Parkinson’s Disease

Introduction:

Parksinson’s diease (PD) is a progressive neurological disorder known for its characteristic motor symptoms, which include tremor, regidity, and slowness of movement. Among these, rest or resting tremor (RT) – a shaking that occurs when muslces are relaxed -is one of the most recognizable yet least understood. (“Parkinson’s symptomk resting remor, relates to dopamine in unexpected way” Noember 18, 2024.)

Pathology:

Alpha-Synuclein: has been identified as the major component of such inclusions and it is found in the brains of PD patients and patients wtih other degenerative disorders such as the LB variant of Alzheimer’s disease.

Dodel (US 2013/0052200) discloses naturally occurring autoantibodies that bind to alpha-Synuclien from human sera and commercial IgG preparations (IVIG).

Alpha-synuclein is a protein which builds up in PD pateints. (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” June 20, 2024). Aggregates of the brain protein alpha-synuclein (alpha-Syn) are generally considered to have a major role in the pathological development and progression of PD. Cao (US 10,653,759)

–Associated Proteins with Alpha-Synuclein:

Dawson and others have discovered that a cell surface marker, Aplp1, binds to Lag3 and drives PD. Interestingly, Aplp1 has been associated with the spread of alpha-synuclein throughout the brain once binding with Lag3. Aplp1 bound to Lag3 allows brain cells to accmulate clumps of alph-asynuclein, which resutls in cell death promoting PD symptoms. The binding of aplp1 and Lag3 suggests that by targeting this interaction, PD symptoms could be significanlty delayed. This discovery is exciting becasue Lag3 checkpoint inhibiotrs is alreay FEDA approved and could reasibly apply to PD pateints in cominbation with other treamtents. Researchers discvoered that mice lacking Aplp1 and Lag3 had 90% reduction of alpha-synuclein adsorption. Anti-Lag3 also prevented the adsorption of alpha-synuclein and significantly slowed PD symptoms. (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” Immunology, June 20, 2024)

Dopamine levels:

Parkinson’s Disease (PD) is a degenerative neurological condition linked to reduced dopamine levels in the brain, caused by degeneration and death of “dopaminergic” neurons. PD is the second most common neurodegenerative disorder globally as it affects about 1% of the population over 65 years old worldwide. It is clinically characterized by resting tremor, slowness of movement, muscular rigidity and impairment of postural reflexes. The progressive loss of dopaminergic neurons in the substantin migran and formation of fibrillar cytoplasmic inclusions term “Lewy bodies” and “Lewy neurites” are the nueropathological hallmarks of PD.

However, a new study from the Champalimaud Foundation, led by scientifists at the Nueral Circuits Dysfunction Lab in collaboration with the Neuropsychiatry and Nuclear Medicine Labs, indicated the preserved dopamine in certain brain regions may actually contribute to remor symptoms, challenging common beliefs. Paradoxically, they discovered that patietns who exhibit tremor have ore dopamine preserved in the caudate nucleus, a part of the brain important for movement planning and cognition. This challenges traditional udnerstanding of how dopamine loss related to PD symptoms and highlights the importance of looking beyond general classificaitons in PD and underscores the need for mroe nuanced approches informed by underlying biology, which culd ultimately hep to inform on therapeutic strategies. Dopamine loss in brain regions including the putamen, assocaited with movement regulation, is a well established hallmark of PD. Dopamine loss is also necessary for rest tremor to be present. However, while some patients experience significant tremor relief with dopamine replacement therpaies, such as L-DOPA, toehrs see little to no improvement, or even a worsening of symptoms. This suggests that the link between dopamine depletion and RT is more complex than a simple DA dose dependency model, the term noted. Resting remor (RT) is a Parkinson’s disease symptom with an unclear relationship to the dopaminergic system. By combining imaging data with measurements from these sensors, they observed a clear link between dopamine function in the caudate nucleus and global severity of resting tremor. The analysis suggested that the more dopamine activity preserved in the caudate, the stronger the tremor. An in more intriguing finding was that the more dopamine was preserved in the caudate on one side of the brain (each hemisphere has its own caudate), the more tremor there was on teh same side of the body. (usually, each side of the brain controls movement on the oppsite side of the body) The study also noted that not all dopamine cells are alike. They have different genetic maekups, connections and functions. This means that which cells a patient loses or keeps could affect theri symptoms. For example remor might be tied to the loss or preservation of specific dopamine populations that connect to certain brain areas. This variation in cell type loss could further expalin the wide range of symptoms among PD patietns. “Parkinson’s symptomk resting remor, relates to dopamine in unexpected way” Noember 18, 2024.)

Alpah-synuclein (alpha-Syn) and other misfoled proteins:

Parkinson’s Disease (PD) is a neurodegenerative disease casued by progressive accumulation of abnormal intracellular aggregates of alpha synuclein (alpha-Syn) protein existing as Lewy bodies, the pathological hallmark of the disease. Lewy bodies first appear in the olfactory bulb and medulla and gradually spread to midbrain, at which time, the first motor sign of PD appear. Concomitantly, inflammatory responses form resident microglia result in T-cell recruitment, setting off an exacerbating inflammatory cascade. ogether, these events lead to the progressive demise of nigrostriatal dopaminergi nuerons, resulting in the classical clinical signs of bradkykinesis, rest tremor and regidity. Symptomatic relief is provided by dopamine replacement, but the underlying disease process continues unabated. Cao (US Patent Application No: 2017/0196948, published as US 10,653,759)

Structurally, human alpha-Syn is an intrinsically disordered 140 amino acid long protein consisting of three distinct regions: an N-temrinal region (residues 1-60) which forms a helical structure and interats with the cellular membrane, a central highy aggregation-prone non-Abeta component region (residues 61-95) and a C terminal region (residues 96-140) that is highly enriched in acidic residues and prolines. Cao (US Patent Application No: 2017/0196948, published as US 10,653,759)

Preclinical evidence ahs suggested that other misfoled proteins including hyperphosphorylated tau, prior proteins, huntington, TAR DNA binding protein 43, and mutant superoxide dismutase 1 (SOD1) can also be targeted for immunotherapeutic strategies Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

Genetic Variants:

Although therapeutic modificaiton of several genetic targets has reached the clinical trail stage, a major obstacle in conducting these trials is that PD pateints are largely unaware of their genetic satus and, therefore, cannot be recruited. Expanding the number of investigated PD related genes and genes related to disorders with overlapping clinical features in large, well phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene targeted clinical trails. (Hanseen, “Relevance of genetic testing in the gene-targeted trails era: the Rostock Parkinson’s disease study” Brain 2024: 147; 2652-2667).

The genetic landscape of PD and related phenotypes is multifaceted. Even when considering only monogenic causes of classical PD, pathogenic variants in seven genes (LRRK2, PRKN, PINK1, SNCA, PARK7, VPS35 and CHCHD2) are implicated. Furthemore, heterozgous changes in GBA1 are a strong risk factor for PD. In addition, >30 other more complex monogenic movement disrders may present with atypical parkinsonism or may have parkinsonism as a prominent or even predominant clinical feature in at elast a subset of patients. (Hanseen, “Relevance of genetic testing in the gene-targeted trails era: the Rostock Parkinson’s disease study” Brain 2024: 147; 2652-2667)

The ROPAD study is an observational clinical study which assesssed the frequency and type of pathogenic variants in known PD related genes adn genes realted to other movement disorders or dementia in a multicentry, international setting. The study is registed at clinicaltrials.gov (NCT03866603) and is a collaboration between CENTOGENE GmbH (Rostock, Germany), the University of Lubeck and Denali Therapeutics (San Francisco, CA).

Treatment:

Treatments to manage Parkinson’s disease (PD) symptoms include medications that target depression, tremors, pain, and pysical movement. Most of the medications increase the levels of dopamine in the brain, which is a chemical that helps relay information from your brain to the rest of your body. However, new therapeies are being investiated to better control and slow down the progression of PD (Morreale, “Cancer Immunotherapy applied to Parkinson’s Disease” June 20, 2024).

Tehre are about 20 therapies on the market that address the syptoms of Parkinson’s diease. However, currently there are no dieasese modifying treatments becasue the underlying cause of the disease is still unclear. (McKenzi, “7 Alzheimer’s and Parkinson’s Programs Discarded in 2024” BioSpace, November 4, 2024).

Dopamine Receptor Stimulators:

–Rotigotin: is a dopamine receptor stimulator that has been used to treat Parkinson’s since the 1990s.

A rotigotine transdermal path is sold by UCB Manufacturing.

–Tavapadon (Cerevel Therapeutics aquired by Abbvie)is a partial agonist that activates dopamine D1/D5 receptors, which regulate motor activity. It is taken once daily and can be used as a monotherapy or in combination with other drugs.

–Vyalev (Abbvie) combines two drugs that help boost dopamine levels in the brain and keep symptoms under control for a full 24 hours. Instead of taking pills throughout the day, this treatment is delivered through a small pump that continuously injects the medication under the skin. This new treatment offers an alternative to oral medications, which can become less effective as Parkinson’s progresses. The most common side effects include skin reactions where the injection is given, involuntary movements (dyskinesia), and hallucinations (seeing or hearing things that aren’t there).

Antibodies:

–Anti-alpha-synuclein:

Cao (US Patent Application No: 15/313,810, published as US 10,653,759) discloses methods of protecting against dopaminergic neuron cell death which includes administering an anti-alpha-synuclein peptide to a subject in need thereof, where dopaminergic neurons are protected from cell death due to alpha-synuclein mediated neurodegeneration. In preferred dmeobdiments, the anti-alpha-synuclein peptide anitibody is specific for the N-temrinal region of the alpa-synuclein protein.

It has also been reported that anti-alpha-Syn mAbs directed against the C terminal of alpha-Syn enhanced the clearing of intracellular alpha-Syn aggregates. Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

Vaccines:

—-DC Vaccines:

Dendritic cell (DC) vaccination is a cell based therapy that elicits an immune response by using antigen-loaded DCs as the vehicle for immunization. DCs loaded with peptide directly interact with the immune system without eliciting generalized inflammation that typically occurs in adjuvant-containing vaccines. Moreover, peptide sensitized DC vaccines trigger a longer laster antigen-specific T cell response unlike the shorter respones to traditional vaccines. Cao (US Patent Application No: 15/313,810, published as US 10,653,759)

—-Against Alpha-Syn:

Antigen sensitved DCs have been used as vaccines for treating PD. For example, Cao (US Patent Application No: 15/313,810, published as US 10,653,759) discloses a DC vaccine against alpha-synuclein. In some embodiments, more than one antigen sensitized DC is utilized in the mixture of compositions. In certain embodiments DCs sensitived with full lengh rh-alpha-Syn or with peptide fragments from h-alpha-Sun are effective in triggering the generation of anti-alpha-Syn antibodies in a Tg alpha-Sun mouse model of synucleinopathy.