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Barcelona: Is Parkinson’s Pathology Treatable?

Series - International Conference on Alzheimer's & Parkinson's Diseases 2011:

Short answer: Not yet. But scientists are hammering away at the problem, and this series features progress reports on some experimental PD therapies. For Parkinson’s disease, unlike Alzheimer’s, physicians have numerous effective treatments to reduce symptoms and improve their patients’ quality of life. Yet none of these treatments halt the underlying neurodegeneration or cure the disease. Almost 200 years after PD was first described, disease-modifying treatments remain an elusive goal. Indeed, the majority of PD treatments in the development pipeline are symptomatic, said Cristina Sampaio of the European Medicines Agency, speaking at the 10th International Conference on Alzheimer’s and Parkinson’s Diseases, held 9-13 March 2011 in Barcelona, Spain (see ARF related news story). The approaches that have been tried, such as cell replacement and gene therapy, have yielded, at best, mixed results so far.

Why has PD pathology been such a difficult target? One barrier has been the lack of good biomarkers to prove that a therapy alters pathology, Sampaio said, a point echoed by other scientists. Another issue is that, as in AD, available animal models for PD do not model the full complexity of the disease, which may cause problems for translating therapies from the bench to the clinic. Manuel Buttini at Elan Pharmaceuticals, South San Francisco, California, pointed out that the classic PD animal models, which are produced by lesioning the striatum with toxins, are particularly limited in the disease features they model. Newer transgenic mouse models, such as Richfield mice, Line 61, and other strains, express familial PD genes in the substantia nigra and are more versatile, Buttini said. Their brain pathology more closely resembles that of PD patients, and they reveal subtle motor and cognitive defects similar to those in people. Localized, moderate α-synuclein overexpression most closely mirrors human PD, Buttini said, while higher levels of expression produce greater neurodegeneration. He noted that there is still no ideal model, and the best choice of animal depends on the particular research questions being asked.

Despite these obstacles, numerous academic scientists and pharmaceutical companies continue to plug away at the problem of disease-modifying treatments, and AD/PD 2011 featured a number of progress reports. Scientists provided more data on why cell replacement has failed to cure the disease, held out hope for gene therapy, and discussed early, preclinical efforts to directly attack the underlying pathology by blocking α-synuclein deposits or transmission.

Fetal Grafts: A Checkered History
The motor symptoms of PD begin after more than half of the dopamine-producing neurons in the substantia nigra have died. Replacing these lost cells, therefore, was one of the earliest disease-modifying treatments tried. Many of the approximately 350 patients who received grafts of fetal dopaminergic neurons initially did well, moving more easily and with better control. One- to two-year-old transplants examined at autopsy looked “fabulous,” said Jeffrey Kordower at Rush University Medical Center, Chicago, Illinois. Kordower is also a founder of Ceregene, Inc., a biotech company in San Diego, California, that is developing gene therapy for AD and PD. Kordower said the transplanted neurons not only survived, but also innervated the host tissue and robustly expressed tyrosine hydroxylase, the enzyme that produces the precursor to dopamine.

Over time, however, problems cropped up. In some groups, about half the people who received grafts developed dyskinesias, or involuntary movements. The reason for this is controversial, with some researchers suggesting it is because the grafts produce too much dopamine. Other scientists say the quality of the grafted tissue is a major factor. Some studies indicate that solid-tissue grafts trigger more inflammation, leading to dyskinesias (see Kirik and Björklund, 2005), or that contaminating serotonergic neurons cause the uncontrolled movements (see ARF related news story). Additionally, some PD symptoms, such as gait problems and falls, do not respond to dopamine. These problems worsened several years after surgery, Kordower told ARF.

Perhaps most disturbingly, the young grafts succumbed to PD pathology within 10 years after transplant, developing Lewy bodies and Lewy neurites (see ARF related news story). First reported in 2008, Kordower said this has now been shown to be a widespread phenomenon. Clinicians including Patrik Brundin at Lund University, Sweden; William Langston at The Parkinson’s Institute, Sunnyvale, California; and Curt Freed at the University of Colorado, Aurora, have all reported the same thing, Kordower said (see, e.g., Li et al., 2010 and Brundin et al., 2010). About 6 to 8 percent of the grafted neurons develop Lewy bodies, comparable to the percentage in host tissue. Levels of dopamine transporter and tyrosine hydroxylase also drop off. This pathology is specific to the PD process and not just a general inflammatory response, Kordower said, because fetal grafts in Huntington’s patients show inflammation and degeneration, but no Lewy bodies. “Whatever is causing Parkinson’s disease is still there,” Kordower concluded. Cell replacement does not change the underlying disease. Experiments in mice have now shown that virally overexpressed α-synuclein in the striatum moves into grafted neurons, implying that the same mechanism could be at work in people (see Hansen et al., 2011).

What’s Next for Cell Replacement?
Even so, Kordower told ARF that he believes fetal grafts are still a viable therapy, because the majority of the transplanted cells remain healthy and patients often experience years of motor improvement. Brit Mollenhauer at the Paracelsus-Elena-Klinik, Kassel, Germany, told ARF that, because the initial damage in PD is so localized, grafts might still be a reasonable treatment strategy if the malignancies surrounding this therapy could be gotten under control. At present, however, deep-brain stimulation (DBS) is a much better therapy, these clinicians agreed. DBS, in essence, has set a standard that grafts would have to surpass (see ARF DBS series).

TRANSEURO, a European research consortium coordinated by Roger Barker at Cambridge University, U.K., is working to improve the efficacy of fetal cell replacement, using lessons from past efforts. The group plans to start a new round of clinical trials, paying careful attention to how tissue is prepared and delivered, and how patients are selected. Also, the researchers will suppress patients’ immune systems after surgery to avoid inflammation that might lead to dyskinesias or graft rejection. Kordower, who consults for the consortium, said that in the future, TRANSEURO may switch from using fetal neurons to cultured stem cells. Embryonic or adult stem cells are more readily available than fetal tissue, and could be coaxed to form purer populations of dopaminergic neurons.

Other groups are also interested in the potential of stem cells to replace lost brain cells. At AD/PD, Shimon Slavin at Bar-Ilan University, Ramat-Gan, Israel, described a Phase 2 clinical trial in which mesenchymal stem cells from a patient’s bone marrow are injected into the brain or bloodstream. The stem cells migrate to inflammatory sites and differentiate into neural cells, Slavin said. His group has now treated more than 100 patients, most of whom had multiple sclerosis (MS) or amyotrophic lateral sclerosis, and seen no serious safety issues (see ARF related news story on Karussis et al., 2010). MS patients had the best response, Slavin said, with about 60 percent of them showing improvement so far. In some patients, the results were “spectacular,” Slavin said, noting the case of a man who was confined to a wheelchair before treatment, and now bikes and plays golf. However, this outcome is not typical, and in a difficult field riddled with setbacks, Lazarus stories from Phase 1 tend to provoke skepticism and some concern about inspiring false hopes that are later dashed in Phase 2 or 3. In the meantime, the researchers are trying to find ways to get a more consistent treatment response, Slavin said, for example, by differentiating the stem cells before transplanting them. A similar mesenchymal stem cell approach is currently in a single-center clinical trial for PD patients in India.

Even if these stem cell therapies work, they will have to circumvent the problems that cropped up with fetal grafts. For example, “We have to make sure that stem cells don’t cause off-medication dyskinesias,” Kordower said, adding that this will be hard to test because there are no good animal models for dyskinesia. For a discussion of other treatments in the works, see Part 2.—Madolyn Bowman Rogers.

This is Part 1 of a two-part series. See also Part 2.

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References

News Citations

  1. Barcelona: Straight Talk From a Regulator on Trials in Parkinson’s
  2. Serotonin Neurons—Culprits in Graft-Related Parkinson Dyskinesia
  3. Dopaminergic Transplants—Stable But Prone to Parkinson’s?
  4. Deep-Brain Stimulation: Decade of Surgical Relief, Not Just for PD
  5. Stem Cells Pass Initial Safety Muster in ALS, Multiple Sclerosis
  6. Barcelona: Parkinson’s Treatments on the Horizon

Paper Citations

  1. Kirik D, Björklund A. Histological analysis of fetal dopamine cell suspension grafts in two patients with Parkinson's disease gives promising results. Brain. 2005 Jul;128(Pt 7):1478-9. PubMed.
  2. Li JY, Englund E, Widner H, Rehncrona S, Björklund A, Lindvall O, Brundin P. Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson's disease. Mov Disord. 2010 Jun 15;25(8):1091-6. PubMed.
  3. Brundin P, Barker RA, Parmar M. Neural grafting in Parkinson's disease Problems and possibilities. Prog Brain Res. 2010;184:265-94. PubMed.
  4. Hansen C, Angot E, Bergström AL, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li JY, Brundin P. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest. 2011 Feb 1;121(2):715-25. PubMed.
  5. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, Bulte JW, Petrou P, Ben-Hur T, Abramsky O, Slavin S. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010 Oct;67(10):1187-94. PubMed.

External Citations

  1. Elan Pharmaceuticals
  2. Richfield mice
  3. Line 61
  4. other strains
  5. Ceregene, Inc.
  6. Paracelsus-Elena-Klinik
  7. TRANSEURO
  8. Phase 2 clinical trial
  9. single-center clinical trial

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