Amyotrophic Lateral Sclerosis ALS Jessica Lloyd Claire Seabrook

Amyotrophic Lateral Sclerosis (ALS) Jessica Lloyd & Claire Seabrook

WHAT IS ALS? ● Discovered in 1869 by French Neurologist, Jean-Martin Charcot. ● Amyotrophic Lateral Sclerosis is a progressive neurodegenerative disease that causes the death of neurons controlling voluntary muscles by affecting nerve cells in the brain and the spinal cord. ○ People may lose the ability to speak, eat, move and breathe. ○ Life expectancy is between 2 -5 years and there is no cure. ● There are two types of ALS: ○ Familial: 5 -10% of all cases in the US. ■ Inherited disease, where there is a 50% chance each offspring will inherit the gene mutation and may develop the disease. ○ Sporadic: 90 -95% of all cases in the US.

ALS FACTS ● ● ALS usually strikes people between the ages of 40 and 70, with the average of diagnosis being 55. For unknown reasons, military veterans are approximately twice as likely to be diagnosed with the disease as the general public. Football players are four times as likely to be diagnosed with the disease as the general public. This is likely due to the high incidence of concussions. A few notable individuals who have been diagnosed with ALS include: ○ Baseball Players: Lou Gehrig, Jim “Catfish” Hunter, and Pete Frates ○ Theoretical physicist, cosmologist and author: Stephen Hawking

ALS FACTS ● ● More than 5, 000 people are diagnosed with ALS each year. There are only 4 drugs on the market approved to manage symptoms and slow the progression of ALS (Riluzole, Nuedexta, Radicava, and Tiglutik), but there is still no cure. $250, 000 is the estimated out-of-pocket cost for caring for a patient with ALS. It can take months to years to diagnose ALS, which is very significant as the average life expectancy is only 2 -5 years, with only half of all patients diagnosed living up to 5 years; 20% of patients surviving more than 5 years; and 10% of patients surviving for more than 10 years. ○ This fact severely impacts research studies as often patients lose their battle before being able to fully participate in much needed studies. ○ Such a differential rate of disease progression makes prognosis difficult to predict and treatments challenging to develop. http: //www. alsa. org/news/public-awareness/als-awareness-month/2016/what-is-als. html

ALS FACTS ● ● ALS shares some clinical characteristics with other neurodegenerative disease, like ALzheimer’s and Parkinson’s. ○ ALS presents with insidious rather than acute onset of neurologic dysfunction like that of Alzheimer’s and Parkinson’s. ○ ALS remains a clinical diagnosis with no definitive imaging or blood/cerebrospinal fluid biomarkers. Neurologic Deficits: Disease Concentration of Neurological Deficits Alzheimer’s Cognitive and behavioral Parkinson’s Slowed movement and tremor ALS Weakness of voluntary skeletal muscles

Incidence and Prevalence Rate ● ALS occurs in higher percentages as men and women grow older. ● Men are 20% more likely to develop ALS than women. ● The ALS Association suggests that the incidence rate of ALS to be 1. 8 to 2 per 100, 000 people. ○ ● 5, 760 to 6, 400 new diagnoses per year. The incidence of ALS increases with age, usually starting in the 40 s and continuing until the age of around 80 years. However, this does not cross out the probability of young people in their early 20 s and 30 s to get affected with ALS. ● ALS affects people from all races and ethnicities. ● According to the global estimates, there around 4 -6 people per 100, 000 living with ALS at any given point in time. ● Around 93% of the ALS patients in the U. S. are Caucasian and 60 % are men.

Incidence and Prevalence Rate ● The incidence or number of new cases per year is increasing, with an estimated 2 new ALS cases each year within a population of 100, 000 people. ● It is important to note that Physicians have also identified reports that reflect increasing numbers of younger ALS patients, however these studies require further investigation. https: //alstreatment. com/amyotrophic-lateral-sclerosis-incidence/

Etiology ● ALS affects the nerve cells that control voluntary muscle movements such as walking and talking (motor neurons). ● ALS causes the motor neurons to gradually deteriorate, and then die. ○ Motor neurons extend from the brain to the spinal cord to muscles throughout the body. ○ When motor neurons are damaged, they stop sending messages to the muscles, so the muscles can't function. ● ALS often begins with muscle twitching and weakness in a limb, or slurred speech. Eventually, ALS affects control of the muscles needed to move, speak, eat and breathe. There is no cure for this fatal disease.

Etiology https: //youtu. be/xr. Ij. FVMli. OQ

The Ice Bucket Challenge ● ● The Ice Bucket Challenge raised more than $115 million for the ALS Association: ○ $84 million of the funds were designated to research. ○ 200+ research projects have been started as a result of the money raised. ○ 5 new genes were found as a result of the money raised for research that will help spark new therapies. ○ $23 million, or 20%, were given to patient and community services. More than 17 million people participated in the challenge worldwide. ○ In the U. S. , there were 2. 5 million participants. http: //www. alsa. org/fight-als/edau/ibc-progress-infographic. html

The Ice Bucket Challenge https: //www. youtube. com/watch? v=Sm. NV 9 N 13 L 5 E&feature=youtu. be

Treatments ● Only four drugs are currently FDA-approved to treat ALS: Riluzole, Tiglutik, Nuedexta, and Radicava. ● The estimated cost to develop a drug to slow or stop the progression of ALS from an idea to an approved drug is between $2 billion and $3 billion. ● There is some evidence that people with ALS are living longer, at least partially due to clinical management interventions and possibly other compounds and drugs under investigation. ● Physical and Occupational Therapies are extremely important in the lives of ALS patients as it may allow for prolonged abilities to complete independent activities of daily living. https: //zahsi. com/wp-content/uploads/2017/09/Amyotrophic-Lateral-Sclerosis-ALS. png

Treatments: Riluzole ● ● ● Riluzole was the first treatment approved by the U. S. FDA to treat ALS in 1995. The exact mechanism by which Riluzole treats ALS is unknown, but it is thought to block the release of glutamate from nerve cells. This may reduce the rate of glutamate-induced deterioration in nerve cells, slowing the progression of symptoms. Riluzole delays the need for a tracheostomy and may increase survival rates by two to three months Yale University is reformulating Riluzole to be used as a generalized anxiety and mood disorder treatment

Treatments: Tiglutik ● ● ● ● TIGLUTIK (Riluzole) is a neuroprotective agent indicated for the treatment of amyotrophic lateral sclerosis (ALS). Approved by the US Food and Drug Administration (FDA) in September 2018 as an easy-to-swallow thickened riluzole formulation for the treatment of ALS. Expected to help patients with swallowing difficulties. Drug became commercially available in the US in October, 2018. Riluzole contained in TIGLUTIK™ is a glutamate antagonist that inhibits postsynaptic glutamate receptor signalling and reduces the release of glutamate, which is the most prominent neurotransmitter in the vertebrate nervous system. Glutamate reduction slows down disease progression and prevents damage to nerves. The drug is available as a 5 mg/ml oral suspension to be administered twice-daily using a syringe. https: //www. clinicaltrialsarena. com/projects/tiglutik-riluzole-treatment-amyotrophic-lateral-sclerosis/

Treatments: Nuedexta ● Nuedexta is approved to treat pseudobulbar affect, difficulty with emotional control, including inappropriate laughing and crying, which impacts some people with ALS. ○ PBA (Pseudo. Bulbar Affect) causes sudden, frequent, uncontrollable episodes of crying and/or laughing that are exaggerated and/or don’t match how you feel. PBA is a separate neurologic condition that can happen as a result of certain neurologic conditions or brain injury. ● Nuedexta contains a combination of two drugs, which include dextromethorphan hydrobromide and quinidine sulphate. ● The exact mechanism of action of the drug is not known completely but it is believed to work by regulating excitatory neurotransmissions through the sigma-1 receptor agonist activity and NMDA receptor antagonist activity. The drug also slows the breakdown of dextromethorphan in the brain. https: //www. clinicaltrialsarena. com/projects/nuedexta-treatment-pseudobulbar-affect-pba/

Treatments: Radicava ● ● ● RADICAVA (Edaravone) is an intravenous drug used in Japan for stroke patients Approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of amyotrophic lateral sclerosis (ALS) after initial trials in Japan At initial launch, the drug cost $145, 000 USD per dose Mechanism by which Radicava is effective in ALS is unknown Radicava is an antioxidant. This is important to note as it is believed that oxidative stress is what causes neurons to be killed in people with ALS Three early trials have shown that Radicava may work in less than 5% of all ALS population https: //www. clinicaltrialsarena. com/projects/radicava-edaravone-for-the-treatment-of-amyotrophic-lateral-sclerosis-als/

ALS CLINICAL TRIALS https: //www. youtube. com/watch? v=ar. Dpe. Om 2 s_4 Minute 7: 10 - 13: 30

ALS CLINICAL TRIALS ● ● ● ALS Therapy Development Institute in Cambridge, MA has a staff of more than 30 scientists focusing on research and development Raised and spent over $100 million on research into effective treatments This clinical trial had thousands of applicants but only 16 participants Nur. Own is the clinical trial using mesenchymal stem cells injected into the spinal canal to develop cells that promote the growth of nervous tissue It has slowed down the progression of the disease in 92% of the patients that received the full treatment

Summary ALS is a progressive neurodegenerative disease. Symptoms include loss of voluntary muscle control. The average at diagnosis is 55 years. The average life expectancy is 2 -5 years. There are only 4 drugs on the market currently to treat ALS. There is no cure for this disease. Research studies and trials continue to be difficult as the life expectancy is so short. ● The Ice Bucket Challenge, developed in 2014, has widely increased the knowledge and awareness about ALS and has raised over $100 million dollars for research and the development of new drugs and treatments. ● ● ● ●

REFERENCES Scholarly References: Chiò, A. , Mazzini, L. , & Mora, G. (2020). Disease-modifying therapies in amyotrophic lateral sclerosis. Neuropharmacology , 167. https: //doi-org. citadel. idm. oclc. org/10. 1016/j. neuropharm. 2020. 107986 Vallerand, A. H. , & Sanoski, C. A. (2018). Davis’ Drug Guide for Nurses (15 th ed. ). Philadelphia, PA: F. A. Davis Company. Gothelf, Y. , Kaspi, H. , Abramov, N. , & Aricha, R. (2017). mi. RNA profiling of Nur. Own®: mesenchymal stem cells secreting neurotrophic factors. Stem Cell Research & Therapy , 1, 1. https: //doi-org. citadel. idm. oclc. org/10. 1186/s 13287 -017 -0692 -1 Hulisz, D. (2018, August 23). Amyotrophic Lateral Sclerosis: Disease State Overview. Retrieved from https: //www. ajmc. com/journals/supplement/2018/managed-care-perspective-als/amyotrophic-lateral-sclerosis-disease-state-overview Mitsumoto, H. (2009). Amyotrophic Lateral Sclerosis A Guide for Patients and Families: Vol. 3 rd ed. Demos Health. Riluzole. AHFS Consumer Medication Information. January 2020: 1. Accessed February 20, 2020. http: //search. ebscohost. com. citadel. idm. oclc. org/login. aspx? direct=true&db=l 0 h&AN=78169818&site=eds-live Nabavi, S. M. , Arab, L. , Jarooghi, N. , Bolurieh, T. , Abbasi, F. , Mardpour, S. , Azimyian, V. , Moeininia, F. , Maroufizadeh, S. , Sanjari, L. , Hosseini, S. E. , & Aghdami, N. (2019). Safety, Feasibility of Intravenous and Intrathecal Injection of Autologous Bone Marrow Derived Mesenchymal Stromal Cells in Patients with Amyotrophic Lateral Sclerosis: An Open Label Phase I Clinical Trial. Cell Journal (Yakhteh), 20(4), 592– 598. https: //doi-org. citadel. idm. oclc. org/10. 22074/cellj. 2019. 5370 Napodano, J. , & Napodona, J. (2017, January 16). Time to Go Long on Brain. Storm Cell Therapeutics? Retrieved from https: //www. streetwisereports. com/article/2017/01/16/time-to-go-long-brainstorm-cell-therapeutics. html

REFERENCES PR Newswire. (2019). Mitsubishi Tanabe Pharma America to Present Real-World Data on RADICAVA® (edaravone) for ALS at the 30 th International Symposium on ALS/MND. PR Newswire US. Accessed February 20, 2020. http: //search. ebscohost. com. citadel. idm. oclc. org/login. aspx? direct=true&db=bwh&AN=201912041634 PR. NEWS. USPR. NY 57283&site=edslive Quadagno, J. S. (2018). Aging and the life course: an introduction to social gerontology (7 th ed. ). New York, NY: Mc. Graw-Hill Education. Smith, R. , Pioro, E. , Myers, K. , Sirdofsky, M. , Goslin, K. , Meekins, G. , Yu, H. , Wymer, J. , Cudkowicz, M. , Macklin, E. A. , Schoenfeld, D. , & Pattee, G. (2017). Erratum to: Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial. Neurotherapeutics: The Journal Of The American Society For Experimental Neurotherapeutics , 14(3), 830. https: //doi-org. citadel. idm. oclc. org/10. 1007/s 13311 -017 -0517 -z Viswanad, V. , P. , A. , & P. , S. (2017). Advancement of Riluzole in Neurodegenerative Disease. International Journal of Pharmaceutical and Clinical Research , 9(3). https: //doi. org/10. 25258/ijpcr. v 9 i 3. 8321 Zarei, S. , Carr, K. , Reiley, L. , Diaz, K. , Guerra, O. , Altamirano, P. F. , … Chinea, A. (2015, November 16). A comprehensive review of amyotrophic lateral sclerosis. Retrieved from https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 4653353/

REFERENCES Photos: https: //en. wikipedia. org/wiki/Stephen_Hawking#/media/File: Stephen_Hawking. Star. Child. jpg https: //www. cnet. com/news/pete-frates-who-inspired-the-als-ice-bucket-challenge-has-died-at-34/ http: //webnc. alsa. org/site/Page. Navigator/NC_2_catfishhunter. html https: //www. pinstripealley. com/2016/7/14/12165936/lou-gehrig-yankees-history-streak-record-babe-ruth-cal-ripken http: //www. alsa. org/news/public-awareness/als-awareness-month/2016/what-is-als. html https: //alstreatment. com/amyotrophic-lateral-sclerosis-incidence/ https: //zahsi. com/wp-content/uploads/2017/09/Amyotrophic-Lateral-Sclerosis-ALS. png Videos: https: //www. youtube. com/watch? v=ar. Dpe. Om 2 s_4 https: //www. youtube. com/watch? v=Sm. NV 9 N 13 L 5 E&feature=youtu. be https: //youtu. be/xr. Ij. FVMli. OQ

REFERENCES Web Page Resources: http: //www. alsa. org/about-als/what-is-als. html http: //www. catfishfoundation. org/ https: //petefrates. com/donate/ https: //alstreatment. com/amyotrophic-lateral-sclerosis-treatment/ https: //www. clinicaltrialsarena. com/projects/tiglutik-riluzole-treatment-amyotrophic-lateral-sclerosis/ https: //alsnewstoday. com/nurown/ http: //www. alsa. org/research/radicava-frequently-asked-questions. html https: //www. clinicaltrialsarena. com/projects/nuedexta-treatment-pseudobulbar-affect-pba/ https: //www. clinicaltrialsarena. com/projects/tiglutik-riluzole-treatment-amyotrophic-lateral-sclerosis/ Webinar: https: //youtu. be/ov 2 KPu. SW 8 kg (CDC Public Health Grand Rounds: National Amyotrophic Lateral Sclerosis (ALS) Registry: Impact, Challenges, and Future Directions). 4/18/17.