Currently there are no treatments that slow the progression of frontotemporal dementia (FTD), and no new mechanism-based candidate drugs are being tested in clinical trials. Pharmaceutical treatment options for FTD are even sparser than for Alzheimer’s disease, where acetylcholinesterase inhibitors and an NMDA receptor antagonist drug provide at least a small measure of relief to a large minority of patients who respond to these drugs. This dismal picture may change in the next decade. At the 7th International Conference on Frontotemporal Dementias, held in Indianapolis, Indiana, on 6-8 October 2010, many scientists said the progress in identifying the basic biology behind FTDs encouraged them to believe that this greater understanding will soon translate into new therapeutic targets. Many speakers echoed the theme that a wave of clinical trials is coming, and that advances in imaging and protein biomarkers will make these trials more effective than past efforts.

They tempered their optimism because they know that a wave of trials in neurodegenerative disease does not equal a wave of treatments. A large majority of drug trials in this area fail. And yet trials are the only way to treatments, so even just having trials in the pipeline represents tangible progress over the current situation. As some drugs fail, others will succeed. In particular, researchers are excited by the discovery that about half of FTDs are characterized by accumulations of TAR DNA binding protein 43 (TDP-43). Because this finding is only four years old, however, clinical trials for this type of frontotemporal lobar degeneration (FTLD) are still some years off.

In contrast, scientists have known for many years that nearly one-half of FTDs are characterized by tau protein deposits. Tau tangles are also a major feature of Alzheimer’s disease, implying that tauopathy treatments might be effective for both types of dementia. But tau has proven to be an elusive target, and despite efforts in academia and by drug companies, only a handful of potential treatments for tau diseases are in human trials, and no new ones from major pharmaceutical companies.

Michael Hutton of Eli Lilly in Windlesham, U.K., discussed some of the reasons for this. One of the major problems, Hutton said, is that, to date, scientists have not reached a consensus on how tau contributes to disease. It could be that tau aggregates (tangles) themselves are harmful, or it might be that tau detaching from microtubules destabilizes these neuronal highways to the point where the cell withers. Without knowing the primary pathogenic mechanism, pharmaceutical companies lack a specific pathway to target. Moreover, Hutton said, many of the proteins involved in tau processing have multiple biological roles, and efforts to target some of those proteins, for example, tau kinases, have led to undesirable side effects. In addition, tau-based disease models suitable for drug development have only recently become available. Despite these problems, Hutton said that the big pharmaceutical companies do have tau drug discovery programs and are doing preclinical work.

More tau therapies are likely to appear in the near future, Hutton predicted. For one, transgenic mouse models of tauopathy that allow treatment hypotheses to be tested are now available; for another, research programs such as the Alzheimer’s Disease Neuroimaging Initiative are developing biomarkers of disease progression that will allow clinicians to assess treatment effects more easily.

Hutton suggested, as did other speakers, that the tau-based syndrome, progressive supranuclear palsy (PSP), might be an ideal first test case or proof of concept for tau-based therapies, because it is a pure tauopathy, with no amyloid or other pathologies to confound results. Because this disease progresses rapidly, Hutton said, it also has the potential to show a more dramatic treatment effect than more slowly progressing tauopathies such as Alzheimer’s disease. PSP causes physical problems such as stiff gait, loss of balance, blurred vision, and slurred speech, as well as personality changes like depression, apathy, and irritability. Unlike Parkinson’s disease, which has similar symptoms, PSP responds poorly to levodopa, leaving it without a good treatment. The Spanish biotech company Noscira has completed recruiting for a Phase 2 trial of a tau kinase inhibitor in PSP.

Despite the challenges of targeting tau, a few treatments are in development or in early pilot trials. On the academic front, Kurt Brunden of the University of Pennsylvania in Philadelphia described a test of microtubule-stabilizing agents in a mouse model of tauopathy (Tg(P301S)PS19). If part of the problem in tauopathies is the loss of microtubules, these drugs could slow disease progression. Microtubule-stabilizing agents are used to treat cancer, but these drugs often have serious side effects and many barely enter the brain. However, Brunden described a class of microtubule-stabilizing compounds, the epothilones, that do get in. These drugs leave the bloodstream after 24 hours, but stay in the brain up to 10 days, suggesting that low doses could do some good in the brain while avoiding systemic side effects. In a study performed on three-month-old mice with tauopathy, one of these compounds, epothilone D, when given at the relatively low dose of 1 mg/kg body weight for three months, decreased axon degeneration and improved cognition in treated animals (see Brunden et al., 2010). Preliminary work on epothilones was discussed at the 2008 International Conference on Alzheimer’s Disease (see ARF related news story). Brunden said he now plans to test the compound on older mice with more established degeneration, and to look at longer-term treatment. Brunden’s drug discovery program has a research agreement with AstraZeneca, a pharmaceutical company that for years has tried to develop anti-tau drugs for neurodegeneration (see press release).

Einar Sigurdsson of New York University in New York City presented a different approach to treating tauopathies. He is trying to harness the immune system to clear tau tangles. Immunotherapies against Aβ in Alzheimer’s disease have so far been rather disappointing, Sigurdsson acknowledged. Because tau pathology correlates more tightly with the degree of dementia than does amyloid load, he believes tau immunotherapy may stand a better chance for treating Alzheimer’s, especially once disease is symptomatic. Tau immunotherapy has worked in two models with aggressive tau aggregation, the JNPL3 P301L mouse model of tauopathy and a new tau AD model generated by Allal Boutajangout in Sigurdsson’s laboratory by crossing two available models, htau and PS1(M146L). Sigurdsson said immunotherapy reduces tau aggregates in both models. It also attenuates motor impairments in JNPL3 and prevents cognitive decline in htau/PS1 mice (see Sigurdsson 2009 and ARF related news story). “Tau immunotherapy is a promising approach,” Sigurdsson concluded. He noted ongoing studies to identify the best candidate for a clinical trial, but no specific sponsor or date.

Finally, two talks featured small human trials for tau therapies. Adam Boxer of the University of California in San Francisco announced the results of a 12-week human safety study of the drug davunetide, derived from a neuronal growth factor called activity-dependent neurotrophic protein. Boxer conducted the trial for the biotechnology company Allon Therapeutics. Davunetide was previously shown to improve memory in a mouse model, and also to have a slight effect on working memory in humans with mild cognitive impairment, Boxer claimed (see trial results and ARF related news story from 2002, 2008, and 2009). In the new trial, eight people diagnosed with a tauopathy received the drug intranasally twice daily, and four received placebo. Participants had mild to moderate adverse effects such as headaches and congestion, Boxer said, but showed no evidence of cognitive benefit. He said that, based on the results of the safety study, they are preparing to enroll people with PSP for a pivotal Phase 2/3 trial.

A human trial described by Gunter Höglinger of Philipps University in Marburg, Germany, took a radically different approach to tauopathy treatment. In previous work, Höglinger and colleagues had found that inhibitors of mitochondrial complex I induced the redistribution of tau and increased neuron death (see Höllerhage et al., 2009). Moreover, mitochondrial function and energy metabolism appear to be damaged in people with progressive supranuclear palsy (see Stamelou et al., 2009), as has been found in numerous neurodegenerative diseases. Because coenzyme Q10 (CoQ10), which forms part of the electron acceptor chain in mitochondria, is known to quench the toxicity of mitochondrial inhibitors, Höglinger and colleagues tested CoQ10’s effects on people with tauopathies. In a six-week Phase 2a trial of 20 people with progressive supranuclear palsy, 10 people received 5 mg/kg per day of CoQ10, 10 received placebo. Several measures of energy metabolism showed improvement in people who got the drug, Höglinger said. Significantly, in those taking CoQ10, motor function and cognition improved, whereas these abilities deteriorated in participants who got placebo (see Stamelou et al., 2010). Höglinger said that further studies of CoQ10 are planned.

It will be one of a flurry of CoQ10 trials in the works for various neurodegenerative diseases. The Lahey Clinic in Burlington, Massachusetts, is currently enrolling 60 people with PSP for a Phase 2/3 trial, following a previous Phase 2/3 study on CoQ10’s effects on people with PSP or corticobasal degeneration. Other CoQ10 trials now recruiting include a Phase 3 trial of 600 people with Parkinson’s disease, a similar Phase 3 trial for Huntington’s disease, as well as a smaller Phase 2 trial for people with preclinical Huntington’s that will test CoQ10’s value as a preventative. CoQ10 has also been tested in Alzheimer’s patients. CoQ10 supplements are available in health food stores, and many people with diseases such as ALS and Parkinson’s already self-medicate with it even though the jury is still out on how much benefit the drug truly provides. A short-term trial on Parkinson’s patients did little to slow the progression of the disease (see ARF related news story); several current trials are designed to measure possible long-term effects.

Davunetide and CoQ10 have both been under investigation for some time, and neither was originally developed to target specific FTD disease mechanisms. The FTD 2010 conference presented no new therapeutic compounds that grew out of recent insights into the basic biology. Many scientists said, however, that they expect more mechanistic drugs to appear over the next few years, and predicted the current handful of FTD clinical trials are but a hint of what is to come. “Therapeutic trials in PSP are going to spill over nicely into the FTLD field,” said Brad Boeve of the Mayo Clinic in Rochester, Minnesota. “We likely will have at least a couple of agents being tested in clinical trials over the next two years.”

Other researchers agreed that therapeutic trials for the other major FTD pathology, marked by progranulin deficiency and TDP-43 deposits, are close behind. UCSF has established the Consortium for Frontotemporal Dementia Research with the goal of finding a cure for FTLD-TDP caused by progranulin mutations within 10 years. Consortium member Bruce Miller at UCSF said, “I believe strongly that the progranulin mutations may be treatable in the next few years.”

Glenda Halliday, of the University of New South Wales in Randwick, Australia, summed up the overarching mood at the conference: “Understanding how proteins interact in the cells gives us a lot more capacity to change those interactions and to have targets that are actually going to be treatable.”—Madolyn Bowman Rogers.

This concludes a four-part series. See also Part 1, Part 2, Part 3. View PDF of the entire series.


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News Citations

  1. Chicago: Brain-Penetrant Microtubule Stabilizer in Tauopathy Mice
  2. Tau Vaccine Detangles Mouse Brain
  3. Stockholm: Could a Whiff of NAP Nip Brain Inflammation in the Bud?
  4. Boston: Neuroprotective Peptide Inches Forward in Clinic
  5. Boston: Drug Development Strategies for Neuro Diseases
  6. Coenzyme Q10 Fails to Quell Parkinson Symptoms
  7. Indianapolis: Frontotemporal Dementia Research Comes of Age
  8. Indianapolis: Neuroimaging Opens Window to Disease, Better Diagnosis
  9. Indianapolis: Dissecting the Pathways Behind Frontotemporal Dementia

Paper Citations

  1. . Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy. J Neurosci. 2010 Oct 13;30(41):13861-6. PubMed.
  2. . Tau-focused immunotherapy for Alzheimer's disease and related tauopathies. Curr Alzheimer Res. 2009 Oct;6(5):446-50. PubMed.
  3. . Natural lipophilic inhibitors of mitochondrial complex I are candidate toxins for sporadic neurodegenerative tau pathologies. Exp Neurol. 2009 Nov;220(1):133-42. PubMed.
  4. . In vivo evidence for cerebral depletion in high-energy phosphates in progressive supranuclear palsy. J Cereb Blood Flow Metab. 2009 Apr;29(4):861-70. PubMed.
  5. . Rational therapeutic approaches to progressive supranuclear palsy. Brain. 2010 Jun;133(Pt 6):1578-90. PubMed.

Other Citations

  1. PS1(M146L)

External Citations

  1. Alzheimer’s Disease Neuroimaging Initiative
  2. Phase 2 trial
  3. Tg(P301S)PS19
  4. press release
  5. JNPL3 P301L
  6. htau
  7. human safety study
  8. trial results
  9. Phase 2/3 trial
  10. Phase 2a trial
  11. Phase 2/3 trial
  12. Phase 2/3 study
  13. Phase 3 trial
  14. Phase 3 trial
  15. Phase 2 trial
  16. Alzheimer’s patients
  17. Consortium for Frontotemporal Dementia Research

Further Reading