Parkinson's disease: fetal cell or stem cell-derived treatments

Abstract

Introduction

The mean age of onset of Parkinson's disease is about 65 years, with a median time of 9 years between diagnosis and death.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of fetal cell or stem cell-derived therapy in people with Parkinson’s disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found two studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: fetal cell therapy versus deep brain stimulation; fetal cell therapy versus sham surgery; stem cell-derived therapy versus deep brain stimulation; stem cell-derived therapy versus sham surgery.

Key Points

The mean age of onset of Parkinson's disease is about 65 years, with a median time of 9 years between diagnosis and death.

As the efficacy of conventional drug treatment wears off, other treatments may be sought. Neural transplantation may be applicable to a subset of patients, in particular younger patients, with advanced disease and a prior good response to levodopa.

We found two double-blind RCTs that compared fetal cell transplant with sham surgery. The RCTs included 74 people in total, all of whom had advanced Parkinson’s disease.

• The RCTs found no good evidence that fetal cell transplant improved clinical outcomes, such as disease severity, or reduced the need for levodopa or other treatment at 1 to 2 years.

• Fetal cell transplant may improve the non-clinical outcome of putaminal fluoro-DOPA uptake, as measured by PET scan.

• Fetal cell transplant may be associated with adverse effects such as graft-induced dyskinesias.

• The findings of the RCTs were in contrast to more favourable outcomes suggested by earlier open-label and uncontrolled studies.

• However, it has been highlighted that some procedures in the two trials might not have been optimal, and follow-up time in at least one of the trials may have been too short.

• Larger-scale RCTs are currently under way to address the benefits and harms of fetal cell transplantation for Parkinson’s disease.

We don’t know how fetal cell therapy versus deep brain stimulation, stem cell-derived therapy versus sham surgery, or stem cell-derived therapy versus deep brain stimulation compare as we found no studies addressing these comparisons.

Clinical context

General background

The mean age of onset of Parkinson's disease is about 65 years, with a median time of 9 years between diagnosis and death. Levodopa and dopamine agonists have been the mainstay of treatment for Parkinson’s disease, but side effects or drug effect wearing-off frequently develops.

Focus of the review

As the efficacy of conventional drug treatment wears off, other treatments may be sought. More recently, deep brain stimulation into the pallidum or subthalamic nucleus has been employed to alleviate the cardinal symptoms of Parkinson's disease. A more permanent and physiological approach would be to reconstruct the nigrostriatal pathways that are degenerated in Parkinson's disease, by transplanting new dopamine-producing cells. Neural transplantation may be applicable to a subset of patients, in particular younger patients, with advanced disease and a prior good-response to levodopa. During the past two decades, several open-label studies have provided proof of principle and provided symptomatic relief for over a decade. However, no randomised control trials to date have proven the benefit of cell therapy as observed in open-label studies, and these issues need to be addressed. So far, stem cell-derived therapy has not been studied in the clinical setting. This review will, therefore, focus on the transplantation of fetal neural tissue for Parkinson’s disease.

Comments on evidence

There only exist two high-quality RCTs, to date, addressing the benefits of cell therapy versus sham surgery for Parkinson’s disease.

Search and appraisal summary

The literature search was carried out in September 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. After deduplication and removal of conference abstracts, 69 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 34 studies, and the further review of 35 full publications. Of the 35 full articles evaluated, two RCTs were included.

About this condition

Definition

Idiopathic Parkinson's disease is an age-related neurodegenerative disorder, which is associated with a combination of asymmetrical bradykinesia, hypokinesia, and rigidity, sometimes combined with rest tremor and postural changes. Clinical diagnostic criteria have a sensitivity of 80% and a specificity of 30% (likelihood ratio +ve test 1.14, –ve test 0.67) compared with the gold standard of diagnosis at autopsy. The primary pathology is progressive loss of cells that produce the neurotransmitter dopamine from the substantia nigra in the brainstem. Treatment aims to replace or compensate for the lost dopamine. A good response to treatment supports, but does not confirm, the diagnosis. Several other catecholaminergic neurotransmitter systems are also affected in Parkinson's disease. There is no consistent definition distinguishing early-stage from late-stage Parkinson's disease. In this review, we consider people with established Parkinson’s disease who have had a good effect with conventional medical (e.g., levodopa) treatment.

Incidence/ Prevalence

Parkinson's disease occurs worldwide, with a male to female ratio of 1.5:1.0. In 5% to 10% of people who develop Parkinson's disease, the condition appears before the age of 40 years (young onset). The mean age of onset is about 65 years. Overall age-adjusted prevalence is 1.0% worldwide, and 1.6% in Europe, rising from 0.6% at age 65 to 69 years to 3.5% at age 85 to 89 years.

Aetiology/ Risk factors

The cause for Parkinson's disease is unknown. Parkinson's disease may represent different conditions with a final common pathway. People may be affected differently by a combination of genetic and environmental factors (viruses, toxins, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine, well water, vitamin E, and smoking). First-degree relatives of affected people may have twice the risk of developing Parkinson's disease (17% chance of developing the condition in their lifetime) compared with the general population. However, purely genetic varieties probably affect a small minority of people with Parkinson's disease. The LRRK2 gene is the most prevalent gene associated with both familial and sporadic Parkinson’s disease. Also, mutations in PARK genes, in particular the PARKIN-1 gene that encodes alpha-synuclein, may be associated with Parkinson’s disease in families with at least one member with young-onset Parkinson’s disease.

Prognosis

Parkinson's disease is currently incurable. Disability is progressive, and is associated with increased mortality (RR of death compared with matched control populations ranges from 1.6–3.0). Treatment can reduce symptoms, but rarely achieves complete control. Whether treatment reduces mortality remains controversial. Levodopa seemed to reduce mortality in the UK for 5 years after its introduction, before a 'catch-up' effect was noted and overall mortality rose towards previous levels. This suggested a limited prolonging of life. An Australian cohort study followed 130 people treated for 10 years. The standardised mortality ratio was 1.58 (P <0.001). At 10 years, 25% had been admitted to a nursing home, and only four people were still employed. The mean duration of disease until death was 9.1 years. In a similar Italian cohort study conducted over 8 years, the relative risk of death for affected people compared with healthy controls was 2.3 (95% CI 1.60 to 3.39). Age at initial census date was the main predictor of outcome (for people aged <75 years: RR of death 1.80, 95% CI 1.04 to 3.11; for people aged >75 years: RR of death 5.61, 95% CI 2.13 to 14.80).

Aims of intervention

To improve symptoms and quality of life; to slow disease progression; to limit short- and long-term adverse effects, such as motor fluctuations.

Outcomes

Disease severity (e.g., measured using Unified Parkinson's Change in Disease Rating Score, a motor component of the Unified Parkinson's Disease Rating Score [UPDRS] in the 'off' state, amount of 'on' time without dyskinesia, amount of 'off' time, dyskinesia); need for levodopa or other treatment; F-DOPA PET scan changes; quality of life (e.g., measured by the Parkinson's Disease Quality of Life Questionnaire and the Parkinson's Disease Questionnaire); adverse effects. We only report outcomes from studies undertaken in human subjects and have excluded studies undertaken in animals or those that are laboratory based.

Methods

BMJ Clinical Evidence search and appraisal September 2014. The following databases were used to identify studies for this systematic review Medline 1966 to September 2014, Embase 1980 to September 2014, and The Cochrane Database of Systematic Reviews 2014, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published systematic reviews and RCTs in the English language, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. All serious adverse effects, or those adverse effects that are reported as statistically significant, will be data extracted for inclusion in the adverse effects table of the review. Prespecified adverse effects identified as clinically important are reported, even if the results are statistically not significant. Graft-induced dyskinesias, haemorrhage, and infection were identified as clinically important adverse effects. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Parkinson's disease: fetal cell or stem cell-derived treatments.

Important outcomes	Disease severity, F-DOPA PET scan changes, Need for levodopa or other treatment, Quality of life
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of fetal cell or stem cell-derived therapy in people with Parkinson's disease?
2 (73)	Disease severity	Fetal cell therapy versus sham surgery	4	–1	0	–2	0	Very low	Quality point deducted for sparse data; directness points deducted for short follow-up in 1 RCT, use of subjective outcome in 1 RCT, procedures that may not be generalisable or reflect current practice (storage of tissue, length of time before transplant of tissue, immunosuppression)
2 (73)	Need for levodopa or other treatment	Fetal cell therapy versus sham surgery	4	–1	0	–2	0	Very low	Quality point deducted for sparse data; directness points deducted for short follow-up in 1 RCT, use of subjective outcome in 1 RCT, procedures that may not be generalisable or reflect current practice (storage of tissue, length of time before transplant of tissue, immunosuppression)
2 (73)	F-DOPA PET scan changes	Fetal cell therapy versus sham surgery	4	–1	0	–2	0	Very low	Quality point deducted for sparse data; directness points deducted for short follow-up in 1 RCT, use of subjective outcome in 1 RCT, procedures that may not be generalisable or reflect current practice (storage of tissue, length of time before transplant of tissue, immunosuppression)

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Motor fluctuations

Fluctuations in motor symptoms, such as bradykinesia, rigidity, and tremor, during a day. Motor fluctuations are sometimes called 'on/off' fluctuations.

Schwab and England Scale

Assessment of functional disability on a scale of 0% = vegetative to 100% = completely independent (able to do all chores without slowness, difficulty, or impairment).

Unified Parkinson's Disease Rating Scale (UPDRS)

A scale used to measure the severity of Parkinson's disease. A higher score denotes greater disability. It has six parts: mentation, behaviour, and mood (UPDRS 1); activities of daily living (UPDRS 2); motor examination (UPDRS 3); complications of treatment (UPDRS 4); a global disability staging score (UPDRS 5); and a global activities of daily living score (UPDRS 6).

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.