Neurodegenerative disease has a large collective burden, not only in terms of the impact of disease experienced by affected families, but also in socio-economic terms (El-Hayek et al., 2019; Jones et al., 2016; Yang et al., 2020). In comparison to other chronic medical disorders, there have been relatively few advances in the development of new therapeutic agents that can ameliorate disease symptoms or significantly slow disease progression to a beneficial degree, with particular reference to Huntington's disease (HD), Parkinson's Disease (PD) and Alzheimer's Disease (AD). The traditional approach of exploiting fundamental understanding of disease mechanisms to identify novel drug targets and subsequently develop pharmaceutical agents to exert a beneficial biological effect at that target have so far failed to yield any disease modifying agents. However, in recent years, there have been several advances in the development of novel, advanced therapeutics for the treatment of neurodegenerative disease, specifically in the HD and PD arenas. We are now at a point where several cell and gene therapies, which have shown promise for HD and PD in pre-clinical testing, are moving forward to in-person evaluation.

In this chapter we will explore aspects of clinical trial design and conduct which should be considered in the evaluation of advanced therapeutics in neurodegenerative disease. In light of the recent focus on Advanced Therapeutic Medicinal Products (ATMPs) for the treatment of HD and PD, the challenges associated with ATMP evaluation in these disorders (Barker, Cutting, & Daft, 2021; Rosser et al., 2022) will be the focus of the discussion. Challenges associated with the development of cell and gene therapies for HD and PD have been covered in other chapters in this volume but we include a brief summary potential ATMP strategies for these diseases here.

The gene mutation that causes HD is a polyglutamine repeat in exon one of the huntingtin gene. Repeats of more than 39 are pathogenic with symptoms first occurring in mid-life with progression of motor, cognitive and behaviors across 15–20 years (McColgan & Tabrizi, 2018). This is underpinned by the selective loss of medium spiny interneurons in the striatum, leading to an overall deterioration of the thalamic neuronal networks essential for normal brain function and global brain atrophy in the latter stages of disease.

One potential way of combatting the effects of this specific neuronal death is to replace the cells that are lost with cells that are free from the underlying genetic mutation. The theory is that a successful graft will allow transplanted stem cells to grow and differentiate into cells of the required identify and thus restore the synaptic connections required for effective network functioning. There have been a few small studies examining transplantation of fetal cells, successfully demonstrating safety, but with limited functional benefit, likely due to a range of delivery issues (Rosser & Bachoud-Lévi, 2012). Currently donor cell source is limited to fetal tissue, which introduces a number of constraints with obtaining sufficient tissue and limited window of time from tissue collection to target delivery in which the tissue must be processed and assessed for quality (Bachoud-Lévi et al., 2020; Bachoud-Levi, Massart, & Rosser, 2020). Consequently, there are several lines of investigation into the generation of stem cell technology to allow the production of pluripotent and progenitor stem cells for provision of a more reliable donor cell source.

In contrast to the premise of cell replacement therapy, gene therapies may also be implemented to combat disease progression in HD. It is thought that if the production of the mutant huntingtin (htt) protein, with its toxic gain of function, can be limited, then the cellular effects of the mutant htt may be mitigated, thus preventing neuronal dysfunction and cell death. One method of doing this is by blocking the translation of huntingtin mRNA into protein using RNA interference technologies. One such example of this is the use of Anti-sense oligonucleotides (ASOs) are short (16-22 base), single-strand RNA or DNA sequences complementary to the target mRNA sequence and are readily taken up into neurons, with dose dependent and reversible effects (Leavitt & Tabrizi, 2020). Their ability to interfere with mRNA transcription can be achieved via multiple mechanisms depending on the nature of the specific target (Quemener et al., 2020). Other strategies include the introduction of microRNAs, short RNA sequences that bind the non-coding regions of target genes, into the cell to prevent protein translation (Quinlan, Kenny, Medina, Engel, & Jimenez-Mateos, 2018). There has already been success in the use of ASOs is degenerative disorders with the success of the ASO Nusinersen in the treatment of spinal muscular atrophy (Finkel et al., 2017). Given that HD, like spinal muscular atrophy, is a single gene disorder, the use of RNA interference technology to prevent the production of the pathogenic protein is an attractive strategy for achieving disease modification, with initial phase 1 trials showing significant promise (Tabrizi et al., 2019).

The motor symptoms primarily associated with PD (tremor, dystonia, rigidity of movement) are caused by the loss of dopaminergic cells in the substantia nigra. Unlike the single genetic cause underlying the pathogenesis of HD, the etiology of PD is believed to be a combination of genetic and environmental risk factors (Jenner et al., 2013). These motor symptoms can be treated with various dopaminergic drugs which serve to restore some of the function lost as a result of the neuronal loss seen in PD, but the effects of these medications diminish with time and can be accompanied by significant unwanted effects (Borovac, 2016). Similarly to HD, it is thought the specific regional cell loss seen in PD can potentially be combatted through the introduction of donor cells unaffected by the disease to restore normal brain function. Trials of fetal cell transplantation have demonstrated safety but with variable effects on function (Freed et al., 1992, Freed et al., 2001; Lindvall et al., 1990; Olanow et al., 2003). Review of the fetal cell transplant trials suggests a series of design differences between these trials (Barker, Barrett, Mason, & Björklund, 2013) may account for the relative differences in function that were reported. These design aspects will be discussed in more detail in later sections of this chapter.

As with the use of fetal cells for transplantation in HD, the utility of fetal cells for transplantation in PD is limited by the availability of donated fetal tissue. The development of stem cell lines to provide a more reliable cell source for transplantation is more advanced in the PD field than in HD, to the point where the first trials of human embryonic stem cell derived cell products (NCT04802733) (Clinical Trials, 2022) and also induced pluripotent stem cell products (Takahashi, 2020; Takahashi & Price-Evans, 2019) have now entered clinical trials with further trials expected to start in 2022 (Kirkeby, Parmar, & Barker, 2017).

The lack of defined genetic cause and multiple etiologies associated with PD pathogenesis means that RNA interference strategies do not currently have a role to play in combatting disease progression. There are however other ways in which gene therapies can be used to treat PD. This includes both the delivery of biochemical elements to boost dopamine action, such as enzymes involved in dopamine synthesis or other factors involved in dopamine pathways and know to be down regulated in PD and the delivery of neurotrophic factors to stimulate the growth and repair of dopaminergic neurons in the substantia nigra (reviewed in (Axelsen & Woldbye, 2018; Blits & Petry, 2017)).