Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)

• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The ALSFRS-R will be administered at -3, -2 and -1 months screening/presurgery, and at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  The Secondary Outcome Measures of the study are to evaluate spinal stem cell transplantation therapy in this patient population using the following 11 assessments. 1. ALSFRS-R is a self-administered ordinal rating scale questionnaire (rating 0-4 for each question, 4 is most functional, 0-48 total) of 12 functional activities. The most functional total score is 48.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The quantitative muscle strength test will be administered at -3, -2, -1 months screening/presurgery and at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  2. Quantitative muscle strength testing using a hand held dynamometer (HHD): Six proximal muscle groups (knee flexion and extension, hip flexion, elbow flexion and extension and shoulder flexion) and three proximal muscle groups (wrist extension, first dorsal interosseous contraction, and ankle dorsiflexion) will be tested bilaterally using the MICROFET 2 HHD.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The hand grip (bilateral) will be administered at -3, -2 and -1 months screening/presurgery, and at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  3. Hand grip (bilateral) will be measured using the Jaymar Grip dynamometer.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The vital capacity (VC) will be measured at -3, -2 and -1 months and -7 days screening/presurgery. It will also be measured at 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  4. Vital Capacity (VC) will be measured using the Renaissance II spirometer. Eligibility will be determined with seated and supine measurements but the secondary outcome measure will be done seated.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The negative inspiratory force (NIF) will be measured at -3, -2 and -1 months and -7 days screening/presurgery. It will also be measured at 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  5. Negative Inspiratory Force (NIF) will be measured with a Negative Inspiratory Force Gauge (Instrumentation Industries).
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The Electrical Impedance Myography (EIM) will be measured at -3, -2 and -1 months screening/presurgery. It will also be measured at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  6. Electrical Impedance Myography (EIM) is a painless and non-invasive quantitative measure of muscle that has been shown to correlate with other physiological and semi-quantitative measures of disease progression in ALS .
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The comprehensive pain assessment will be performed at -3 months and -14 days screening/presurgery. It will also be performed at 2 weeks, 1, 2, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  7. Comprehensive pain assessment utilizing the Neuropathic Pain Scale (NPS).
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: Performed during the screening and at 24 and 48 month follow-up/post surgery visits. MRI of the surgical region only, at 1, 6, 12, 18 and 36 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  8. An MRI will be performed on the entire spine and brain with and without gadolinium contrast. An MRI of the targeted region may be performed if clinically indicated at the 2 week visit.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: Measurements will be taken at -3 months and -14 days at screening/presurgery and at 1, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  9. Urodynamic parameters including incontinence and urinary retention measured by post void residual.
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The questionnaire will be completed at -3 months during the screening/presurgery phase and at the 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  10. ALS Specific Quality of Life Questionnaire - Revised is a scale that balances physical and nonphysical factors in assessing the quality of life in ALS patients
• The Secondary Objectives of the study are to evaluate spinal stem cell transplantation therapy in this patient population. [ Time Frame: The Ashworth Spasticity Scale will be administered at -3, -2, -1 months screening/presurgery and at 1, 3, 6, 9, 12, 18, 24, 30, 36, 42 and 48 month follow-up/post surgery visits. ] [ Designated as safety issue: Yes ]
  11. Ashworth Spasticity Scale.

This is a first-in-human trial of spinal derived stem cells transplanted into the spinal cord of patients with Amyotrophic Lateral Sclerosis (ALS). The goal of the study is to see if the cells and the procedure to transplant them are safe.

These stem cells are called Human Spinal Stem Cells (HSSC) and have been engineered from the spinal cord of a single fetus electively aborted after 8 weeks of gestation. The tissue was obtained with the mother's consent. The cells will be transplanted into the ALS patient's spinal cord after laminectomy, an operation that removes bone surrounding the spine. After the spinal cord is exposed, a device manufactured for this purpose will be mounted onto the patient and will hold a syringe filled with the cells. The syringe will have a needle attached and the needle will enter the spinal cord at 5-10 locations injecting the cells. The device will minimize trauma to the spinal cord by the needle by making the puncture precise and steady and injecting the material at a slow and steady speed.

ALS is a universally fatal neurodegenerative condition that causes weakness leading to paralysis and death. Life expectancy is 2-5 years. The cause is unknown and there is no effective treatment. Previous research has shown that on autopsy, ALS patients are found to have increased levels of the amino acid glutamate accumulated in the brain and spinal cord. This increase is thought to be caused by a decrease in the glutamate transporter which normally "cleans up" glutamate from the cells. HSSC are known to express amino acid transporters and it is hoped that this action will reduce the toxicity of accumulated glutamate and benefit ALS patients. There is a second hypothesized benefit of the HSSC and that is their ability to secrete neurotrophic support factors. Neurotrophic factors support the health of nerves.

The study will include 5 groups of ALS patients. The first group (A) will be made up of six patients and the remaining groups will have three patients each. The groups will have slightly different inclusion criteria and receive different procedures. The first group will include patients with advanced disease who are unable to walk. This group will include both ALS patients with the ability to breathe on their own as well as those with tracheotomies and ventilators. The first three patients will have laminectomy and receive transplant injections on one side of their lower spinal cord. The second three patients in the first group will receive transplant injections on both sides of their lower spinal cord. If all goes well the next groups will be entered in order.

Group B will include ALS patients that are still ambulatory. They will have transplant injections on one side of their lower spine. Group C will include ALS patients that are still ambulatory and will have transplant injections on both sides of their lower spine. Group D patients will be ambulatory with some arm dysfunction and will receive transplant injections on one side of their neck. Lastly group E will include ALS patients that are ambulatory and will receive both injections on one side of their neck and injections on both sides of their lower spine. The groups are designed so that the patients who have the least to lose will go first. There will be a one month period after all group members have received their transplants during which the Safety Monitoring Board (SMB) will review all reports of adverse events. No new group will start until the SMB gives the go-ahead.

The Food and Drug Administration (FDA) has approved this study to go forward however they have restricted this approval to groups A, B and C. They have requested additional data on safety and the investigators will not be permitted to enroll groups D and E until the FDA gives specific permission to proceed.

Because the HSSC are human in origin, their transplantation will be handled in some ways like other organ transplants in that patients will receive immunosuppressive medications to prevent the rejection of the cells. Right before and immediately after surgery patients will receive infusions of a drug called basiliximab. After surgery they will take prednisone and be tapered off that medication over one month. They will also be given two other immunosuppressive agents, tacrolimus and mycophenolate mofetil after surgery and it is expected that the patients will take these drugs for the rest of their lives.

Inclusion Criteria:

1. Have the ability to understand the requirements of the study, provide written informed consent, understand and provide written authorization for the use and disclosure of Protected Health Information (PHI) [per Health Insurance Portability and Accountability Act (HIPAA) Privacy Ruling] and comply with the study procedures.
2. Subjects with sporadic or familial ALS diagnosed as laboratory-supported probable,probable or definite according to the World Federation of Neurology El Escorial Criteria (Appendix A), based on examination by the site PI.
3. Age 18 years or older.
4. Females must have a negative serum pregnancy test and practice an acceptable method of contraception or be of non-childbearing potential (post-menopausal for at least 2 years or surgically sterile [hysterectomy, oophorectomy or surgical sterilization]).
5. Geographic accessibility to the study center and the ability to travel to the clinic for study visits.
6. Presence of a willing and able caregiver.
7. Medically able to undergo lumbar or cervical laminectomy as determined by the Investigator, surgeon and anesthesiologist.
8. Medically able to tolerate immunosuppression regimen consisting of basiliximab, tacrolimus, mycophenolate mofetil, and methylprednisolone as determined by the site Investigator.
9. Agrees to the visit schedule as outlined in the informed consent.
10. Not taking riluzole (Rilutek®) or on a stable dose for ≥30 days.

11. All required vaccinations current: tetanus/diptheria (TDAP), herpes zoster/shingles(Vostavax®: within last 10 years and must be prior to surgery), pneumonia (Pneumovax®),seasonal/H1N1 flu vaccines (as appropriate for season) for Groups B-E.

    In addition, for Group A:

    • Inability to ambulate for > 2 weeks secondary to lower extremity weakness and/or spasticity; the ALS Functional Rating Scale - Revised (ALSFRS-R) lower extremity subscore must be 1 or less. Patients who are non-ambulatory because of severe spasticity must have failed standard antispasticity treatment with baclofen (up to 120 mg/day) and/or tizanidine (up to 12 mg/day), physical therapy (PT), and occupational therapy (OT). Failure of antispasticity medications is defined as continued inability to walk unassisted even at the highest tolerated doses of these medications. Failure of PT and OT means continued inability to walk independently after maximum PT and OT intervention.
    • Vital capacity ≥ 60% of predicted normal for age, height and gender measured in the supine position at the time of screening and ≥ 50% of predicted normal for age,height and gender measured supine during the 7 days prior to surgery OR stable for at least 3 months with tracheostomy and invasive ventilation.

12. In addition, for groups B and C:

    • Ambulatory subjects with impaired gait and approximately symmetrical lower extremity weakness and/or spasticity due to ALS and an ALSFRS-R gate subscore > 2.
    • Vital capacity ≥ 60% of predicted for age, height and gender measured in the supine position at the time of screening and ≥ 50% of predicted for age, height and gender measured supine during the 7 days prior to surgery

13. In addition, for groups D and E:

    • Ambulatory subjects with impaired gait and symmetrical lower extremity weakness and/or spasticity due to ALS and an ALSFRS-R gate subscore > 2.
    • Upper extremity weakness affecting function with an ALSFRS-R arm subscale between 1 and 3.
    • Vital capacity ≥ 60% of predicted normal for age, height and gender measured in the supine position at the time of screening and ≥ 50% of predicted normal for age, height and gender measured supine during the 7 days prior to surgery.

Exclusion Criteria:

1. Etiology of paraplegia or weakness is due to causes other than ALS such as spinal ischemia, traumatic spinal injury, traumatic brain injury, multiple sclerosis, cerebral stroke, cerebral palsy, or infection.
2. VC < 60% predicted normal by standard nomogram at the time of screening and VC < 50% predicted normal measured supine for age at the time of surgery.
3. Current or peak Panel Reactive Antibody (PRA) due to alloantibodies > 20% receiving their first allograft.
4. Any known immunodeficiency syndrome.
5. Receipt of any investigational drug,device or biologic within 30 days of surgery.

6. Any concomitant medical disease or condition limiting the safety to participate:

   • Coagulopathy
   • Active uncontrolled infection
   • Hypotension requiring vasopressor therapy
   • Previous spinal surgery at the site of planned transplantation except for anterior cervical dissection fusion (ACDF)
   • Skin breakdown over the site of surgery
   • Malignancy (except for non-melanoma skin cancer)
   • Primary or secondary immune deficiency
   • Spinal stenosis.
7. Creatinine >1.5, liver function tests (SGOT/SGPT, Bilirubin, Alk Phos) > 2x the upper limit of normal, hematocrit/hemoglobin < 30/10, total WBC < 4000, uncontrolled hypertension (defined as systolic >180 or diastolic >100) or uncontrolled diabetes(defined as hemoglobin A1C >8), evidence of GI bleeding by hemoccult test, positive tuberculosis (TB test: PPD/Mantoux), hepatitis B or C, or human immunodeficiency virus (HIV).

8. Presence of any of the following conditions:

   • Current drug abuse or alcoholism
   • Unstable medical conditions
   • Unstable psychiatric illness including psychosis and untreated major depression within 90 days of screening
   • Positive blood test for hepatitis B or C.
9. Any condition that the site PI feels may interfere with participation in the study.
10. Any condition that the surgeon feels may pose complications for the surgery.
11. Known hypersensitivity to basiliximab, tacrolimus, mycophenolate mofetil, or methylprednisolone.
12. Inability to provide informed consent as determined by screening protocol.
13. Inadequate family or caregiver support as determined by the site PI.