Gene therapy in Parkinson's disease

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Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.

Contents

Current treatments

Parkinson's disease (PD) is a progressive neurological disorder resulting from the death of cells in the substantia nigra that contain and produce dopamine. People with PD may develop disturbance in their motor activities. Some activities can be tremor or shaking, rigidity and slow movements (bradykinesia). Patients may eventually present certain psychiatric problems like depression and dementia. [1] Current pharmacological intervention consist on the administration of L-dopa, a dopamine precursor. The L-dopa therapy increases dopamine production of the remaining nigral neurons. [2] Other therapy is the deep brain electrical stimulation to modulate the overactivity of the subthalamic nucleus to the loss of dopamine signaling in the stratum. [3] However, with this treatment, the number of substantia nigra neurons decrease so it becomes less efficient. [2]

These treatments try to reduce the symptoms of the patient focusing on increasing the production of dopamine but they do not cure the disease. The new treatments for PD are in clinical trials and most of them are centered on gene therapy. With this, researchers expect to compensate the loss of dopamine or to protect the dopamine neurons from degeneration. [2] The pharmacological and surgical therapies for PD focus on compensating the ganglia dysfunction caused by the degeneration of the dopaminergic neuron from substantia nigra. [3]

Gene therapy background

There are many new PD treatments in clinical trials and several of those are focusing on gene therapeutic approaches that compensate the loss of dopamine or protect the nervous system dopamine neurons from degeneration. There are some important reasons for focusing on gene therapy as a treatment for PD. First of all, currently there is no cure for this disease. Secondly, some genes have been identified which can modulate the neuron phenotype or act as neuroprotective agents. Also, the environment of the brain cannot afford repeated injections into the region where the substantia nigra meets the striatum, the nigrostriatum. Therefore, gene therapy could be a single treatment appealing, viral vectors used in the therapy are diffusible and capable to do transduction of the striatum. [2]

Gene therapy bases

The main idea of the gene therapy is to create new generations of cells that produce particular neurotransmitter (dopamine) and then transplant these cells to the patients with PD. [4] This is because the neurons cannot proliferate nor be renewed; and replacing lost neurons it is a process that is currently going under investigation. Also, the use of embryonic dopaminergic cells cannot be used because these cells are difficult to obtain [4] and modifications of cell can only be made on somatic cells, not germline. [3] With the modifications of the transplanted cell, there can be a change in the expression of the genes or normalize them. [3]

Types of gene therapy

There are several types of gene therapy. There are therapies for symptomatic approaches like the production of ectopic L-dopa, the full ectopic dopamine synthesis, the ectopic L-dopa conversion or the use of glutamic acid descarboxylase (GAD). Also there are disease modifying therapies like NTN or GNDF (glial cell line-derived neurotrophic factor), the regulation of the α-synuclein and Parkin gene expression. Currently the main studies are using AAV2 as a vector platform, making it the standard vector for this disease although a lentevirus has also been used. [5] In the different types of the gene therapy, the investigations are encoding enzymes that are necessary for dopamine synthesis, such as tyrosine hydroxylase, GTP cyclohydrolase 1 and AADC. [6]

Symptomatic approaches

A symptomatic approach is a treatment focused on the symptoms of the patients. The first one, consists in the ectopic dopamine synthesis. Here, the production of ectopic L-dopa in the striatum is another alternative gene therapy. This therapy consists on transferring the TH and GTP cyclohydrolase 1 genes into the MSNs because the endogenous AADC activity is able to convert the L-dopa into dopamine. [3] In an experiment in 2005, using tyrosine hydroxylase (TH) and GCH1 altogether with vectors, they could provide normal levels of L-dopa to rats. The results of this experiment showed reduced dyskinesias by 85% as well as, the reversion view of abnormal projections in the striatum using the TH-GCH1 gene transfer. [7]

Dopamine synthesis can be fully ectopic. In this case, the enzyme AADC it is in charge of converting the levodopa to dopamine. In Parkinson disease, the loss of neurons from the nigrostriatum leads to the inability to convert levodopa to dopamine. The goal of AAV2-hAADC is to restore normal levels of AADC in the striatum so there could be more conversion of levodopa, and therefore reducing levodopa- induced dyskinesia. [6] Using the gene therapy, in 2012, an experiment was accomplish with primates testing tyrosine hydroxylase (TH) transgene in primate astrocytes. Gene therapy was made with the transfer of a TH full-length cDNA using rat TH. The results showed behavioural improvement in the monkeys that received the plasmid, unlike the control monkey. [8]

Another type is the ectopic L-dopa conversion in which they use a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN (medium spiny neurons) in the striatum to be able to convert administered L-dopa into dopamine. [3]

Other kind of gene therapy as a symptomatic approach is the use of glutamic acid decarboxylase (GAD) expression in the subthalamic nucleus. This is a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN in the striatum to be able to convert administered L-dopa into dopamine. [3] A phase 2 study, published in the journal Lancet Neurology Parkinson, says that a gene therapy called NLX-P101 dramatically reduces movement damage. In this study, they used glutamic acid decarboxylase (GAD). They introduced genetic material in the brain related to motor functions. The symptoms included tremor, stiffness and difficulty in movements; and were improved in half of the group in gene therapy, while in the control group, 14% improved them. [9]

Disease modifying

There are therapies in development based in the modification of the disease. The first one is the neurotrophic factors gene delivery. In this therapy, GNDF or NTN are used to protect the system. GNDF is a factor of the TGFß superfamily, is secreted by astrocytes (glia cells that are in charge of the survival of the midbrain dopaminergic neurons) and is homologous to NTN, persephin and artemin. Preclinical studies of the nigrostriatal dopaminergic in relation to Parkinson disease system have shown that GNDF and NTN are very potential neuroprotective agents. [6] Another type in the disease's modification technique is the synuclein silencing. Some cases of PD were related to polymorphisms in the α-synuclein promoter and also in the multiplication of the locus that carries the α-synuclein gene. Therefore, trying to down-regulate the α-synuclein expression could impact the development of the disease. There have been explored several viral vector-based gene delivery system that interfere with α- synuclein expression, and they depend on the interference of the RNA (destabilizing the α-synuclein RNAm) and/or the block the protein translation (using short hairpin RNA or micro RNA directed against the α-synuclein RNAm sequence). [3]

The discovery of the Parkin gene is another type of modification of PD. The Parkin gene is linked with mutations associated with autosomal recessive juvenile parkinsonism (previous state of Parkinson with the typical symptoms and pathology but with a slow progression). The mutations in the Parkin gene are responsible for the development of the autosomal recessive juvenile parkinsonism. [10]

New projects and investigations

More gene therapy trials have been conducted for PD (with the adeno-associated virus 2 gene), the objectives and strategies used on the actual researches are clear, the research tries to translate the experience obtained during the trials and try to improve the development of new technology for the gene therapy of PD. [6]

Related Research Articles

<span class="mw-page-title-main">Substantia nigra</span> Structure in the basal ganglia of the brain

The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. Substantia nigra is Latin for "black substance", reflecting the fact that parts of the substantia nigra appear darker than neighboring areas due to high levels of neuromelanin in dopaminergic neurons. Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta.

<span class="mw-page-title-main">Dopamine</span> Organic chemical that functions both as a hormone and a neurotransmitter

Dopamine is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% of the catecholamine content in the brain. It is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical, L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most animals. In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons to send signals to other nerve cells. Neurotransmitters are synthesized in specific regions of the brain, but affect many regions systemically. The brain includes several distinct dopamine pathways, one of which plays a major role in the motivational component of reward-motivated behavior. The anticipation of most types of rewards increases the level of dopamine in the brain, and many addictive drugs increase dopamine release or block its reuptake into neurons following release. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

<span class="mw-page-title-main">Nigrostriatal pathway</span> Bilateral pathway in the brain

The nigrostriatal pathway is a bilateral dopaminergic pathway in the brain that connects the substantia nigra pars compacta (SNc) in the midbrain with the dorsal striatum in the forebrain. It is one of the four major dopamine pathways in the brain, and is critical in the production of movement as part of a system called the basal ganglia motor loop. Dopaminergic neurons of this pathway release dopamine from axon terminals that synapse onto GABAergic medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), located in the striatum.

<small>L</small>-DOPA Chemical compound

l-DOPA, also known as levodopa and l-3,4-dihydroxyphenylalanine, is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize l-DOPA, make it via biosynthesis from the amino acid l-tyrosine. l-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, l-DOPA itself mediates neurotrophic factor release by the brain and CNS. In some plant families, l-DOPA is the central precursor of a biosynthetic pathway that produces a class of pigments called betalains. l-DOPA can be manufactured and in its pure form is sold as a psychoactive drug with the INN levodopa; trade names include Sinemet, Pharmacopa, Atamet, and Stalevo. As a drug, it is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

Aromatic <small>L</small>-amino acid decarboxylase Class of enzymes

Aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase (DDC), tryptophan decarboxylase, and 5-hydroxytryptophan decarboxylase, is a lyase enzyme, located in region 7p12.2-p12.1.

<span class="mw-page-title-main">Carbidopa</span> Chemical compound

Carbidopa (Lodosyn) is a drug given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levodopa to cross the blood–brain barrier for central nervous system effect, instead of being peripherally metabolised into substances unable to cross said barrier.

The pars compacta (SNpc) is one of two subdivisions of the substantia nigra of the midbrain ; it is situated medial to the pars reticulata. It is formed by dopaminergic neurons. It projects to the striatum and portions of the cerebral cortex. It is functionally involved in fine motor control.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

MPP<sup>+</sup> Chemical compound

MPP+ (1-methyl-4-phenylpyridinium) is a positively charged organic molecule with the chemical formula C12H12N+. It is a neurotoxin that acts by interfering with oxidative phosphorylation in mitochondria by inhibiting complex I, leading to the depletion of ATP and eventual cell death.

<span class="mw-page-title-main">VPS35</span> Protein-coding gene in the species Homo sapiens

Vacuolar protein sorting ortholog 35 (VPS35) is a protein involved in autophagy and is implicated in neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). VPS35 is part of a complex called the retromer, which is responsible for transporting select cargo proteins between vesicular structures and the Golgi apparatus. Mutations in the VPS35 gene (VPS35) cause aberrant autophagy, where cargo proteins fail to be transported and dysfunctional or unnecessary proteins fail to be degraded. There are numerous pathways affected by altered VPS35 levels and activity, which have clinical significance in neurodegeneration. There is therapeutic relevance for VPS35, as interventions aimed at correcting VPS35 function are in speculation.

<span class="mw-page-title-main">Dopamine dysregulation syndrome</span> Medical condition

Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dopamine agonist medications for an extended period of time. It is characterized by problems such as addiction to medication, gambling, or sexual behavior.

<span class="mw-page-title-main">Parkinson's disease</span> Long-term neurodegenerative disease

Parkinson's disease (PD), or simply Parkinson's, is a long-term neurodegenerative disease of mainly the central nervous system that affects both the motor system and non-motor systems. The symptoms usually emerge slowly, and as the disease progresses, non-motor symptoms become more common. Usual symptoms are tremor, slowness of movement, rigidity, and difficulty with balance, collectively known as parkinsonism. Parkinson's disease dementia, falls and neuropsychiatric problems such as sleep abnormalities, psychosis, mood swings, or behavioral changes may arise in advanced stages.

Levodopa-induced dyskinesia (LID) is a form of dyskinesia associated with levodopa (l-DOPA), used to treat Parkinson's disease. It often involves hyperkinetic movements, including chorea, dystonia, and athetosis.

Parkinson's disease is the 2nd most prevalent neurological disorder within the United States and Europe, affecting around 1% of the population over the age of 60. While the link connecting the onset of Parkinson's disease to environmental factors is known, the link between dietary patterns and the disease is just beginning to be researched more fully. Additionally, other research has sought to examine the symptoms of the disease and propose methods on how to alleviate these symptoms through changes in diet. Current medications that work to alleviate the symptoms of Parkinson's disease can also be made more effective through changes in diet.

3-<i>O</i>-Methyldopa Chemical compound

3-O-Methyldopa (3-OMD) is one of the most important metabolites of L-DOPA, a drug used in the treatment of the Parkinson's disease.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

<span class="mw-page-title-main">Animal models of Parkinson's disease</span> Models used in Parkinsons disease research

Animal models of Parkinson's disease are essential in the research field and widely used to study Parkinson's disease. Parkinson's disease is a neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of the dopamine neurons in the brain, results in motor dysfunction, ultimately causing the four cardinal symptoms of PD: tremor, rigidity, postural instability, and bradykinesia. It is the second most prevalent neurodegenerative disease, following Alzheimer's disease. It is estimated that nearly one million people could be living with PD in the United States.

<span class="mw-page-title-main">Anders Björklund</span> Swedish histologist (born 1945)

Anders Björklund' is a Swedish neuroscientist and pioneer in the study of cell- and gene-based reparative and neuroprotective mechanisms in the brain. He has spent his academic career at Lund University in Sweden, as professor since 1983 and as senior professor at the Wallenberg Neuroscience Center since his formal retirement in 2012.

<span class="mw-page-title-main">Parkinson's disease in South Asians</span>

Epidemiological studies have shown lower age-related prevalence of Parkinson's disease in South Asians, with the rate of prevalence being around 52.7 per 100,000 as compared to a higher prevalence rate observed in populations with European origin, 108-257 per 100,000. Additionally, several studies have seen a higher prevalence of in women which contrasts with global data that observes a overall higher prevalence seen in men. Compared to most of the rest of the world, the South Asian countries seem to be on the lower end of PD prevalence. However, this is not to say that PD is not of concern in these countries. Over the past couple of years, the rate of Parkinson's has gone up in South Asia meaning that it is of high importance to study this pathological disease in these populations.

Parkinson's disease (PD), the second most common neurodegenerative disease after Alzheimer's disease, affects 1% of people over 60 years of age. In the past three decades, the number of PD cases has doubled globally from 2.5 million in 1990 to 6.1 million in 2016. As of 2022, there are ~10 million PD cases globally. In the United States, the estimated prevalence of PD by 2030 is estimated will be ~1.24 million. These numbers are expected to increase as life expectancy and the age of the general population increase. PD is considered to be a multisystem and multifactorial disease, where many factors, such as the environment, gut, lifestyle and genetics, play a significant role in the onset and progression of the disease.

References

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  5. ↑ Palfi, S. P.; Gurruchaga, J. M.; Ralph, G. S.; Lepetit, H.; Lavisse, S.; Buttery, P. C.; Watts, C.; Miskin, J.; Kelleher, M.; Deeley, S.; Iwamuro, H.; Lefaucheur, J. P.; Thiriez, C.; Fenelon, G.; Lucas, C.; Brugières, P.; Gabriel, I.; Abhay, K.; Drouot, X.; Tani, N.; Kas, A.; Ghaleh, B.; Le Corvoisier, P.; Dolphin, P.; Breen, D. P.; Mason, S.; Guzman, N. V.; Mazarakis, N. D.; Radcliffe, P. A.; Harrop, R. (2014). "Long-term safety and tolerability of Pro Savin, a lentiviral vector-based gene therapy for Parkinson's disease: A dose escalation, open-label, phase 1/2 trial". The Lancet. 383 (9923): 1138–1146. doi:10.1016/S0140-6736(13)61939-X. PMID   24412048. S2CID   4993549.
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  8. ↑ Campos-Romo, Aurelio; Ojeda-Flores, Rafael; Moreno-Briseño, Pablo; et al. (2012). "Behavioral improvement in MPtP-treated nonhuman primates in the HALLWAY task after transfer of tH cdnA to host astrocytes" (PDF). Acta Neurobiol. Exp. 72 (2): 166–176. doi:10.55782/ane-2012-1889. PMID   22810218. Archived from the original (PDF) on 23 September 2015. Retrieved 15 April 2013.
  9. ↑ "Gene Therapy Reverses Symptoms of Parkinson's Disease". Science Daily. Retrieved 12 April 2013.
  10. ↑ Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature. 392 (6676): 605–8. Bibcode:1998Natur.392..605K. doi:10.1038/33416. PMID   9560156. S2CID   4432261.
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