Regenerative Medicine: Advances from Developmental to Degenerative Diseases.

Chronic tissue and organ failure caused by an injury, disease, ageing or congenital defects represents some of the most complex therapeutic challenges and poses a significant financial healthcare burden. Regenerative medicine strategies aim to fulfil the unmet clinical need by restoring the normal tissue function either through stimulating the endogenous tissue repair or by using transplantation strategies to replace the missing or defective cells. Stem cells represent an essential pillar of regenerative medicine efforts as they provide a source of progenitors or differentiated cells for use in cell replacement therapies. Whilst significant leaps have been made in controlling the stem cell fates and differentiating them to cell types of interest, transitioning bespoke cellular products from an academic environment to off-the-shelf clinical treatments brings about a whole new set of challenges which encompass manufacturing, regulatory and funding issues. Notwithstanding the need to resolve such issues before cell replacement therapies can benefit global healthcare, mounting progress in the field has highlighted regenerative medicine as a realistic prospect for treating some of the previously incurable conditions.

The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms.

The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.

Urea cycle disorders: a life-threatening yet treatable cause of metabolic encephalopathy in adults.

Urea cycle disorders are inborn errors of metabolism that, in rare cases, can present for the first time in adulthood. We report a perplexing presentation in a woman 4 days postpartum of bizarre and out-of-character behaviour interspersed with periods of complete normality. Without any focal neurological signs or abnormality on initial investigations, the diagnosis became clear with the finding of a significantly elevated plasma ammonia level, just as she began to deteriorate rapidly. She improved following intravenous dextrose and lipid emulsion, together with sodium benzoate, arginine and a protein-restricted diet. She remains well 12 months later with no permanent sequelae. Whilst this is a rare presentation of an uncommon disease, it is a treatable disorder and its early diagnosis can prevent a fatal outcome.

Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons.

Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organelle transport and are therefore more sensitive to oxidative stress. To test whether these effects are present in neuronal cells, we first generated 11 induced pluripotent stem (iPS) cell lines from fibroblasts of three healthy controls and three HSP patients with different SPAST mutations. These cells were differentiated into FOXG1-positive forebrain neurons and then evaluated for multiple aspects of axonal transport and fragmentation. Patient neurons exhibited reduced levels of SPAST encoded spastin, as well as a range of axonal deficits, including reduced levels of stabilized microtubules, lower peroxisome transport speed as a consequence of reduced microtubule-dependent transport, reduced number of peroxisomes, and higher density of axon swellings. Patient axons fragmented significantly more than controls following hydrogen peroxide exposure, suggesting for the first time that the SPAST patient axons are more sensitive than controls to the deleterious effects of oxidative stress. Treatment of patient neurons with tubulin-binding drugs epothilone D and noscapine rescued axon peroxisome transport and protected them against axon fragmentation induced by oxidative stress, showing that SPAST patient axons are vulnerable to oxidative stress-induced degeneration as a consequence of reduced axonal transport.

Neural grafting for Parkinson's disease: challenges and prospects.

Parkinson's disease (PD) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra. The motor disorder responds well to dopamine-replacement therapies, though these result in significant adverse effects due to non-physiological release of dopamine in the striatum, and off-target effects. Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine, in a physiological manner. Dopaminergic neurons for cell-based therapies can be obtained from several sources. Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors, and has been transplanted into the striatum of PD patients with good results in a number of cases. However, the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting. Induced pluripotent stem cells can be used to generate dopaminergic neurons for transplantation, providing a source of autologous tissue for grafting. This approach means that challenges associated with allografts, such as the potential for immune rejection, can be circumvented. However, the associated cost and difficulty in producing a standardized product from different cell lines means that, at present, this approach is not commercially viable as a cell-based therapy. Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson's disease, with trials due to commence in the next few years. Though there are ethical considerations to take into account when using embryonic tissue, the possibility of producing a standardized, optimized cell product means that this approach can be both effective, and commercially viable.

An Update on the Hereditary Spastic Paraplegias: New Genes and New Disease Models.

AIMS: The hereditary spastic paraplegias (HSPs) are a heterogeneous group of disorders characterized by spasticity in the lower limbs. We provide an overview of HSP with an emphasis on recent developments. METHODS: A PubMed search using the term "hereditary spastic paraplegia" and "hereditary spastic paraparesis" was conducted for a period from January 2012 to January 2015. We discuss and critique the major studies in the field over this 36-month period. RESULTS: A total of 346 publications were identified, of which 47 were selected for review. We provide an update of the common forms of HSP and include patient videos. We also discuss how next-generation sequencing (NGS) has led to the accelerated discovery of new HSP genes, including B4GALNT1,DDHD1, C19orf12,GBA2,TECPR2,DDHD2, C12orf65,REEP2, and IBA57. Moreover, a single study alone identified 18 previously unknown putative HSP genes and created a model for the protein interactions of HSP, called the "HSPome." Many of the newly reported genes cause rare, complicated, autosomal recessive forms of HSP. NGS also has important clinical applications by facilitating the molecular diagnosis of HSP. Furthermore, common genetic forms of HSP have been studied using new disease models, such as neurons derived from induced pluripotent stem cells. These models have been used to elucidate important disease mechanisms and have served as platforms to screen for candidate drug compounds. CONCLUSION: The field of HSP research has been progressing at a rapid pace. The challenge remains in translating these advances into new targeted disease therapies.

Targeted next generation sequencing in SPAST-negative hereditary spastic paraplegia.

Molecular characterization is important for an accurate diagnosis in hereditary spastic paraplegia (HSP). Mutations in the gene SPAST (SPG4) are the most common cause of autosomal dominant forms. We performed targeted next generation sequencing (NGS) in a SPAST-negative HSP sample. Forty-four consecutive HSP patients were recruited from an adult neurogenetics clinic in Sydney, Australia. SPAST mutations were confirmed in 17 subjects, and therefore 27 SPAST-negative patients were entered into this study. Patients were screened according to mode of inheritance using a PCR-based library and NGS (Roche Junior 454 sequencing platform). The screening panel included ten autosomal dominant (AD) and nine autosomal recessive (AR) HSP-causing genes. A genetic cause for HSP was identified in 25.9 % (7/27) of patients, including 1/12 classified as AD and 6/15 as AR or sporadic inheritance. Several forms of HSP were identified, including one patient with SPG31, four with SPG7 (with one novel SPG7 mutation) and two with SPG5 (including two novel CYP7B1 frameshift mutations). Additional clinical features were noted, including optic atrophy and ataxia for patients with SPG5 and ataxia and a chronic progressive external ophthalmoplegia-like phenotype for SPG7. This protocol enabled the identification of a genetic cause in approximately 25 % of patients in whom one of the most common genetic forms of HSP (SPG4) was excluded. Targeted NGS may be a useful method to screen for mutations in multiple genes associated with HSP. More studies are warranted to determine the optimal approach to achieve a genetic diagnosis in this condition.