Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access.

BACKGROUND: Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD. METHODS: This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01560182. FINDINGS: At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64-7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3-42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6-12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9-82·3]) and early-juvenile MLD (42% [12·3-71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were related to conditioning or to background disease. The only adverse event related to arsa-cel was the transient development of anti-ARSA antibodies in four patients, which did not affect clinical outcomes. INTERPRETATION: Treatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy. FUNDING: Orchard Therapeutics, Fondazione Telethon, and GlaxoSmithKline.

Hippocampal dysfunction defines disease onset in Huntington's disease.

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterised by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of frontostriatal networks. However, emerging evidence from animal models of HD suggests that some of the early cognitive deficits may have a hippocampal basis. The objective of this study was to link previous rodent findings in this area to clinical practice. METHODS: In this study, 94 participants included patients with early HD, premanifest HD and age-matched controls underwent hippocampal-based cognitive assessments. These included a virtual reality version of the Morris water maze, a task involved participants having to swim through a virtual pool to find a submerged platform using a joystick, and the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning task, a test also known to rely on hippocampal integrity. RESULTS: Patients with early HD showed impaired performance in both the virtual Morris water maze and the CANTAB paired associates learning. Such deficits were also correlated with estimated years to diagnosis in premanifest participants. CONCLUSIONS: This study highlights the merit of using analogous tests in the laboratory and clinic and demonstrates that hippocampal impairments are an early feature of HD in patients as previously shown in rodent models of the disease. As such, they could be used not only to assist in the diagnosis of disease onset, but may also be useful as an outcome measure in future therapeutic trials.

Dopamine and Huntington's disease.

Huntington's disease (HD) is an incurable, inherited, progressive neurodegenerative disorder that is defined by a combination of motor, cognitive and psychiatric features. Pre-clinical and clinical studies have demonstrated an important role for the dopamine (DA) system in HD with dopaminergic dysfunction at the level of both DA release and DA receptors. It is, therefore, not surprising that the drug treatments most commonly used in HD are anti-dopaminergic agents. Their use is based primarily on the belief that the characteristic motor impairments are a result of overactivation of the central dopaminergic pathways. While this is a useful starting place, it is clear that the behavior of the central dopaminergic pathways is not fully understood in this condition and may change as a function of disease stage. In addition, how abnormalities in dopaminergic systems may underlie some of the non-motor features of HD has also been poorly investigated and this is especially important given the greater burden these place on the patients' and families' quality of life. In this review, we discuss what is known about central dopaminergic pathways in HD and how this informs us about the mechanisms of action of the dopaminergic therapies used to treat it. By doing so, we will highlight some of the paradoxes that exist and how solving them may reveal new insights for improved treatment of this currently incurable condition, including the possibility that such drugs may even have effects on disease progression and pathogenesis.

Effects of the KIBRA Single Nucleotide Polymorphism on Synaptic Plasticity and Memory: A Review of the Literature.

There has been a great deal of interest recently in genetic effects on neurocognitive performance in the healthy population. KIBRA -a postsynaptic protein from the WWC family of proteins- was identified in 2003 in the human brain and kidney and has recently been associated with memory performance and synaptic plasticity. Through genome-wide screening, a single nucleotide polymorphism (SNP) was detected in the ninth intron of KIBRA gene (T→ C substitution) and was implicated in human memory and the underlying neuronal circuitry. This review presents a synopsis of the current findings on the effects of the KIBRA SNP on human memory and synaptic plasticity. Overall the findings suggest impaired memory performance and less efficient or impaired hippocampal/medial temporal lobe (MTL) activation in CC homozygotes (in comparison to T carriers) with some differences between young and older subjects. This review also highlights limitations and potential sources for variability of studies' imaging findings along with future perspectives and implications for the role of KIBRA in memory-related brain systems.