The gene therapy era can be said to have begun in 1990, when the first gene therapy clinical trial took place. Some 3,000 clinical trials have followed that first study, a resounding affirmation of innovators’ increasing recognition of gene therapy’s breakthrough possibilities for treating a diverse range of disorders — especially afflictions with limited or no established treatments.

Patients with Parkinson’s disease (PD) are among the potential beneficiaries of gene therapy. Although there are currently numerous available treatments for PD, these merely target symptomatic relief, leaving disease onset or progression largely unmet and sometimes producing significant adverse effects. Those limitations underscore the need for novel therapeutic approaches.

Compared to conventional pharmacological and surgical approaches to treating PD, gene therapy has several potential advantages including preservation or restoration of dopaminergic neurons; addressing underlying pathophysiological imbalances, possibly resulting in less fluctuation in response and reduced risk of dyskinesias.

In vivo gene therapy — the direct, vector-delivered, intra-cerebral injection of genetic material — appears to hold great promise in PD. Its success depends on efficient uptake of the therapeutic gene by the target cells and on the gene’s expression capability. Viral vector-based in vivo gene therapy is less invasive than transplantation techniques, leaving the striatal circuitry undisturbed by cellular implants.

Challenges inherent in the promise of gene therapy

For all its promise, gene therapy for PD has several potential limitations, including:

  • Short-lived therapeutic effect, possibly requiring several rounds of therapy
  • Immune response, potentially reducing treatment effectiveness
  • Viral vector-associated toxicity, inflammatory responses, gene control (i.e., controlled turning on and off of gene expression), and off-target effects
  • Insertional mutagenesis, resulting from misplaced DNA integration, such as within a tumour suppressor gene.

The gene therapy regulatory environment

Gene therapy developers must navigate a continually evolving regulatory environment. In the United States, the National Institutes of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules define recombinant and synthetic nucleic acids, and include further guidelines for human gene transfer. Gene therapies are regulated under the Food and Drug Administration’s (FDA) Coordinated Framework for Regulation of Biotechnology. In recent years the FDA has issued several guidance documents to support the development of gene therapy, some of which are particularly relevant for PD.

Whereas the European Medicines Agency classifies gene therapy products as Advanced Therapeutic Medicinal Products (ATMPs), the European Union (EU) Directive 2001/83/EC articulates two conditions for ATMPs, both of which must be fulfilled simultaneously:

  • The product must be of biological origin and contain recombinant nucleic acid(s)
  • The recombinant nucleic acid(s) must be directly involved in the mechanism.

Gene therapy products can also be defined per directive 2001/18/EC as a genetically modified organism (GMO) or micro-organism (GMM). The assessment of risk of such GMOs is split into two major categorizations that dictate the respective directive that should be followed.

The route taken depends on the product and country in which the clinical trial is taking place. Generally:

  • Contained use (Directive 2009/41/EC), which covers activities “for which specific containment measures are used to limit their contact with, and to provide a high level of safety for, the general population and the environment”
  • Deliberate release (Directive 2001/18/EC), covering “any intentional introduction into the environment … for which no specific containment measures are used”.

In general, the EU and US guidance for gene therapy clinical trials are very similar, with a few exceptions. In the US, when human gene transfer occurs, the study protocol must be submitted to an institutional biosafety committee (IBC); most IBCs are local, though some sites use a central IBC. In the EU, gene therapy clinical trials that fall under the GMO/GMM definition must be submitted to additional country- or site-level GMO authorities or committee(s) and require a specific GMO dossier that necessitates careful preparation to enable a timely review process.

Study design considerations

As is typical in clinical development, most gene therapy clinical programmes start with open-label cohort studies to establish the appropriate dose before proceeding to proof of concept (POC). Given that many gene therapy studies are conducted in rare disease populations, often involving paediatric patients, historical controls and natural history studies are frequently used as dose comparators. In PD programmes, however, the FDA has been known to request placebo-controlled POC studies due to research demonstrating the magnitude of the placebo effect specifically in PD and in surgical studies, and to reduce the current trend of failed sham-controlled studies following successful open-label studies.

European regulators, in contrast, do not always follow this approach, citing concerns about the patient risk/benefit ratio due to increased patient burden, increased risk of sham neurosurgery, and ensuring that patients understand that surgery may not imply gene therapy.

There is no definitive answer to the question of whether placebo control is required for a POC study in PD. Early engagement with US and EU regulators is therefore critical to avoid delays in securing final protocol approval.Investigational medicinal product availability

Due to the limited number of vector manufacturing facilities and open slots, biotech companies are increasingly building their own facilities rather than depending on vendors. But regardless of where manufacturing occurs, vector availability is key.

That makes it important to consider the full chain of the vector from manufacturing, to transport and storage, to receipt, storage, preparation, and administration at the trial site, as well as return or destruction processes as necessary. Sites must also have their own standard operating procedures for GMO handling.

PD trial sponsors should therefore consider an investigational medicinal product’s commercialisation potential early in development planning, as a well-designed clinical trial can enable translation of vector manufacturing, transport, and site processes to commercial processes without the need for additional studies.Additional PD trial considerations

In addition to the above, sponsors need to consider the following factors when planning gene therapy trials in PD:

  • Surgical considerations: Many gene therapies involve vector administration directly into the central nervous system, making site and neurosurgeon identification critical. The neurosurgeon must have demonstrated capability to perform the procedure and the site must have all the requisite imaging equipment, such as MRI, for guidance during the procedure. A comprehensive surgical manual can facilitate adherence to best practices
  • Device considerations: Any device used for vector administration must be approved for its intended use in all countries and areas where the trial takes place and any country where commercialisation is planned. Any changes to a device, including customisations, may require new approvals, underscoring the importance of early discussions with regulators
  • Patient considerations: Patients and advocacy groups need to be involved early in clinical planning and protocol design, as they can provide valuable support in identifying relevant endpoints, reducing the patient burden, and ensuring the availability of appropriately worded participant materials. Advocacy groups can also help recruit participants for PD trials, which often require treatment-naïve or newly diagnosed patients.

Long-term follow-up

Figure 1 outlines the interplay of long-term strategic, protocol, patient, and data quality considerations for gene therapy trials, which may require up to 15 years of follow-up. The key is to strike a balance between collecting long-term safety and efficacy data relevant for regulators and payers and reducing participants’ on-site burden and maximising patient retention.

A basket study — a long-term study involving patients from more than one protocol requiring the same type of follow-up — can help reduce the financial and logistical burden of a gene therapy clinical programme. However, a basket study may require other types of approval and safety follow-up as the therapy progresses to commercialisation.Future directions

As a potential treatment modality for PD, gene therapy is highly promising and constantly evolving, with numerous approaches for both disease-modifying and non-disease-modifying therapies. However, after numerous reports of clinical improvement in animal and Phase I studies, most double-blind Phase II studies thus far have been negative, raising some important questions:

  • Do animal models adequately mirror the pathophysiology of PD in humans?
  • Is there a potentially relevant placebo effect in open-label Phase 1 studies that does not appear in double-blind Phase 2 studies?
  • Has the ideal injection site been identified? Is it the substantia nigra, the striatum, or the subthalamic region?
  • How to address uncertainties in dose selection?

Continued advancement of newer therapeutic techniques such as optogenetics, chemogenetics, and genome-editing technology may yield answers to some of these questions in the next few years. In the meantime, early engagement with regulators, patient advocates, and even payers can keep a clinical programme moving forward. This requires considerable upfront planning, though timeline pressures and patient needs may complicate even the most well-intentioned plans. Nevertheless, given the urgency of those needs, the promise of gene therapy for PD must be explored fully and expeditiously.