Niemann-Pick Type C (NPC) is a genetic disorder that leads to severe neurological decline and is difficult to diagnose, with currently no approved treatment. Recent trials with the drug miglustat showed some improvements in symptoms for patients, while research into stem cell therapy, including intra-cranial transplants, is ongoing and has demonstrated early positive outcomes in a patient named Aaditya. The hope for NPC children lies in advances in both pharmaceutical and stem cell therapies to improve their quality of life and potentially find a cure.

1. INTRA-CRANIAL STEM CELL TRANSPLANT FOR NPC POSSIBILITY OF CURE FOR NIEMANN PICK TYPE C DISEASE

2. What is Niemann-Pick Type C Niemann-Pick disease is an inherited condition involving lipid metabolism (the breakdown and use of fats and cholesterol in the body) in which harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain.

3. What is Niemann-Pick Type C… There are three variants of Niemann-Pick disease based on the genetic cause and the symptoms exhibited by the patient. All variants are inherited in an autosomal recessive pattern. Mutations in the NPC1, NPC2, and SMPD1 genes cause Niemann-Pick disease

4. What is Niemann-Pick Type C… Type C is characterized by onset in childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. People with this disorder can survive into adulthood.

5. What is Niemann-Pick Type C…. Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease, type C. The NPC1 gene produces a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal build up of lipids and cholesterol within cell membranes.

6. What is Niemann Pick Type C…. Chromosome 18 Defined: A disease that causes progressive deterioration of the nervous system by blocking movement of cholesterol within cells. The gene responsible for it, known as NPC1, is located on human chromosome 18.

7. Search for a cure NP-C is a fatal, recessively inherited neurodegenerative disease primarily affecting children and teenagers, but which can strike at any age. The intricacies of the complex process of the two genes involved in trafficking of lipids and other large molecules within the cells – a key process in cellular maintenance are the subject of active research. The symptoms are proportional to the excess storage of cholesterol and glycosphingolipids (GSL) within certain cells in the body, including the brain. NP-C is relentlessly progressive and most patients die within five to ten years of diagnosis. Neurological deterioration is a key feature of the disease and can manifest itself as clumsy movements, impaired balance, slow and slurred speech, difficulty in swallowing, impaired rapid eye movements, hearing loss and seizures. Intellectual decline is universal but may be subtle in the early stages of illness. In the final stages of the disease, affected children and young adults are frequently bedridden, with limited muscle control and intellectual impairment. NP-C is difficult to diagnose owing to the variable age of onset and heterogeneity of the symptoms. There is currently no treatment option approved for this condition.

8. Hope for a Cure Actelion Ltd (SWX: ATLN) announced the online publication in "The Lancet Neurology" of the one-year results from a randomized controlled study evaluating safety and efficacy of miglustat (Zavesca®) in patients suffering from Niemann-Pick type C (NP-C) [1]. NP-C is an autosomal recessive genetic disease affecting children, juveniles and adults, characterized by progressive, severe and heterogeneous neurological manifestations, and reduced life expectancy [2]. Horizontal saccadic eye movement (HSEM)-α velocity has improved in miglustat treated juvenile/adult patients versus those receiving standard care; results reached statistical significance when patients taking benzodiazepines, a known confounder, were excluded (p=0.028). Children showed an improvement of HSEM-α velocity of similar magnitude. Improvement in swallowing capacity, stable auditory acuity and a slower deterioration in ambulatory index were observed in juvenile/adult treated patients. http://www.nnpdf.org/documents/MiglustatinNPCPoster.pdf

9. Niemann-Pick Disease Foundation is also testing an approach to compensate for the low lysosomal calcium levels in NPC by elevating the levels of calcium in the cytoplasm of the cell, using the natural product curcumin. We have found that curcumin therapy results in benefit. In the first part of the NNPDF grant we have combined miglustat with curcumin to target two different steps of the disease process and found that the benefits of combination therapy are greater than using either drug alone. We are now doing a larger scale experiment to validate this finding and explore the effects of combination therapy in more detail . Hope for a Cure

10. Hope for a cure through Stem cells Hematopoietic stem cells are adult stem cells found mainly in the bone marrow and they provide the blood cells required for daily blood turnover and for fighting infections. Compared to adult stem cells from other tissues, hematopoietic stem cells are easy to obtain, as they can be either aspirated directly out of the bone marrow or stimulated to move into the peripheral blood stream, where they can be easily collected.

11. Hope for a cure through stem cells… Mesenchymal stem cells are another well-characterized population of adult stem cells. These cells, also found in the bone marrow, can form a variety of cell in the laboratory, including fat cells, cartilage, bone, tendon and ligaments, muscles cells, skin cells and even nerve cells. Mesenchymal stem cells have been studied in great detail and scientists have advanced knowledge about how to grow these cells in culture.

12. Hope for a cure through Stem cells… Mesenchymal stem cells can be obtained in quantities appropriate for clinical applications, making them good candidates for use in tissue repair. Techniques for isolation and amplification of mesenchymal stem cells in culture have been established and the cells can be maintained and propagated in culture for long periods of time, without loosing their capacity to form all cell types.

13. Hope for a Cure through Stem cells….. Mesenchymal stem cells can also be frozen to preserve them, and when they are thawed they function apparently normally, thus allowing for future "off-the-shelf" therapy approaches. Animal trials looking at reconstitution of damaged tissues such as cartilage, bone, muscle, heart muscle and tendon using mesenchymal stem cells have shown great promises for human applications. These stem cells can be derived from a small bone marrow, expanded in culture, and injected to the patient. Clinical trials are currently underway in several clinical centers, to assess safety and effectiveness of these techniques in humans.

14. Hope for a cure through Stem cells… Umbilical cord blood stem cells can be obtained from the umbilical cord immediately after birth. Like bone marrow, umbilical cord blood is another rich source of hematopoietic stem cells. These hematopoietic stem cells are usually referred to as neonatal stem cells and are less mature than those stem cells found in the bone marrow of adults or children. The advantages of using cord blood as a source of stem cells are its non-invasive procurement and its vast abundance; thousands of babies are born each day. Until recently, umbilical cord blood was discarded after birth, along with the placenta. Now, in several countries around the world, cord blood is collected and either banked in public banks for general use, or stored by private companies for private use, in private cord blood banks.

15. Intra-cranial Stem cell transplant Future Research 3-5 day embryonic stem cells Immune privileged cord blood cells injected into the hypothalamus of the brain of NPC mice have shown improvement in their lifespan and quality of life The aim is to replicate the process before opening up human trials.

16. Jeevan Stem cell Bank Facility available for research Pediatric Neurosurgeon, Dr S Suresh available at Mediscan Mediscan diagnostic support through Dr Sujatha Cord blood –immune privileged cells available in Korea –Dr Kang

17. Mediscan-Chennai with Dr Sujatha and Dr Srinivasan

18. Harvesting

19. Stempeutics-Manipal Hospital Bangalore Meeting with Dr Karthik and Dr Vijay Sharma

20. Clean Room

21. Frozen Stem Cells

22. December 18 th 2008 –Historic Day Aaditya received a cutting edge treatment in India in which a stereotactic implantation of stem cells was performed on his brain. The hope is these cells will graft into new brain neurons and restore function for Aaditya and save his life. Dr Venkatramana, a renowned Neurosurgeon at BGS Global teamed together with Dr Vijay Sharma of the Stempeutics department at Manipal Hospital to conduct this procedure after appropriate approvals from the Indian Government and the Ethics committee at BGS Global. Intracranial stem cells transplants treatment that Aaditya received is not even available in the United States. Stem cells were put directly through his skull, into his brain and past the blood brain barrier. Most stem cells injections people get in China or Mexico go through the neck/vertebra or through IV infusions.

23. Aaditya receives a Transplant While this procedure is considered a long shot and radical, there is a glimmer of hope that mesenchymal stem cells could restore function to Aaditya and save his life.

24. The first Intra-cranial stem cell Transplant for Niemann-Pick Type C disease Some of the hair on Aaditya’s head was removed and the 40 million mesenchymal stem cells were injected with a special 4 prong needle into eight areas of his brain through two, three inch cuts.

25. Observation Journal 20 th Dec. 2008 : 48 hrs after surgery I found Aaditya trying to talk ; trying to mouth words. When I was mouthing “I love you” to him from a distance he was looking straight into my eyes and opening his mouth as if to say the same. The same night when his cousin was asking him to go to sleep , he was having a bad cough and I was telling him to ask Rizu, “how could he sleep with that cough ?” , he looked at her and tried to say “how ?”. he has also been nodding to say yes or no. His eye contact is better than it was before.

26. Observations continued…. 21 st Dec. 2008. : 24 hours later he was turning over to his side comfortably. This morning during his sponge bath he turned over from his back to his front easily and with very little assistance. I find the stiffness in his body much reduced as compared to before this procedure. 22 nd Dec. 2008 : Today we have given Aaditya apple juice. His cough is still not under control, perhaps because he had to have a break in his Antibiotic before the surgery. I find his right hand thumb which always used to fold inward into a fist is remaining open when brought out. Today he is getting discharged and Dr. Venkataramana says they will hand over to Dr. Karthik from here on. He said they have inserted lots of cells ( 40 million ) ; more than they normally insert . they used a special needle which has 4 outlets. This was done in 8 areas of the brain and also the ventricle. Last night after many days he laughed his gurgle laugh at Rizu’s antics.

27. Observations cont…. 24 th Dec. 2008 : Last night Aadi kept lifting his right hand ( which he has seldom been using ) all the way up straight. He is looking much better. Suresh has resumed his physioyherapy yesterday. Anita , Farru and family left today and though they did not say bye he knew all along and even shed a few tears. 25 th Dec. 2008 : yesterday evening Aaditya kept getting small jerks, no full fledged seizures though. When we were giving him a hot water bath in the evening he felt good and was straightening out his body. He was holding the bar and almost standing on his own. I was only supporting him at his waist. After his bath, I massaged the ayurveda oil and the physiotherapist, Suresh came and made him do his exercise. He slept well and looked comfortable.

28. Observations cont….. 26 th Dec. 2008 : Aaditya has eaten Chicken Biriyani for lunch . He passed a motion without using a suppository. He is only on Augmentin DDS, Setzine, and Jr. Lanzol. He had fried rice for lunch today. 27 th Dec. 2008 : Yesterday his stitches were removed. The Doctors were happy with the healing and have asked us to keep the dressing for another 3 days and said he could have a head bath after another week.

29. Observations cont…. 28 th Dec. 2008 : Aaditya can sit erect on the floor when his legs are folded for him. He is also able to stand erect with his feet flat on the ground ( not on his toes ). He is able to lift his head and can focus on people who are speaking to him far better than before his procedure. He is still coughing , especially while eating and drinking. We hope to build up his health by feeding him and with the Physiotherapist and Occupational therapist help build back his lost muscles and strength.

30. Hope for Aaditya brings Hope to all NPC kids and kids with other Neurogdegenerative diseases

31. Hope is the thing with feathers, That perches in the soul, And sings the tune--without the words, And never stops at all…. Emily Dickinson www.HopeforAaditya.org