Guest post by Paul Jaffe, MAADDSG@aol.com; coordinator, Manhattan Adult Attention Deficit Disorder Support Group; New York, NY, USA. [7/17/08]

Recently, gene-therapy researchers — who have had their ups and downs — scored a point: the restoration of some vision to patients with retinal degeneration [1,2].

To effect this, they used a generally harmless adeno-associated virus (AAV). The goal was to deliver, to the retina, a functioning copy of a defective gene thought to trigger the illness. This viral “vector” was injected through a surgical procedure deemed reasonably safe.

Within gene therapy, AAV vectoring – which may soon turn a corner [3] — is now standard. This includes a well-publicized effort [4,5,6] — and a less-publicized effort [7] — to treat Parkinson’s Disease.

Unlike the above, which might be termed corrective gene therapy, the PD applications are closer to compensatory gene therapy. Here, the aim is to alter the brain so as to mimic a treatment several steps removed from an underlying pathology.

In each PD clinical trial, a gene has been inserted to encode a specific enzyme. These are:

• glutamic acid decarboxylase (GAD), which catalyzes the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA); and
• human aromatic l-amino acid decarboxylase (AADC or hAADC), which does the same for dopamine (DA).

The vectors are known, respectively, as the AAV-GAD and the AAV-AADC.

The PD research might — or might not — succeed. (One vector is in US Phase II testing; the other, in Phase I.) The question here is: might either be used elsewhere?

IDEA #1: AAV-GAD FOR ANXIETY?

Decades ago, the emergence of a new class of calming drugs — meprobamate and the early benzodiazepines, chlordiazepoxide and diazepam — put the anxiety-disorders field on the map. It turned out that these agents facilitated the brain’s use of a common chemical transmitter: GABA.

But relief from chronic fear, or sporadic terror, was jeopardized by coexisting effects: sedation and addiction. These — for many patients — rendered the GABA-centered treatments untenable.

For safety reasons, benzodiazepines gave way to tricyclics, and then SSRIs. To this pharmacological compromise, talk therapy was often added.

Enter AAV-GAD, which — in the PD research — is injected into the subthalamic nucleus, which projects to the motor cortex.

This circuit makes use of the brain’s principal excitory transmitter: glutamate. Which, chemically, is one step away from the brain’s main inhibitory transmitter: GABA. In effect, the extra GAD turns glutamate neurons into GABA neurons.

As it happens, glutamate also shows up in a number of anxiety-related conditions. Among them: phobias; panic attacks; post-traumatic stress; generalized anxiety; and anxiety-driven depressions.* It seems as if:

• Glutamate — when it works through NMDA or AMPA receptors — is anxiogenic [8,9,10].
• GABA — when it works through GABA-A or GABA-B receptors — is anxiolytic [11,12,13].

In this circumstance, each conversion of a glutamate neuron to a GABA neuron could represent a pro-therapeutic double whammy.

Two suggestions:

1) Search for a brain region which a) has a sizeable number of glutamate neurons; b) offers a favorable ratio of NMDA and AMPA receptors to other glutamate receptors; c) features a selection of GABA-A and GABA-B receptors; and d) pops up regularly — as being overactive — in the anxiety-disorders imaging literature.

Candidates might include the anterior cingulate; the dorsomedial hypothalamus; the dorsolateral periaqueductal gray; the lateral amygdala; or the bed nucleus of the stria terminalis [14,15,16]. Or perhaps the anterior limb of the internal capsule [17].

2) Pick a rodent fear/avoidance experiment — there are dozens — and rerun it. But, instead of the usual pharmacological intervention, try the AAV-GAD vector.

*Obsessive-compulsive disorder – which can also feature glutamate – deserves a separate discussion.

IDEA #2: AAV-AADC FOR THE “ATTENTION DEFICIT” ASPECT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER?

Also stuck in neutral: the AD/HD field.

While some patients who seek help are helped, others — for the most part — are not.

True, the use of stimulant medication — typically, some version of methylphenidate or amphetamine — remains a cornerstone of AD/HD treatment.

But: while patients are often moved in the right direction, some aren’t taken far enough. For others, the therapeutic effects are more potent, but are then defeated by side effects. Still others do well for a time, only to watch their gains recede as a tolerance develops to this or that medication.

To address these gaps, a series of downstream interventions — behavior training, attitude training, social-skills training, life-skills training, attention training — aim at building compensatory skills.

Stimulant use has, however, transformed AD/HD research. An early inference was that AD/HD is the outcome of a dopamine-system deficiency [18]; or a family of such. Though much needs to be explained, the notion has stood up reasonably well [19,20,21,22].

For example, a recent study [23] used PET — for eight AD/HD subjects and six controls — to track DA synthesis.

The authors report: “In most brain areas in the subjects with AD/HD the rate of dopamine synthesis was lower than in the healthy controls, with the values being particularly low in the subcortical regions [caudate, accumbens, putamen]. The low synthesis in the subcortical areas correlates with the severity of the attention deficit symptoms, assessed according to the DSM-IV.”

In a broad sense, this study was updated by the second PD study. In which patients — in the left and right putamen — were injected with the AADC gene, with the express goal of accelerating DA synthesis. Success at this — along with symptom abatement — has been reported in rats [24] and monkeys [25].

Between these two sets of findings, might they suggest — if a suitable animal model can be found — a pathway in AD/HD research?

Could imaging locate a series of targets — the putamen, the accumbens, the caudate, the cerebellar vermis — for AADC-gene infusion? With the aim of boosting local DA synthesis, to ease the cognitive aspect of AD/HD? Of the AD/HD symptom clusters, the inability to concentrate is less likely to be outgrown, and maybe less likely to respond to medication.

On the receiving end, of course, would be a cellular environment different than would be found with PD. But is it possible that extra AADC could 1) speed up the production of DA by existing DA neurons; or 2) create new DA neurons out of monoenzymatic cells containing tyrosine hydroxylase [26]?

Finally, is it possible that a variety of genes — e.g.

• for DA D2, D3, D4 or D5 receptors [27]; or
• for a cocktail of D1 and alpha-2a receptors [28]; or
• for a set of dopamine-neuron-activating (and behavior-changing) potassium channels [29,30]

– could be isolated, cultured, and infused into selected brain sites?

AN UNFINISHED TASK

It might be noted that an AD/HD-anxiety comorbidity can be both debilitating [31] and difficult to treat [32].

More generally, decades after the proclamation of the Biological Revolution in Psychiatry, many patients — despite numerous prescriptions — have not been substantially helped. For each, the clock is ticking.

Against this backdrop, the above therapeutic shortcuts might:

1) relieve researchers of the burden of determining the pathogenesis of anxiety or AD/HD;

2) exploit existing knowledge, which – with current treatments for either condition – mostly goes to waste;

3) make use of emerging technologies;

4) deliver targeted treatments, with more remedial impact and fewer side effects; and – down the road –

5) devise treatments on a patient-by-patient basis: the much-anticipated personalized medicine.

Could gene therapy [33,34,35] help take us to this level? If so, how could this be wrought — and by whom?

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