or Glial_cell_line-Derived_Neurotrophic_Factor is a protein that promotes the survival of many types of neurons. In rodents, GDNF has been shown to stimulate an increase in midbrain dopamine levels, protect dopamine neurons from some neurotoxins, and restore injured dopamine neurons. Trials have been conducted in human patients with mixed results but a Phase II trial is nearing completion (2016). GDNF will not pass the Blood-Brain barrier and therefore research has concentrated on optimising systems for accurately delivering it into the targeted areas of the brain.

Progress and Prospects to date
At the time of writing, June 2016, a Phase II clinical trial of GDNF is nearing completion. Open label trials over a decade ago gave very encouraging results but were eclipsed by some randomised control trials which did not show significant effectiveness and manifested some worrying potentially adverse reactions. The possibility that the disappointing results which contrasted with those of the open label study were a consequence of a different design of the delivery mechanism have been addressed by a radical redesign of equipment and methodology by the Bristol group.

A good account of the saga to this point is related in a video of a Royal Institution Lecture from 2013.

GDNF as a therapy for Parkinson's
GDNF is a naturally occurring Neurotrophic factor which means that it supports the growth, survival and differentiation of neurons. It is crucial for the long-term maintenance of the nigrostriatal system.

It is one of several such growth factors that have been explored as a therapy for Parkinson's. The problem with such proteins is that they cannot penetrate the blood-brain barrier and are rapidly degraded and so are not effective when administered by injection into the bloodstream. It is therefore necessary to deliver them directly to the site where they are required. In the case of Parkinson's it is to the neurons whose cell bodies are in the substantia nigra pars compactor at the base of the brain. These are the neurons which degenerate and give rise to the incapacitating motor symptoms of Parkinson's. The axons of these neurons project to the putamen and the degeneration of the terminals there interrupt the dopamine-dependent circuitry of the basal ganglia. Research in animal models - and in the open label trial referred to above - showed that the putamen was an effective target for the delivery of GDNF. The targeting had to be accurate because GDNF is not able to diffuse very far through neural tissue.

There is a good summary in some open access review articles published in the last few years

In the first open label clinical trial reported in 2003, the GDNF was delivered through catheters reaching into the putamen fed by a pump embedded in the abdomen

GDNF Action
GDNF is involved in the initial development of dopaminergic neurons but when infused into the adult brain does not appear to stimulate the production of new neurons. It does, however, affect existing neurons and stimulate the recovery of damaged neurons and enables existing dopamine neurons to 'sprout' to make new connections that partly compensate for those that have been lost. (Diagram of sprouting?)

The restoration of neural terminals in the putamen after GDNF infusion therapy has been demonstrated by PET scans. In the open label trials these neural changes accompanied the motor improvements. (Find a quote)(Images needed - from http://www.parkinsons.org.uk/sites/default/files/gdnftrial_patientinfosheet.pdf - p12, Fig 1 ??).

Other ways of GDNF delivery
Focussed Ultrasound and microbubbles

Transcranial magnetic stimulation (TMS)

Regulatable AAV vector mediating GDNF biological effects

Some naturally-occurring substances stimulate GDNF production

Previous Research
1996

Gash et al  evaluated the effects of GDNF injected intracerebrally in rhesus monkeys with Parkinson's disease symptoms induced by the neurotoxin MPTP.

The recipients of GDNF displayed significant improvements in three of the cardinal symptoms of parkinsonism: bradykinesia, rigidity and postural instability. GDNF administered every four weeks maintained functional recovery. Dopamine levels in the midbrain and globus pallidus were twice as high, and nigral dopamine neurons were, on average, 20% larger, with an increased fibre density.

2000

Kordower et al  injected GDNF into the striatum and substantia nigra of monkeys with Parkinsonism induced by the application of MPTP. The result was a reversal of the motor deficits in a hand reach task.

2003

Gill et al   delivered GDNF directly into the putamen of five Parkinson patients in a phase 1 safety trial, and noted a a significant improvement in PD symptoms after 18 months.

2005

Love et al  described the sprouting of neurons caused by GDNF. 2009

Johnston et al tested the safety and efficacy of an adeno-associated virus (AAV2) encoding human glial cell-derived neurotrophic factor (GDNF) in aged nonhuman primates. They noted:-

"AAV2-GDNF did not significantly affect dopamine in the ipsilateral putamen or caudate, but increased dopamine turnover in HD groups."

2010

Kells et al applied GDNF to rhesus monkeys previously rendered Parkinsonian with MPTP. They observed:-

"Progressive amelioration of functional deficits, recovery of dopamine and regrowth of fibers to the striatal neuropil."

Extensive distribution of GDNF within the putamen and transport to the severely lesioned substantia nigra, after convection-enhanced delivery (CED) of AAV2-GDNF into the putamen.

Biju et al took advantage of the fact that bone marrow stem cell–derived macrophages are able to pass the BBB and successfully delivered GDNF to the brains of mice. They were then able to demonstrate the rescue of these mice from MPTP-induced PD.